diff --git a/Input/Content/Alfentanil_adults.md b/Input/Content/Alfentanil_adults.md new file mode 100644 index 0000000..ea4faaf --- /dev/null +++ b/Input/Content/Alfentanil_adults.md @@ -0,0 +1,20 @@ +### Alfentanil model + +Alfentanil is another potent, short-acting synthetic opioid analgesic drug, used for anaesthesia in surgery, which is solely metabolized by CYP3A4, with less than 1% of an alfentanil dose being excreted unchanged in urine after intravenous administration. The model has been build and evaluated in healthy adults and published by Hanke et al. [1] The model applies metabolism by CYP3A4 and glomerular filtration. The alfentanil PBPK model adequately described the pharmacokinetics of alfentanil in adults. + +The published alfentanil model [1] was developed using data of the following publications: + +- Kharasch ED, Francis A, London A, Frey K, Kim T, Blood. Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction. Clin Pharmacol Ther. 2011 Jul;90(1):100-8. doi: 10.1038/clpt.2011.59. Epub 2011 May 11. +(https://www.ncbi.nlm.nih.gov/pubmed/21562488) +- Kharasch ED, Walker A, Hoffer C, Sheffels P. Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther. 2004 Nov;76(5):452-66. +(https://www.ncbi.nlm.nih.gov/pubmed/15536460) +- Phimmasone S, Kharasch ED. A pilot evaluation of alfentanil-induced miosis as a noninvasive probe for hepatic cytochrome P450 3A4 (CYP3A4) activity in humans. Clin Pharmacol Ther. 2001 Dec;70(6):505-17. +(https://www.ncbi.nlm.nih.gov/pubmed/11753266) +- Kharasch ED, Russell M, Mautz D, Thummel KE, Kunze KL, Bowdle A, Cox K. The role of cytochrome P450 3A4 in alfentanil clearance. Implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology. 1997 Jul;87(1):36-50. +(https://www.ncbi.nlm.nih.gov/pubmed/9232132) + +### References + +[1] Hanke N, Frechen S, Moj D, Britz H, Eissing T, Wendl T, Lehr T. PBPK models for CYP3A4 and P-gp DDI prediction: a modeling network of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil and digoxin. CPT: Pharmacometrics & Systems Pharmacology (2018), https://doi.org/10.1002/psp4.12343. + +The compound properties used for input are illustrated below. \ No newline at end of file diff --git a/Input/Content/Alfentanil_children.md b/Input/Content/Alfentanil_children.md new file mode 100644 index 0000000..7c5f050 --- /dev/null +++ b/Input/Content/Alfentanil_children.md @@ -0,0 +1,12 @@ +### Alfentanil model + +Alfentanil PBPK predictions in children were evaluated using pharmacokinetic (PK) data reported in the following studies: + +- den Hollander JM, Hennis PJ, Burm AG, Vletter AA, Bovill JG. Pharmacokinetics of alfentanil before and after cardiopulmonary bypass in pediatric patients undergoing cardiac surgery: Part I. J Cardiothorac Vasc Anesth. 1992 Jun;6(3):308-12. +- Meistelman C, Saint-Maurice C, Lepaul M, Levron JC, Loose JP, Mac Gee K. A comparison of alfentanil pharmacokinetics in children and adults. Anesthesiology. 1987 Jan;66(1):13-6. + +The pediatric PBPK model predicted the AUC values of alfentanil observed in pediatric studies reasonably across all available age groups, ranging from 3.6 months to 9 years old. The ratios of mean predicted over observed AUC values are illustrated in the table below as well as in the predicted versus observed AUC ratio plot, showing that most predictions in children were within 2-fold error of observed values. Another reported study on alfentanil pharmacokinetics in children [1] showed systematically higher exposure for most individuals compared to the other herein included studies. This deviation may have been caused by different impact of individual pathophysiologies of the target study population, inaccurate in vitro assay-techniques or other study differences. + +### References + +[1] Goresky GV, Koren G, Sabourin MA, Sale JP, Strunin L., The pharmacokinetics of alfentanil in children. Anesthesiology. 1987 Nov;67(5):654-9. \ No newline at end of file diff --git a/Input/Content/Alfentanil_diagnostics.md b/Input/Content/Alfentanil_diagnostics.md new file mode 100644 index 0000000..b86670b --- /dev/null +++ b/Input/Content/Alfentanil_diagnostics.md @@ -0,0 +1,3 @@ +### Alfentanil adult PBPK model performance + +Below you find the input goodness-of-fit visual diagnostic plots for alfentanil PBPK model performance (observed versus individually simulated plasma concentration and weighted residuals versus time) of all adult data. diff --git a/Input/Content/Concentration_time_profiles.md b/Input/Content/Concentration_time_profiles.md new file mode 100644 index 0000000..c834cc0 --- /dev/null +++ b/Input/Content/Concentration_time_profiles.md @@ -0,0 +1,2 @@ +#### Concentration-Time Profiles + diff --git a/Input/Content/Concentration_time_profiles_adults.md b/Input/Content/Concentration_time_profiles_adults.md new file mode 100644 index 0000000..d60a589 --- /dev/null +++ b/Input/Content/Concentration_time_profiles_adults.md @@ -0,0 +1,3 @@ +#### Concentration-Time Profiles + +Simulated versus observed plasma concentration-time profiles of all data are listed below. \ No newline at end of file diff --git a/Input/Content/Concentration_time_profiles_children.md b/Input/Content/Concentration_time_profiles_children.md new file mode 100644 index 0000000..e13f7d3 --- /dev/null +++ b/Input/Content/Concentration_time_profiles_children.md @@ -0,0 +1,3 @@ +#### Concentration-Time Profiles + +Predicted versus observed plasma concentration-time profiles are listed below. Only simulations where observed data was available for comparison are shown. Depending if the observed data were individual data or aggregated data, individual predictions or population predictions including variability are shown, respectively. \ No newline at end of file diff --git a/Input/Content/Section1.md b/Input/Content/Section1.md new file mode 100644 index 0000000..1d826e8 --- /dev/null +++ b/Input/Content/Section1.md @@ -0,0 +1,43 @@ +The presented qualification report evaluates the predictive performance of the OSP suite to predict cytochrome P450 3A4 (CYP3A4)-mediated drug clearance in children. + +Therefore, PBPK models of specific *in vivo* probe substances covering children aged below 6 months up to adolescents were built and evaluated. All models are whole-body PBPK models, allowing for dynamic pediatric translation in organs expressing CYP3A4. The qualification report demonstrates the level of confidence of the OSP suite with regard to reliable PBPK predictions of age-related CYP3A4-mediated drug clearance during model-informed drug development. The presented PBPK models as well as the respective qualification plan and qualification report are provided open-source and transparently documented (https://github.com/Open-Systems-Pharmacology/Pediatric-Qualification-Package-CYP3A4). + + +## Translation of Adult PBPK to Children + +Using a developed and validated (adult) PBPK model for an *in vivo* probe substance, a pediatric PBPK model can be established for children by translating physiology, clearance processes (as parameterized in the adult model) and age-dependent protein binding including the variability therein.