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

Abstract

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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