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 (C₂₄; 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 C₂₄ (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). 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: HAART; HIV; bioavailability; physiologically based pharmacokinetic modeling; tenofovir disoproxil fumarate.

FIG 1

Process of converting the prodrug TDF to TFV and ultimately to the active substance TFV diphosphate.

FIG 2

Validation of the physiologically based pharmacokinetic model strategy against clinical data of TDF once-daily, day 7 profiles for dose sizes of 300 mg (A), 75 mg (B), 150 mg (C), and 600 mg (D). Data are from reference .

FIG 3

Amounts of TDF and tenofovir absorbed via each intestinal segment following a single 300-mg oral dose of TDF (mean ± SD 24 h postdose). J1, jejunum section 1; J2, jejunum section 2; I1, ileum section 1; I2, ileum section 2; I3, ileum section 3.