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Physiologically based pharmacokinetic tissue compartment model selection in drug development and risk assessment.

ABSTRACT: A well-stirred tank (WST) has been the predominant flow-limited tissue compartment model in physiologically based pharmacokinetic (PBPK) modeling. Recently, we developed a two-region asymptotically reduced (TAR) PBPK tissue compartment model through an asymptotic approximation to a two-region vascular-extravascular system to incorporate more biophysical detail than the WST model. To determine the relevance of a flow-limited TAR (F-TAR) approach, 75 structurally diverse drugs were evaluated herein using a priori predicted tissue:plasma partition coefficients along with hybrid and whole-body PBPK of eight rat tissues to determine the impact of model selection on simulation and optimization. Simulations showed that the F-TAR model significantly improved the ability to predict drug exposure, with hybrid and whole-body WST model error approaching 50% for tissues with larger vascular volumes. When optimization was used to fit F-TAR and WST models to pseudo data, WST-optimized drug partition coefficients more appropriately represented curve-fitting parameters rather than biophysically meaningful partition coefficients. Median F-TAR-optimized error ranged from -0.4% to +0.3%, whereas WST-optimized median error ranged from -22.2% to +1.8%. These studies demonstrated that the use of F-TAR represents a more accurate, biophysically realistic PBPK tissue model for predicting tissue exposure to drug and that it should be considered for use in drug development and regulatory review.

SUBMITTER: Thompson MD

PROVIDER: S-EPMC3314064 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Physiologically based pharmacokinetic tissue compartment model selection in drug development and risk assessment.

Thompson Matthew D MD Beard Daniel A DA

Journal of pharmaceutical sciences 20111003 1

A well-stirred tank (WST) has been the predominant flow-limited tissue compartment model in physiologically based pharmacokinetic (PBPK) modeling. Recently, we developed a two-region asymptotically reduced (TAR) PBPK tissue compartment model through an asymptotic approximation to a two-region vascular-extravascular system to incorporate more biophysical detail than the WST model. To determine the relevance of a flow-limited TAR (F-TAR) approach, 75 structurally diverse drugs were evaluated herei ...[more]

PMID: 21968734

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Project description:AimsCanagliflozin is a recently approved drug for use in the treatment of type 2 diabetes. The potential for canagliflozin to cause clinical drug-drug interactions (DDIs) was assessed.MethodsDDI potential of canagliflozin was investigated using in vitro test systems containing drug metabolizing enzymes or transporters. Basic predictive approaches were applied to determine potential interactions in vivo. A physiologically-based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of cytochrome P450 (CYP) inhibition by canagliflozin.ResultsCanagliflozin was primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase 1A9 and 2B4 enzymes. Canagliflozin was a substrate of efflux transporters (P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein-2) but was not a substrate of uptake transporters (organic anion transporter polypeptide isoforms OATP1B1, OATP1B3, organic anion transporters OAT1 and OAT3, and organic cationic transporters OCT1, and OCT2). In inhibition assays, canagliflozin was shown to be a weak in vitro inhibitor (IC50 ) of CYP3A4 (27 μmol l -1 , standard error [SE] 4.9), CYP2C9 (80 μmol l -1 , SE 8.1), CYP2B6 (16 μmol l-1 , SE 2.1), CYP2C8 (75 μmol l -1 , SE 6.4), P-glycoprotein (19.3 μmol l -1 , SE 7.2), and multidrug resistance-associated protein-2 (21.5 μmol l -1 , SE 3.1). Basic models recommended in DDI guidelines (US Food & Drug Administration and European Medicines Agency) predicted moderate to low likelihood of interaction for these CYPs and efflux transporters. PBPK DDI simulations of canagliflozin with CYP probe substrates (simvastatin, S-warfarin, bupropion, repaglinide) did not show relevant interaction in humans since mean areas under the concentration-time curve and maximum plasma concentration ratios for probe substrates with and without canagliflozin and its 95% CIs were within 0.80-1.25.ConclusionsIn vitro DDI followed by a predictive or PBPK approach was applied to determine DDI potential of canagliflozin. Overall, canagliflozin is neither a perpetrator nor a victim of clinically important interactions.

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Physiologically based pharmacokinetic tissue compartment model selection in drug development and risk assessment.

Publications

Physiologically based pharmacokinetic tissue compartment model selection in drug development and risk assessment.

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