[[1](#reference)] + +The PBPK models are developed with clinical data of healthy adult subjects obtained from the literature, covering available dosing ranges for e.g. intravenous as well as oral administration, to capture both systemic clearance as well gut-wall metabolic clearance processes. For orally administered drugs, the same formulations that are used in children should ideally be included in the model for adults. Plasma concentrations following multiple-dose application, mass balance information and other clinical measurements need to be included for model development, if available. During model translation from adults to children for a specific substance, uncertainties in data-quality caused by impact of disease or the target study population, inaccurate in vitro assay-techniques regarding mass balance, as well as study differences may cause not being able to adequately predict the PK in children for all reported studies. + +Prediction performance of the PBPK model for these probe substances in children are then shown by means of e.g. predicted versus observed area under the plasma concentration (AUC)-ratio plots, of which the results support an adequate prediction of the ontogeny function for the application of PBPK model translation of adult PBPK to children. + +For qualification purpose, during the translation of adult PBPK to children the following assumptions and considerations were made: + +- when translating an adult model to children, it was assumed that the metabolism and excretion pathways are qualitatively the same in children as in adults. +- no further changes to input parameters other than those for the physiology and protein binding. All other parameters (e.g. lipophilicity, intestinal permeability, solubility) were kept unchanged. + +## Anthropometric and Physiological Information + +Regarding the age-dependencies of the relevant anthropometric (height, weight) and physiological parameters (e.g. blood flows, organ volumes, binding protein concentrations, hematocrit, cardiac output) in children was gathered from the literature and has been previously published [[2](#reference)]. The information was incorporated into PK-Sim® and was used as default values for the simulations in children. + +The applied ontogeny and variability of plasma proteins and active processes that are integrated into PK-Sim® for translation to children are described in the publicly available ‘PK-Sim® Ontogeny Database Version 7.3' [[3](#reference)] or otherwise referenced for the specific process. + +## Qualification of **CYP3A4 enzyme ontogeny** + +To qualify the OSP suite for the pediatric translation of the pharmacokinetics of new drugs that are metabolized by CYP3A4, the following set of probe substances was included: + +- Alfentanil [[4](#reference)] + +- Sufentanil [[5](#reference)] + +## References + +[1] [Maharaj AR, Barrett JS, Edginton AN. A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. The AAPS journal. 2013;15(2): 455-464.](https://www.ncbi.nlm.nih.gov/pubmed/23344790) + +[2] [Edginton AN, Schmitt W, Willmann S. Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet. 2006;45(10):1013-34.](https://www.ncbi.nlm.nih.gov/pubmed/16984214) + +[3] [OSPSuite.Documentation/PK-Sim Ontogeny Database Version 7.3.pdf ](https://github.com/Open-Systems-Pharmacology/OSPSuite.Documentation/blob/38cf71b384cfc25cfa0ce4d2f3addfd32757e13b/PK-Sim%20Ontogeny%20Database%20Version%207.3.pdf) + +[4] [Alfentanil-Model, Whole-body PBPK model of Alfentanil. https://github.com/Open-Systems-Pharmacology/Alfentanil-Model](https://github.com/incei/Alfentanil-Model) + +[5] [Sufentanil-Model, Whole-body PBPK model of Sufentanil. https://github.com/Open-Systems-Pharmacology/Sufentanil-Model](https://github.com/incei/Sufentanil-Model) \ No newline at end of file diff --git a/Input/Content/Section2.md b/Input/Content/Section2.md new file mode 100644 index 0000000..f1c0f2a --- /dev/null +++ b/Input/Content/Section2.md @@ -0,0 +1,4 @@ +## Evaluation of Adult PBPK models + +The PBPK models of **sufentanil** and **alfentanil** were developed with clinical pharmacokinetic data covering at least administrations given in children. Plasma concentrations following intravenous administration, oral administration, multiple dose application, fractions excreted to urine or bile and other clinical measurements were included for model development whenever available. + diff --git a/Input/Content/Section3.md b/Input/Content/Section3.md new file mode 100644 index 0000000..3160d9f --- /dev/null +++ b/Input/Content/Section3.md @@ -0,0 +1,14 @@ +## Evaluation of Pediatric translation + +All pediatric translations are pure retrospective predictions, no pediatric pharmacokinetic studies were used to inform model parameters. All parameters necessary to model the pediatric populations, such as demographics (age, weight, height), as well as dosing formulation information were taken from the respective pediatrics studies from literature in order to evaluate their predictive performance. + +The models were evaluated by ratio plots of area under the plasma concentration-time curve (AUC), or clearance (CL) values resulting from our predictions to the values observed during clinical studies, and by comparison of concentration-time profiles if available. As a quantitative measure of the descriptive and predictive performance of each model, the geometric mean fold error was calculated according to Eq. 1: + +Eq. 1: GMFE=10^((Σ|log10(pred PK parameter∕obs PK parameter)|)∕n) + +with GMFE = geometric mean fold error of all AUC or CL predictions of the respective model, pred PK parameter = predicted AUC or CL, obs PK parameter = observed AUC or CL, and n = number of observed values. + +The ratios of predicted over observed mean AUC or CL values from all compound were also plotted across all age groups in the figure below. As illustrated, most of the prediction were within the 0.5 to 2.0 range (2-fold error). + +In the next sections the demographics as well as the evaluation results of the predictive performance of the specific compound PBPK models in children can be found. + diff --git a/Input/Content/Sufentanil_adults.md b/Input/Content/Sufentanil_adults.md new file mode 100644 index 0000000..f81937a --- /dev/null +++ b/Input/Content/Sufentanil_adults.md @@ -0,0 +1,11 @@ +### Sufentanil adult PBPK model + +Sufentanil is a potent synthetic opioid. Like other opioids, sufentanil creates a stable hemodynamic environment in cardiovascularly compromised pediatric patients. Sufentanil has a high lipid solubility, which accounts for the fast onset when given intravenously. The commercial solution comes as preservative‐free sufentanil citrate, injectable with a pH of 4.5–7.0 (Jansen‐Cilag AB, Sweden). Sufentanil is solely metabolised by CYP3A4. Due to the high hepatic extraction ratio, for the overall clearance of sufentanil both CYP3A4 values as well as liver blood flow rate play dominant roles in the elimination in adult populations. The final sufentanil model applies metabolism by CYP3A4 and glomerular filtration and adequately described the pharmacokinetics of sufentanil in adults. + +The Sufentanil model was developed using data of the following publications: + +- Bovill JG, Sebel PS, Blackburn CL, Oei-Lim V, Heykants JJ. The pharmacokinetics of sufentanil in surgical patients. Anesthesiology. 