Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

Sager, Jennifer E.; Yu, Jinngjing; Ragueneau‐Majlessi, Isabelle; Isoherranen, Nina

doi:10.1124/dmd.115.065920

Cited by 381 publications

(295 citation statements)

References 165 publications

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“…PBPK models represent a quantitative system that combines human physiology and drug-specific information, in which the impact of physiological changes (including those pertaining to age-dependent development) on drug absorption, distribution, metabolism, and excretion processes can be evaluated. The past decade observed an increased interest in applying PBPK in academic research and drug development (Rowland et al, 2011;Sager et al, 2015). The advent of specialized PBPK platforms further broadens the use of PBPK (Edginton et al, 2006;Johnson et al, 2006Johnson et al, , 2010Edginton and Willmann, 2008;Rowland et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Mehrotra¹,

Bhattaram²,

Earp³

et al. 2016

Drug Metabolism and Disposition

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Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twicedaily regimen, different once-daily dosing regimens for treatmentnaïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.

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Section: Discussionmentioning

confidence: 99%

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Mehrotra¹,

Bhattaram²,

Earp³

et al. 2016

Drug Metabolism and Disposition

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“…Thus, many dynamic methods, assuming either full or semi PBPK models, have been proposed previously. 4) Their basic concept is to simulate the in vivo levels of a perpetrator and a victim by inputting plural in vitro drug specific parameters as well as predetermined physiological parameters (bottom-up approaches). However, it was a concern that in vitro parameters such as K i, u would have a large bias, and that the plurality of the input parameters would reduce the flexibility of the simulation, making it difficult to achieve an accurate fit of the timedependent plasma victim levels.…”

Section: Traditional Methods For Dynamic Prediction Of Ddimentioning

confidence: 99%

“…13) The AUCR predicted by either a static method [constant unbound inhibitor (I u )-based method] as shown below, or a dynamic method (time-dependent I u -based method) employing physiologically-based pharmacokinetic (PBPK) model, wherein the well-stirred model was applied for the hepatic extraction kinetics, was no more than 5. 4) Typically, the value of AUCR estimated by a well-stirred model-based static method * To whom correspondence should be addressed. e-mail: kiga@dwc.doshisha.ac.jp Table 1.…”

Section: Unusualness Of Ramelteon (Ram)-victimizedmentioning

confidence: 99%

“…Thus, in the common cases, the regulatory agencies recommend their prediction from the in vitro and limited in vivo data. [4][5][6] Nevertheless, in light of the Food and Drug Administration (FDA) guidance and current findings in this field of research, [7][8][9][10][11] many issues in regard to DDI prediction remain to be solved (Table 1).…”

Section: Introductionmentioning

confidence: 99%

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Usefulness of Two-Compartment Model-Assisted and Static Overall Inhibitory-Activity Method for Prediction of Drug–Drug Interaction

Iga

Kiriyama

2017

Biological & Pharmaceutical Bulletin

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Our study of drug-drug interaction (DDI) started with the clarification of unusually large DDI observed between ramelteon (RAM) and fluvoxamine (FLV). The main cause of this DDI was shown to be the extremely small hepatic availability of RAM (vF h ). Traditional DDI prediction assuming the well-stirred hepatic extraction kinetic ignores the relative increase of vF h by DDI, while we could solve this problem by use of the tube model. Ultimately, we completed a simple and useful method for prediction of DDI. Currently, DDI prediction becomes more complex and difficult when examining issues such as dynamic changes in perpetrator level, inhibitory metabolites, etc. The regulatory agents recommend DDI prediction by use of some sophisticated methods. However, they seem problematic in requiring plural in vitro data that reduce the flexibility and accuracy of the simulation. In contrast, our method is based on the static and two-compartment models. The two-compartment model has advantages in that it uses common pharmacokinetics (PK) parameters determined from the actual clinical data, guaranteeing the simulation of the reference standard in DDI. Our studies confirmed that dynamic changes in perpetrator level do not make a difference between static and dynamic methods. DDIs perpetrated by FLV and itraconazole were successfully predicted by use of the present method where two DDI predictors [perpetrator-specific inhibitory activities toward CYP isoforms (pA i, CYP s) and victim-specific fractional CYP-isoform contributions to the clearance (vf m, CYP s)] are determined successively as shown in the graphical abstract. Accordingly, this approach will accelerate DDI prediction over the traditional methods.

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“…The bioavailability of orally administered TDF is estimated at around 25% of the total dose (25), and the bioavailability of 300 mg of orally administered TDF was determined from our simulations (mean Ϯ standard deviation, with minimum and maximum range) as a comparison to further validate the model. As a predetermined measure of success for the model validation, a 0.5-fold difference or less between clinical and predicted pharmacokinetic parameters was deemed acceptably accurate (26,27). Pharmacokinetic parameters were determined by noncompartmental analysis using PK Solutions 2.0 (Summit Research Services, UK).…”

Section: Methodsmentioning

confidence: 99%

Simulating Intestinal Transporter and Enzyme Activity in a Physiologically Based Pharmacokinetic Model for Tenofovir Disoproxil Fumarate

Moss

Domanico

Watkins

et al. 2017

Antimicrob Agents Chemother

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Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation (carboxylesterase). However, the influence of luminal pancreatic enzymes is not fully understood. Physiologically based pharmacokinetic (PBPK) modeling has utility for estimating drug exposure from in vitro data. This study aimed to develop a PBPK model that included luminal enzyme activity to inform dose reduction strategies. TDF and tenofovir stability in porcine pancrelipase concentrations was assessed (0, 0.48, 4.8, 48, and 480 U/ml of lipase; 1 mM TDF; 37°C; 0 to 30 min). Samples were analyzed using mass spectrometry. TDF stability and permeation data allowed calculation of absorption rates within a human PBPK model to predict plasma exposure following 6 days of once-daily dosing with 300 mg of TDF. Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration (C max ; 335 ng/ml), time to C max (T max ; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ; 3,045 ng · h/ml), and concentration at 24 h (C 24 ; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated C max (238 ng/ml), T max (3 h), AUC 0 -24 (3,036 ng · h/ml), and C 24 (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (pϽ0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies.KEYWORDS tenofovir disoproxil fumarate, physiologically based pharmacokinetic modeling, HIV, bioavailability, HAART H uman immunodeficiency virus (HIV) is the cause of a currently incurable disease which constitutes a serious global health crisis. Oral antiretroviral therapy is the mainstay of current therapy and involves coadministration of drugs targeting multiple viral targets. Both drug-related adverse reactions and drug resistance have led to the development of newer antiretroviral drugs and drug classes. However, the cost and dosing schedule of treatments are a significant concern in low-and middle-income countries (L&MICs). Several effective antiretroviral drugs are now manufactured as generics and are marketed with significant cost savings to payers (1, 2).Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), is a cornerstone of first-line treatment in low-income and middle-income countries. TDF is a nucleotide

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Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

Cited by 381 publications

References 165 publications

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling

Usefulness of Two-Compartment Model-Assisted and Static Overall Inhibitory-Activity Method for Prediction of Drug–Drug Interaction

Simulating Intestinal Transporter and Enzyme Activity in a Physiologically Based Pharmacokinetic Model for Tenofovir Disoproxil Fumarate

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