Use of In Vitro to In Vivo Extrapolation to Predict the Optimal Strategy for Patients Switching from Efavirenz to Maraviroc or Nevirapine

Schipani, Alessandro; Back, David; Owen, Andrew; Davies, Geraint R.; Khoo, Saye; Siccardi, Marco

doi:10.1007/s40262-014-0184-8

Cited by 2 publications

(3 citation statements)

References 35 publications

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“…In fact, several PBPK models for efavirenz were recently used to support the clinical pharmacology reviews of new drug applications with focus on assessing the modest CYP3A4 induction effect . There have been several studies in the literature that reported the application of PBPK models to predict the interindividual variability in efavirenz pharmacokinetics (PKs) due to CYP2B6 pharmacogenetics, and to support dose adjustment . A comparison of all available efavirenz models in the literature revealed that there are differences in several of the key model input parameters (e.g., plasma protein binding, CYP3A4/2B6 induction parameters).…”

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confidence: 99%

“…[7][8][9] There have been several studies in the literature that reported the application of PBPK models to predict the interindividual variability in efavirenz pharmacokinetics (PKs) due to CYP2B6 pharmacogenetics, and to support dose adjustment. [10][11][12] A comparison of all available efavirenz models in the literature revealed that there are differences in several of the key model input parameters (e.g., plasma protein binding, CYP3A4/2B6 induction parameters). These differences perhaps reflect the fact that many of these efavirenz models are "fit-for-purpose" and the aims of the simulations were different.…”

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confidence: 99%

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Towards a Best Practice Approach in PBPK Modeling: Case Example of Developing a Unified Efavirenz Model Accounting for Induction of CYPs 3A4 and 2B6

Barter

Rowland‐Yeo

et al. 2016

CPT Pharmacom & Syst Pharma

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In this study, we present efavirenz physiologically based pharmacokinetic (PBPK) model development as an example of our best practice approach that uses a stepwise approach to verify the different components of the model. First, a PBPK model for efavirenz incorporating in vitro and clinical pharmacokinetic (PK) data was developed to predict exposure following multiple dosing (600 mg q.d.). Alfentanil i.v. and p.o. drug‐drug interaction (DDI) studies were utilized to evaluate and refine the CYP3A4 induction component in the liver and gut. Next, independent DDI studies with substrates of CYP3A4 (maraviroc, atazanavir, and clarithromycin) and CYP2B6 (bupropion) verified the induction components of the model (area under the curve [AUC] ratios within 1.0–1.7‐fold of observed). Finally, the model was refined to incorporate the fractional contribution of enzymes, including CYP2B6, propagating autoinduction into the model (Racc 1.7 vs. 1.7 observed). This validated mechanistic model can now be applied in clinical pharmacology studies to prospectively assess both the victim and perpetrator DDI potential of efavirenz.

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Towards a Best Practice Approach in PBPK Modeling: Case Example of Developing a Unified Efavirenz Model Accounting for Induction of CYPs 3A4 and 2B6

Barter

Rowland‐Yeo

et al. 2016

CPT Pharmacom & Syst Pharma

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“…Andrew Owen [ 42 , 43 ] described mathematical approaches in pharmacokinetics (PK), contrasting population PK (starting with clinical data and fitting a model) with physiological PK (predicting clinical outcome from models of transport data). Such PK models can already be used to simulate different treatment regimens and predict how they might work for patients with different transporter SNPs (single-nt polymorphisms) [ 42 , 43 ]. Secondly, multi-drug transporters are partially responsible for cancer drug resistance, which causes tens of thousands of cancer deaths each year.…”

Section: Abc Transporters In Health and Disease: From Bench To Bedsidmentioning

confidence: 99%

ABC transporter research: going strong 40 years on

Theodoulou

Kerr

2015

Biochemical Society Transactions

231

150

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In most organisms, ABC transporters constitute one of the largest families of membrane proteins. In humans, their functions are diverse and underpin numerous key physiological processes, as well as being causative factors in a number of clinically relevant pathologies. Advances in our understanding of these diseases have come about through combinations of genetic and protein biochemical investigations of these transporters and the power of in vitro and in vivo investigations is helping to develop genotype–phenotype understanding. However, the importance of ABC transporter research goes far beyond human biology; microbial ABC transporters are of great interest in terms of understanding virulence and drug resistance and industrial biotechnology researchers are exploring the potential of prokaryotic ABC exporters to increase the capacity of synthetic biology systems. Plant ABC transporters play important roles in transport of hormones, xenobiotics, metals and secondary metabolites, pathogen responses and numerous aspects of development, all of which are important in the global food security area. For 3 days in Chester, this Biochemical Society Focused Meeting brought together researchers with diverse experimental approaches and with different fundamental questions, all of which are linked by the commonality of ABC transporters.

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Use of In Vitro to In Vivo Extrapolation to Predict the Optimal Strategy for Patients Switching from Efavirenz to Maraviroc or Nevirapine

Abstract: IVIVE modelling successfully predicted patient drug exposure. This modelling technique is able to inform the design of clinical studies, and allows assessment of pragmatic dosing strategies under complex therapeutic scenarios.

Cited by 2 publications

References 35 publications

Towards a Best Practice Approach in PBPK Modeling: Case Example of Developing a Unified Efavirenz Model Accounting for Induction of CYPs 3A4 and 2B6

Towards a Best Practice Approach in PBPK Modeling: Case Example of Developing a Unified Efavirenz Model Accounting for Induction of CYPs 3A4 and 2B6

ABC transporter research: going strong 40 years on

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