1984 Nov;61(5):502-6. (https://www.ncbi.nlm.nih.gov/pubmed/6238552) +- Willsie SK, Evashenk MA2, Hamel LG, Hwang SS, Chiang YK, Palmer PP. Pharmacokinetic properties of single- and repeated-dose sufentanil sublingual tablets in healthy volunteers. Clin Ther. 2015 Jan 1;37(1):145-55. doi: 10.1016/j.clinthera.2014.11.001. Epub 2014 Dec 24. +(https://www.ncbi.nlm.nih.gov/pubmed/25544247) + +The compound properties used for input are illustrated below. \ No newline at end of file diff --git a/Input/Content/Sufentanil_children.md b/Input/Content/Sufentanil_children.md new file mode 100644 index 0000000..6b47e7d --- /dev/null +++ b/Input/Content/Sufentanil_children.md @@ -0,0 +1,9 @@ +### Sufentanil model + +Sufentanil PBPK predictions in children were evaluated using pharmacokinetic (PK) data reported in the following studies: + +- Davis PJ, Cook DR, Stiller RL, Davin-Robinson KA. Pharmacodynamics and pharmacokinetics of high-dose sufentanil in infants and children undergoing cardiac surgery. Anesth Analg. 1987 Mar;66(3):203-8. +- Guay J, Gaudreault P, Tang A, Goulet B, Varin F. Pharmacokinetics of sufentanil in normal children. Can J Anaesth. 1992 Jan;39(1):14-20. + +The pediatric PBPK model predicted the clearance values of sufentanil observed in pediatric studies reasonably across all available age groups, ranging from 5 months to 8.75 years old. The ratios of mean predicted over observed clearance values are illustrated in the table below as well as in the predicted versus observed clearance ratio plot, showing that most predictions in children were within 2-fold error of observed values. + diff --git a/Input/Content/Sufentanil_diagnostics.md b/Input/Content/Sufentanil_diagnostics.md new file mode 100644 index 0000000..026830a --- /dev/null +++ b/Input/Content/Sufentanil_diagnostics.md @@ -0,0 +1,4 @@ +### Sufentanil adult PBPK model performance + +Below you find the input goodness-of-fit visual diagnostic plots for sufentanil PBPK model performance (observed versus individually simulated plasma concentration and weighted residuals versus time) of all adult data. + diff --git a/Input/Content/titlepage.md b/Input/Content/titlepage.md new file mode 100644 index 0000000..c8bea56 --- /dev/null +++ b/Input/Content/titlepage.md @@ -0,0 +1 @@ +# Pediatric Qualification Package: CYP3A4 Ontogeny \ No newline at end of file diff --git a/Input/PK-Parameters.csv b/Input/PK-Parameters.csv new file mode 100644 index 0000000..dd6b383 --- /dev/null +++ b/Input/PK-Parameters.csv @@ -0,0 +1,114 @@ +ID,Study,Reference,Grouping,Analyte,t0,tend,t Unit,AUC Avg,AUC AvgUnit,AUC AvgType,AUC Var,AUC VarUnit,AUC VarType,AUC Type,Cmax Avg,Cmax AvgUnit,Cmax AvgType,Cmax Var,Cmax VarUnit,Cmax VarType,Cmax Type,CL Avg,CL AvgUnit,CL AvgType,CL Var,CL VarUnit,CL VarType,CL Type,Comment,Notghi +108,Bovill 1984,https://www.ncbi.nlm.nih.gov/pubmed/6238552,mean,Sufentanil,0,8,h,,,,,,,,,,,,,,,12.66,mL/kg/min,arith. Mean,0.78,mL/kg/min,arith. SEM,CL total,Table 3,0 +467,Willsie 2015,https://www.ncbi.nlm.nih.gov/pubmed/25544247,mean,Sufentanil,0,1440,min,273.8,pg*h/mL,arith. mean,61.1,pg*h/mL,arith. SD,AUC_tau,,,,,,,,,,,,,,,,0 +121,Davis 1987,https://www.ncbi.nlm.nih.gov/pubmed/2950809,mean,Sufentanil,0,120,min,0.545454545,mg*min/mL,,,,,AUC_tau,,,,,,,,27.5,mL/kg/min,arith. Mean,9.3,mL/kg/min,arith. Mean,CL total,"Table 3, last samples taken 120 OR until the initiation of cardiopulmonary bypass, AUCinf imputed based on reported Dose/CL",0 +122,Davis 1987,https://www.ncbi.nlm.nih.gov/pubmed/2950809,mean,Sufentanil,0,120,min,0.828729282,mg*min/mL,,,,,AUC_tau,,,,,,,,18.1,mL/kg/min,individual,10.7,mL/kg/min,arith. Mean,CL total,"Table 3 ,AUCinf imputed based on reported Dose/CL",0 +194,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID1,Sufentanil,0,360,min,0.00010838,mg*min/mL,,,,,AUC_tau,,,,,,,,17.9,mL/kg/min,individual,,,,,"t_end is time to reach limit of quanititation after dose, AUCinf imputed based on reported Dose/CL",0 +195,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID2,Sufentanil,0,60,min,4.63E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,40.6,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +196,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID3,Sufentanil,0,240,min,8.92E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,39.7,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +197,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID4,Sufentanil,0,240,min,8.26E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,34,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +198,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID5,Sufentanil,0,300,min,6.63E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,29.7,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +199,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID6,Sufentanil,0,120,min,6.73E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,29.7,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +200,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID7,Sufentanil,0,420,min,0.000134872,mg*min/mL,,,,,AUC_tau,,,,,,,,19.5,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +201,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID8,Sufentanil,0,240,min,6.99E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,44.9,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +202,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID9,Sufentanil,0,120,min,4.36E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,44.7,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +203,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID10,Sufentanil,0,240,min,8.53E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,36.1,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +204,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID11,Sufentanil,0,420,min,0.000135498,mg*min/mL,,,,,AUC_tau,,,,,,,,23.1,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +205,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID12,Sufentanil,0,240,min,7.55E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,26.5,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +206,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID13,Sufentanil,0,420,min,0.000161538,mg*min/mL,,,,,AUC_tau,,,,,,,,18.2,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +207,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID14,Sufentanil,0,420,min,0.000151832,mg*min/mL,,,,,AUC_tau,,,,,,,,19.1,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +208,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID15,Sufentanil,0,180,min,0.000127542,mg*min/mL,,,,,AUC_tau,,,,,,,,23.6,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +209,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID16,Sufentanil,0,240,min,5.71E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,25.9,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +210,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID17,Sufentanil,0,180,min,6.17E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,32.9,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +211,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID18,Sufentanil,0,180,min,0.000035,mg*min/mL,,,,,AUC_tau,,,,,,,,28,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +212,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID19,Sufentanil,0,240,min,7.36E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,40.1,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +213,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID20,Sufentanil,0,180,min,5.65E-05,mg*min/mL,,,,,AUC_tau,,,,,,,,35.2,mL/kg/min,individual,,,,,AUCinf imputed based on reported Dose/CL,0 +282,Kharasch 2004,https://www.ncbi.nlm.nih.gov/pubmed/15536460,iv Control (Perpetrator Placebo),Alfentanil,146,inf,h,64.8,ng*h/mL,arith. mean,26.6,ng*h/mL,arith. SD,AUC_inf,90.2,ng/mL,arith. mean,22.2,ng/mL,arith. SD,Cmax,4.39,mL/min/kg,arith. Mean,1.48,mL/min/kg,arith. SD,Cliv,,0 +283,Kharasch 2004,https://www.ncbi.nlm.nih.gov/pubmed/15536460,iv with Perpetrator (Rifampicin),Alfentanil,0,129,h,24.3,ng*h/mL,arith. mean,6.5,ng*h/mL,arith. SD,AUC_inf,90.5,ng/mL,arith. mean,25.5,ng/mL,arith. SD,Cmax,10.8,mL/min/kg,arith. Mean,2.1,mL/min/kg,arith. SD,Cliv,,0 +284,Kharasch 2004,https://www.ncbi.nlm.nih.gov/pubmed/15536460,iv with Perpetrator (GFJ),Alfentanil,146,inf,h,68.3,ng*h/mL,arith. mean,19.9,ng*h/mL,arith. SD,AUC_inf,93.7,ng/mL,arith. mean,19.7,ng/mL,arith. SD,Cmax,4.02,mL/min/kg,arith. Mean,1.34,mL/min/kg,arith. SD,Cliv,,0 +287,Kharasch 2004,https://www.ncbi.nlm.nih.gov/pubmed/15536460,po #1 (60 g/kg) Control (Perpetrator Placebo),Alfentanil,0,inf,h,103,ng*h/mL,arith. mean,30,ng*h/mL,arith. SD,AUC_inf,45,ng/mL,arith. mean,14.5,ng/mL,arith. SD,Cmax,10.6,mL/min/kg,arith. Mean,30,mL/min/kg,arith. SD,CL/F,,0 +288,Kharasch 2004,https://www.ncbi.nlm.nih.gov/pubmed/15536460,po #1 (60 g/kg) with Perpetrator (Rifampicin),Alfentanil,132,inf,h,4.7,ng*h/mL,arith. mean,4.6,ng*h/mL,arith. SD,AUC_inf,5,ng/mL,arith. mean,3.6,ng/mL,arith. SD,Cmax,339,mL/min/kg,arith. Mean,4.6,mL/min/kg,arith. SD,CL/F,,0 +291,Kharasch 2004,https://www.ncbi.nlm.nih.gov/pubmed/15536460,po #2 (23 g/kg) Control (Perpetrator Placebo),Alfentanil,0,inf,h,38,ng*h/mL,arith. mean,13.3,ng*h/mL,arith. SD,AUC_inf,61.3,ng/mL,arith. mean,9.8,ng/mL,arith. SD,Cmax,11.2,mL/min/kg,arith. Mean,3.8,mL/min/kg,arith. SD,CL/F,,0 +292,Kharasch 2004,https://www.ncbi.nlm.nih.gov/pubmed/15536460,po #2 (23 g/kg) with Perpetrator (GFJ),Alfentanil,0,inf,h,62.5,ng*h/mL,arith. mean,19.3,ng*h/mL,arith. SD,AUC_inf,30.4,ng/mL,arith. mean,6.9,ng/mL,arith. SD,Cmax,6.7,mL/min/kg,arith. Mean,2.5,mL/min/kg,arith. SD,CL/F,,0 +298,Kharasch 2011,https://www.ncbi.nlm.nih.gov/pubmed/21562488,iv Control (Perpetrator Placebo),Alfentanil,0,inf,h,78,ng*h/mL,arith. mean,30.7,ng*h/mL,arith. SD,AUC_inf,102,ng/mL,arith. Mean,37,ng/mL,arith. SD,Cmax,3.7,mL/min/kg,arith. mean,1.4,mL/min/kg,arith. SD,CLiv,,1 +299,Kharasch 2011,https://www.ncbi.nlm.nih.gov/pubmed/21562488,iv with Perpetrator (Rifampicin @ 5 mg),Alfentanil,109,133,h,61.7,ng*h/mL,arith. mean,19.4,ng*h/mL,arith. SD,AUC_inf,106,ng/mL,arith. Mean,35,ng/mL,arith. SD,Cmax,4.4,mL/min/kg,arith. mean,1.2,mL/min/kg,arith. SD,CLiv,,1 +300,Kharasch 2011,https://www.ncbi.nlm.nih.gov/pubmed/21562488,iv with Perpetrator (Rifampicin @ 10 mg),Alfentanil,109,133,h,55.5,ng*h/mL,arith. mean,16.7,ng*h/mL,arith. SD,AUC_inf,107,ng/mL,arith. Mean,23,ng/mL,arith. SD,Cmax,4.9,mL/min/kg,arith. mean,1.4,mL/min/kg,arith. SD,CLiv,,1 +301,Kharasch 2011,https://www.ncbi.nlm.nih.gov/pubmed/21562488,iv with Perpetrator (Rifampicin @ 25 mg),Alfentanil,109,133,h,44,ng*h/mL,arith. mean,15.9,ng*h/mL,arith. SD,AUC_inf,102,ng/mL,arith. Mean,27,ng/mL,arith. SD,Cmax,6.3,mL/min/kg,arith. mean,1.8,mL/min/kg,arith. SD,CLiv,,1 +302,Kharasch 2011,https://www.ncbi.nlm.nih.gov/pubmed/21562488,iv with Perpetrator (Rifampicin @ 75 mg),Alfentanil,109,133,h,37,ng*h/mL,arith. mean,37,ng*h/mL,arith. SD,AUC_inf,105,ng/mL,arith. Mean,26,ng/mL,arith. SD,Cmax,7.1,mL/min/kg,arith. mean,1.4,mL/min/kg,arith. SD,CLiv,,1 +308,Kharasch 2011,https://www.ncbi.nlm.nih.gov/pubmed/21562488,po Control (Perpetrator Placebo),Alfentanil,0,inf,h,146,ng*h/mL,arith. mean,84,ng*h/mL,arith. SD,AUC_inf,51,ng/mL,arith. Mean,21,ng/mL,arith. SD,Cmax,11.1,mL/min/kg,arith. mean,5.7,mL/min/kg,arith. SD,CL/F,,1 +309,Kharasch 2011,https://www.ncbi.nlm.nih.gov/pubmed/21562488,po with Perpetrator (Rifampicin @ 5 mg),Alfentanil,133,inf,h,101,ng*h/mL,arith. mean,42,ng*h/mL,arith. SD,AUC_inf,44,ng/mL,arith. Mean,15,ng/mL,arith. SD,Cmax,14.8,mL/min/kg,arith. mean,7.2,mL/min/kg,arith. SD,CL/F,,1 +310,Kharasch 2011,https://www.ncbi.nlm.nih.gov/pubmed/21562488,po with Perpetrator (Rifampicin @ 10 mg),Alfentanil,133,inf,h,81,ng*h/mL,arith. mean,41,ng*h/mL,arith. SD,AUC_inf,44,ng/mL,arith. Mean,17,ng/mL,arith. SD,Cmax,19.7,mL/min/kg,arith. mean,11.6,mL/min/kg,arith. SD,CL/F,,1 +311,Kharasch 2011,https://www.ncbi.nlm.nih.gov/pubmed/21562488,po with Perpetrator (Rifampicin @ 25 mg),Alfentanil,133,inf,h,43,ng*h/mL,arith. mean,27,ng*h/mL,arith. SD,AUC_inf,25,ng/mL,arith. Mean,12,ng/mL,arith. SD,Cmax,41.9,mL/min/kg,arith. mean,28.7,mL/min/kg,arith. SD,CL/F,,1 +312,Kharasch 2011,https://www.ncbi.nlm.nih.gov/pubmed/21562488,po with Perpetrator (Rifampicin @ 75 mg),Alfentanil,133,inf,h,18,ng*h/mL,arith. mean,13,ng*h/mL,arith. SD,AUC_inf,13,ng/mL,arith. Mean,10,ng/mL,arith. SD,Cmax,91.7,mL/min/kg,arith. mean,44.6,mL/min/kg,arith. SD,CL/F,,1 +390,Phimmasone 2001,https://www.ncbi.nlm.nih.gov/pubmed/11753266,Control (Perpetrator Placebo),Alfentanil,0,inf,h,6680,ng*min/mL,arith. Mean,3480,ng*min/mL,arith. SD,AUC_inf,,,,,,,,2.84,mL/min/kg,arith. Mean,1.44,mL/min/kg,arith. SD,CLiv,,1 +391,Phimmasone 2001,https://www.ncbi.nlm.nih.gov/pubmed/11753266,with Perpetrator (Rifampicin),Alfentanil,107,inf,h,2890,ng*min/mL,arith. Mean,568,ng*min/mL,arith. SD,AUC_inf,,,,,,,,5.33,mL/min/kg,arith. Mean,0.95,mL/min/kg,arith. SD,CLiv,,1 +277,Kharasch 1997,https://www.ncbi.nlm.nih.gov/pubmed/9232132,Control (Perpetrator Placebo),Alfentanil,0,inf,h,,,,,,,,,,,,,,,5.3,mL/min/kg,arith. mean,2.3,mL/min/kg,arith. SD,CLiv,,1 +278,Kharasch 1997,https://www.ncbi.nlm.nih.gov/pubmed/9232132,with Perpetrator (Rifampicin),Alfentanil,120.5,inf,h,,,,,,,,,,,,,,,14.6,mL/min/kg,arith. mean,3.8,mL/min/kg,arith. SD,CLiv,Significantly different from control (P<0.05). Microconstants were not statistically compared.,1 +5127,Bovill 1984,https://www.ncbi.nlm.nih.gov/pubmed/6238552,mean,Sufentanil,0,8,h,,,,,,,,,,,,,,,12.66,mL/min/kg,arith. Mean,0.78,mL/kg/min,arith. SEM,CLiv,Table 3, +5128,Willsie 2015,https://www.ncbi.nlm.nih.gov/pubmed/25544247,mean,Sufentanil,0,1440,min,273.8,pg*h/mL,arith. Mean,61.1,pg*h/mL,arith. SD,AUC_inf,,,,,,,,,,,,,,CLiv,, +5129,Davis 1987,https://www.ncbi.nlm.nih.gov/pubmed/2950809,mean,Sufentanil,0,120,min,0.000545455,mg*min/mL,arith. Mean,,,,AUC_tau,,,,,,,,27.5,mL/min/kg,arith. Mean,9.3,mL/kg/min,arith. Mean,CLiv,"Table 3, last samples taken 120 OR until the initiation of cardiopulmonary bypass, AUCinf imputed based on reported Dose/CL", +5130,Davis 1987,https://www.ncbi.nlm.nih.gov/pubmed/2950809,mean,Sufentanil,0,120,min,0.000828729,mg*min/mL,individual,,,,AUC_tau,,,,,,,,18.1,mL/min/kg,arith. Mean,10.7,mL/kg/min,arith. Mean,CLiv,"Table 3 ,AUCinf imputed based on reported Dose/CL", +5131,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID1,Sufentanil,0,360,min,0.00010838,mg*min/mL,individual,,,,AUC_tau,,,,,,,,17.9,mL/min/kg,individual,,,,CLiv,"t_end is time to reach limit of quanititation after dose, AUCinf imputed based on reported Dose/CL", +5132,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID2,Sufentanil,0,60,min,4.63E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,40.6,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5133,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID3,Sufentanil,0,240,min,8.92E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,39.7,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5134,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID4,Sufentanil,0,240,min,8.26E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,34,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5135,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID5,Sufentanil,0,300,min,6.63E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,29.7,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5136,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID6,Sufentanil,0,120,min,6.73E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,29.7,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5137,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID7,Sufentanil,0,420,min,0.000134872,mg*min/mL,individual,,,,AUC_tau,,,,,,,,19.5,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5138,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID8,Sufentanil,0,240,min,6.99E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,44.9,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5139,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID9,Sufentanil,0,120,min,4.36E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,44.7,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5140,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID10,Sufentanil,0,240,min,8.53E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,36.1,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5141,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID11,Sufentanil,0,420,min,0.000135498,mg*min/mL,individual,,,,AUC_tau,,,,,,,,23.1,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5142,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID12,Sufentanil,0,240,min,7.55E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,26.5,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5143,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID13,Sufentanil,0,420,min,0.000161538,mg*min/mL,individual,,,,AUC_tau,,,,,,,,18.2,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5144,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID14,Sufentanil,0,420,min,0.000151832,mg*min/mL,individual,,,,AUC_tau,,,,,,,,19.1,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5145,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID15,Sufentanil,0,180,min,0.000127542,mg*min/mL,individual,,,,AUC_tau,,,,,,,,23.6,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5146,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID16,Sufentanil,0,240,min,5.71E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,25.9,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5147,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID17,Sufentanil,0,180,min,6.17E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,32.9,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5148,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID18,Sufentanil,0,180,min,0.000035,mg*min/mL,individual,,,,AUC_tau,,,,,,,,28,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5149,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID19,Sufentanil,0,240,min,7.36E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,40.1,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5150,Guay 1991,https://www.ncbi.nlm.nih.gov/pubmed/1531117,ID20,Sufentanil,0,180,min,5.65E-05,mg*min/mL,individual,,,,AUC_tau,,,,,,,,35.2,mL/min/kg,individual,,,,CLiv,AUCinf imputed based on reported Dose/CL, +5151,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,I1,Alfentanil,0,45,min,21.1,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5152,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,I2,Alfentanil,0,45,min,14,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5153,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,I3,Alfentanil,0,45,min,19.8,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5154,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,I4,Alfentanil,0,45,min,18.5,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5155,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,I5,Alfentanil,0,45,min,15.9,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5157,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,C1,Alfentanil,0,45,min,12.4,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5158,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,C2,Alfentanil,0,45,min,24.3,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5159,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,C3,Alfentanil,0,45,min,11.3,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5160,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,C4,Alfentanil,0,45,min,18.6,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5161,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,C5,Alfentanil,0,45,min,20.7,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5162,den Hollander 1992,https://www.ncbi.nlm.nih.gov/pubmed/1610996,C6,Alfentanil,0,45,min,22.7,mg*min/L,individual,,,,AUC_tau,,,,,,,,,,,,,,,, +5163,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID1,Alfentanil,0,360,min,0.005882353,mg*min/mL,individual,,,,AUC_tau,,,,,,,,3.4,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5164,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID2,Alfentanil,0,360,min,0.003389831,mg*min/mL,individual,,,,AUC_tau,,,,,,,,5.9,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5165,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID3,Alfentanil,0,360,min,0.002409639,mg*min/mL,individual,,,,AUC_tau,,,,,,,,8.3,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5166,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID4,Alfentanil,0,360,min,0.004347826,mg*min/mL,individual,,,,AUC_tau,,,,,,,,4.6,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5167,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603 ,ID5,Alfentanil,0,360,min,0.005405405,mg*min/mL,individual,,,,AUC_tau,,,,,,,,3.7,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5168,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID6,Alfentanil,0,360,min,0.004166667,mg*min/mL,individual,,,,AUC_tau,,,,,,,,4.8,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5169,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID7,Alfentanil,0,360,min,0.004545455,mg*min/mL,individual,,,,AUC_tau,,,,,,,,4.4,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5170,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID8,Alfentanil,0,360,min,0.007407407,mg*min/mL,individual,,,,AUC_tau,,,,,,,,2.7,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5171,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,mean child,Alfentanil,0,360,min,0.004255319,mg*min/mL,arith. Mean,,,,AUC_tau,,,,,,,,4.7,mL/min/kg,arith. Mean,0.6,mL/min/kg,arith. SD,CLiv,AUCinf imputed based on reported Dose/AUC, +5172,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID9,Alfentanil,0,360,min,0.002777778,mg*min/mL,individual,,,,AUC_tau,,,,,,,,7.2,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5173,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID10,Alfentanil,0,360,min,0.005128205,mg*min/mL,individual,,,,AUC_tau,,,,,,,,3.9,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5174,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID11,Alfentanil,0,360,min,0.007407407,mg*min/mL,individual,,,,AUC_tau,,,,,,,,2.7,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5175,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID12,Alfentanil,0,360,min,0.005128205,mg*min/mL,individual,,,,AUC_tau,,,,,,,,3.9,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5176,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,ID13,Alfentanil,0,360,min,0.006060606,mg*min/mL,individual,,,,AUC_tau,,,,,,,,3.3,mL/min/kg,individual,,,,,AUCinf imputed based on reported Dose/AUC, +5177,Meistelman 1987,https://www.ncbi.nlm.nih.gov/pubmed/3099603,mean adult,Alfentanil,0,360,min,0.004761905,mg*min/mL,arith. Mean,,,,AUC_tau,,,,,,,,4.2,mL/min/kg,arith. Mean,1.7,mL/min/kg,arith. SD,CLiv,AUCinf imputed based on reported Dose/AUC, +5178,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID1,Alfentanil,0,360,min,5543,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5179,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID2,Alfentanil,0,360,min,4609,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5180,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID3,Alfentanil,0,360,min,5753,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5181,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID4,Alfentanil,0,360,min,8086,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5182,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID5,Alfentanil,0,360,min,6923,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5183,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID6,Alfentanil,0,360,min,6736,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5184,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID7,Alfentanil,0,360,min,6089,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5185,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID8,Alfentanil,0,360,min,5702,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5186,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID9,Alfentanil,0,360,min,6972,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5187,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID10,Alfentanil,0,360,min,9343,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5188,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID11,Alfentanil,0,360,min,4837,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5189,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID12,Alfentanil,0,360,min,5492,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5190,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID13,Alfentanil,0,360,min,9100,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5191,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID14,Alfentanil,0,360,min,14704,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5192,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID15,Alfentanil,0,360,min,11003,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5193,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID16,Alfentanil,0,360,min,17707,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5194,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID17,Alfentanil,0,360,min,140909,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, +5195,Goresky 1987,https://www.ncbi.nlm.nih.gov/pubmed/3118743,ID18,Alfentanil,0,360,min,21587,ng*min/mL,individual,,,,AUC_inf,,,,,,,,,,,,,,,, diff --git a/Input/Qualification-Ontogeny-CYP3A4.json b/Input/Qualification-Ontogeny-CYP3A4.json new file mode 100644 index 0000000..a246a7c --- /dev/null +++ b/Input/Qualification-Ontogeny-CYP3A4.json @@ -0,0 +1,1083 @@ +{ + "$schema": 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Open circles represent mean ratios of PBPK predicted AUC over observed AUC of all drugs in children 3.6 months to 9 years old. Blue dashed lines and red dotted lines represent the 1.5-fold and 2-fold error, respectively.", + "Color": "#000000", + "PKParameter": "AUC", + "SectionId": 2, + "PKRatios": [ + { + "Project": "Sufentanil", + "Simulation": "Davis 1987 15.5months", + "Output": "Organism|ArterialBlood|Plasma|Sufentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5130 + }, + { + "Project": "Sufentanil", + "Simulation": "Davis 1987 5.2months", + "Output": "Organism|ArterialBlood|Plasma|Sufentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5129 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 1", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5131 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 2", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5132 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 3", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5133 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 4", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5134 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 5", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5135 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 6", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5136 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 7", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5137 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 8", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5138 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 9", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5139 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 10", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5140 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 11", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5141 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 12", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5142 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 14", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5144 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 15", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5145 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 16", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5146 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 17", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5147 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 18", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5148 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 19", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5149 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 20", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5150 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 1", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5151 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 2", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5152 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 3 (for Ratioplot)", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5153 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 4", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5154 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 5", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5155 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind C2", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5158 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind C3", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5159 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind C4", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5160 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind C5", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5161 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind C6", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5162 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.1", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5163 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.2", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5164 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.3", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5165 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.4", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5166 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.5", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5167 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.6", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5168 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.7", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5169 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.8", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5170 + } + ] + }, + { + "Title": "Overall predictivity of the sufentanil PBPK model. Open circles represent mean ratios of PBPK predicted AUC over observed AUC of sufentanil in children 5 months to 8.75 years old. Blue dashed lines and red dotted lines represent the 1.5-fold and 2-fold error, respectively.", + "Color": "#000000", + "PKParameter": "AUC", + "SectionId": 31, + "PKRatios": [ + { + "Project": "Sufentanil", + "Simulation": "Davis 1987 15.5months", + "Output": "Organism|ArterialBlood|Plasma|Sufentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5130 + }, + { + "Project": "Sufentanil", + "Simulation": "Davis 1987 5.2months", + "Output": "Organism|ArterialBlood|Plasma|Sufentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5129 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 1", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5131 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 2", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5132 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 3", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5133 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 4", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5134 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 5", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5135 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 6", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5136 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 7", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5137 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 8", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5138 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 9", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5139 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 10", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5140 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 11", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5141 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 12", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5142 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 14", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5144 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 15", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5145 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 16", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5146 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 17", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5147 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 18", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5148 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 19", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5149 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 20", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5150 + } + ] + }, + { + "Title": "Overall predictivity of the alfentanil PBPK model. Open circles represent mean ratios of PBPK predicted AUC over observed AUC of alfentanil in children 3.6 months to 9 years old. Blue dashed lines and red dotted lines represent the 1.5-fold and 2-fold error, respectively.", + "Color": "#000000", + "PKParameter": "AUC", + "SectionId": 33, + "PKRatios": [ + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 1", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5151 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 2", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5152 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 3 (for Ratioplot)", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5153 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 4", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5154 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 5", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5155 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind C2", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5158 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind C3", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5159 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind C4", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5160 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind C5", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5161 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind C6", + "Output": "Organism|ArterialBlood|Plasma|Alfentanil|Concentration in container", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5162 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.1", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5163 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.2", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5164 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.3", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5165 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.4", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5166 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.5", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5167 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.6", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5168 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.7", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5169 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 ped.8", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "PK-Parameter", + "ObservedDataRecordId": 5170 + } + ] + } + ], + "GOFMergedPlots": [ + { + "Title": "Goodness-of-fit visual diagnostic plots of the alfentanil PBPK model performance: observed versus individually predicted plasma concentration versus time of all adult data.", + "SectionId": 44, + "PlotType": "predictedVsObserved", + "Groups": [ + { + "Caption": "Alfentanil iv", + "Symbol": "Circle", + "OutputMappings": [ + { + "Project": "Alfentanil", + "Simulation": "Ferrier 1985, Alfentanil iv", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Ferrier et al. 1985 - healthy controls - Alfentanil 50 ugperkg iv", + "Color": "#000000" + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 1997, Alfentanil iv", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Kharasch 1997, Alfentanil 20 ugperkg iv, n=9", + "Color": "#000000" + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 2004, Alfentanil iv", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Kharasch 2004, Alfentanil 15 ugperkg iv, n=10", + "Color": "#000000" + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 2011b, Alfentanil iv", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Kharasch 2011b, Alfentanil 15 ugperkg iv, n=12", + "Color": "#000000" + }, + { + "Project": "Alfentanil", + "Simulation": "Phimmasone 2001, Alfentanil iv", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral 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"Symbol": "Circle", + "OutputMappings": [ + { + "Project": "Alfentanil", + "Simulation": "Ferrier 1985, Alfentanil iv", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Ferrier et al. 1985 - healthy controls - Alfentanil 50 ugperkg iv", + "Color": "#000000" + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 1997, Alfentanil iv", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Kharasch 1997, Alfentanil 20 ugperkg iv, n=9", + "Color": "#000000" + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 2004, Alfentanil iv", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Kharasch 2004, Alfentanil 15 ugperkg iv, n=10", + "Color": "#000000" + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 2011b, Alfentanil iv", + "Output": "Organism|PeripheralVenousBlood|Alfentanil|Plasma (Peripheral 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+ }, + { + "Title": "Goodness-of-fit visual diagnostic plots of the sufentanil PBPK model performance: observed versus individually predicted plasma concentration versus time of all adult data.", + "SectionId": 41, + "PlotType": "predictedVsObserved", + "Groups": [ + { + "Caption": "Sufentanil iv", + "Symbol": "Circle", + "OutputMappings": [ + { + "Project": "Sufentanil", + "Simulation": "Bovill 1984", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Bovill_1984_the pk of sufentanil in surgical patients.Bovill 1984 Figure 1", + "Color": "#000000" + }, + { + "Project": "Sufentanil", + "Simulation": "Willsie 2014 adults IV (for reporting)", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Willsie 2014 Figure 1 IV mean (for reporting)", + "Color": "#000000" + }, + { + "Project": "Sufentanil", + "Simulation": "Taverne 1992 (for reporting)", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Taverne 1992 Figure 1 mean (for reporting)", + "Color": "#000000" + } + ] + } + ] + }, + { + "Title": "Goodness-of-fit visual diagnostic plots of the sufentanil PBPK model performance: weighted residuals versus time of all adult data.", + "SectionId": 41, + "PlotType": "residualsOverTime", + "Groups": [ + { + "Caption": "Sufentanil iv", + "Symbol": "Circle", + "OutputMappings": [ + { + "Project": "Sufentanil", + "Simulation": "Bovill 1984", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Bovill_1984_the pk of sufentanil in surgical patients.Bovill 1984 Figure 1", + "Color": "#000000" + }, + { + "Project": "Sufentanil", + "Simulation": "Willsie 2014 adults IV (for reporting)", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Willsie 2014 Figure 1 IV mean (for reporting)", + "Color": "#000000" + }, + { + "Project": "Sufentanil", + "Simulation": "Taverne 1992 (for reporting)", + "Output": "Organism|PeripheralVenousBlood|Sufentanil|Plasma (Peripheral Venous Blood)", + "ObservedData": "Taverne 1992 Figure 1 mean (for reporting)", + "Color": "#000000" + } + ] + } + ] + } + ], + "AllPlots": [ + { + "Project": "Sufentanil", + "Simulation": "Bovill 1984", + "SectionId": 42 + }, + { + "Project": "Sufentanil", + "Simulation": "Willsie 2014 adults IV (for reporting)", + "SectionId": 42 + }, + { + "Project": "Sufentanil", + "Simulation": "Taverne 1992 (for reporting)", + "SectionId": 42 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 11", + "SectionId": 32 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 3", + "SectionId": 32 + }, + { + "Project": "Sufentanil", + "Simulation": "Guay 1991 patient 8", + "SectionId": 32 + }, + { + "Project": "Alfentanil", + "Simulation": "Ferrier 1985, Alfentanil iv", + "SectionId": 45 + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 1997, Alfentanil iv", + "SectionId": 45 + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 2004, Alfentanil iv", + "SectionId": 45 + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 2004, Alfentanil po", + "SectionId": 45 + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 2011b, Alfentanil iv", + "SectionId": 45 + }, + { + "Project": "Alfentanil", + "Simulation": "Kharasch 2011b, Alfentanil po", + "SectionId": 45 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987, 20µg/kg, adult male individual", + "SectionId": 45 + }, + { + "Project": "Alfentanil", + "Simulation": "Phimmasone 2001, Alfentanil iv", + "SectionId": 45 + }, + { + "Project": "Alfentanil", + "Simulation": "den Holländer 1992 ind 3", + "SectionId": 34 + }, + { + "Project": "Alfentanil", + "Simulation": "Meistelman 1987 children", + "SectionId": 34 + } + ] + }, + "Sections": [ + { + "Id": 2, + "Title": "Chapter 1: Introduction to Pediatric Translation and CYP3A4 Ontogeny Qualification", + "Content": "Content/Section1.md" + }, + { + "Id": 3, + "Title": "Chapter 2: Pediatric translation qualification results", + "Content": "Content/Section3.md", + "Sections": [ + { + "Id": 31, + "Content": "Content/Sufentanil_children.md", + "Title": "Chapter 2.1: Sufentanil PK Ratio tables and Figures" + }, + { + "Id": 32, + "Content": "Content/Concentration_time_profiles_children.md", + "Title": "Chapter 2.2: Sufentanil Concentration-Time profiles in Children" + }, + { + "Id": 33, + "Content": "Content/Alfentanil_children.md", + "Title": "Chapter 2.3: Alfentanil PK Ratio tables and Figures" + }, + { + "Id": 34, + "Content": "Content/Concentration_time_profiles_children.md", + "Title": "Chapter 2.4: Alfentanil Concentration-Time profiles in Children" + } + ] + }, + { + "Id": 4, + "Title": "Chapter 3: Adult PBPK model building and performance", + "Content": "Content/Section2.md", + "Sections": [ + { + "Id": 40, + "Content": "Content/Sufentanil_adults.md", + "Title": "Chapter 3.1: Sufentanil Input Tables" + }, + { + "Id": 41, + "Content": "Content/Sufentanil_diagnostics.md", + "Title": "Chapter 3.2: Sufentanil Diagnostics Plots" + }, + { + "Id": 42, + "Content": "Content/Concentration_time_profiles_adults.md", + "Title": "Chapter 3.3: Sufentanil Concentration-Time profiles in Adults" + }, + { + "Id": 43, + "Content": "Content/Alfentanil_adults.md", + "Title": "Chapter 3.4: Alfentanil Input Tables" + }, + { + "Id": 44, + "Content": "Content/Alfentanil_diagnostics.md", + "Title": "Chapter 3.5: Alfentanil Diagnostics Plots" + }, + { + "Id": 45, + "Content": "Content/Concentration_time_profiles_adults.md", + "Title": "Chapter 3.6: Alfentanil Concentration-Time profiles in Adults" + } + ] + } + ], + "Inputs": [ + { + "Project": "Sufentanil", + "Name": "Sufentanil", + "Type": "Compound", + "SectionId": 40 + }, + { + "Project": "Alfentanil", + "Name": "Alfentanil", + "Type": "Compound", + "SectionId": 43 + } + ] +} \ No newline at end of file diff --git a/Pediatric_Qualification_Report_CYP3A4_Ontogeny.pdf b/Pediatric_Qualification_Report_CYP3A4_Ontogeny.pdf new file mode 100644 index 0000000..af99ca6 Binary files /dev/null and b/Pediatric_Qualification_Report_CYP3A4_Ontogeny.pdf differ