Effects of Human Immunodeficiency Virus Protease Inhibitors on the Intestinal Absorption of Tenofovir Disoproxil Fumarate In Vitro

Abstract

Human immunodeficiency virus protease inhibitors (PIs) modestly affect the plasma pharmacokinetics of tenofovir (TFV; ؊15% to ؉37% change in exposure) following coadministration with the oral prodrug TFV disoproxil fumarate (TDF) by a previously undefined mechanism. TDF permeation was found to be reduced by the combined action of ester cleavage and efflux transport in vitro. Saturable TDF efflux observed in Caco-2 cells suggests that at pharmacologically relevant intestinal concentrations, transport has only a limited effect on TDF absorption, thus minimizing the magnitude of potential intestinal drug interactions. Most tested PIs increased apical-to-basolateral TDF permeation and decreased secretory transport in MDCKII cells overexpressing P-glycoprotein (Pgp; MDCKII-MDR1 cells) and Caco-2 cells. PIs were found to cause a multifactorial effect on the barriers to TDF absorption. All PIs showed similar levels of inhibition of esterase-dependent degradation of TDF in an intestinal subcellular fraction, except for amprenavir, which was found to be a weaker inhibitor. All PIs caused a dose-dependent increase in the accumulation of a model Pgp substrate in MDCKII-MDR1 cells. Pgp inhibition constants ranged from 10.3 M (lopinavir) to >100 M (amprenavir, indinavir, and darunavir). Analogous to hepatic cytochrome P450-mediated drug interactions, we propose that the relative differences in perturbations in TFV plasma levels when TDF is coadministered with PIs are based in part on the net effect of inhibition and induction of intestinal Pgp by PIs. Combined with prior studies, these findings indicate that intestinal absorption is the mechanism for changes in TFV plasma levels when TDF is coadministered with PIs.Tenofovir disoproxil fumarate (TDF; Viread, Gilead Sciences, Inc.), a prodrug of the nucleotide reverse transcriptase inhibitor tenofovir (TFV), is used to effectively deliver TFV across the gut wall. Following absorption, TDF rapidly degrades to TFV and TDF is not observed in the systemic circulation. When administered by itself, TFV has poor oral bioavailability (7). TDF is a common once-a-day backbone for use with human immunodeficiency virus (HIV) protease inhibitors (PIs). Clinical trials have shown TDF with emtricitabine in combination with either lopinavir (LPV) or atazanavir (ATV), each boosted with ritonavir (RTV, or "r" when referred to as a boosting agent), to be efficacious and well tolerated (22,30).Polypharmacy in HIV patients creates the potential for drug interactions (8,35). No interaction between PIs and TDF would be anticipated due to the lack of cytochrome P450 involvement in the elimination pathway of TDF or TFV (25). However, modest changes in TFV plasma pharmacokinetic parameters have been reported for TDF coadministered with PIs. As summarized in Table 1, PIs can be categorized into three different groups based on their effects on TFV plasma pharmacokinetics. The first group encompasses PIs that cause modest increases in TFV plasma exposure (area under the concentration-time curve from 0 h t...

Steady-State Pharmacokinetics of Tenofovir-Based Regimens in HIV-Infected Pediatric Patients

“…1. This finding was unexpected, as many protease inhibitors modestly alter tenofovir plasma concentrations by Ϫ15% to ϩ37% in adults (17). In group 2, it is likely that low darunavir concentrations did not increase the tenofovir concentrations significantly to detect an interaction.…”

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

“…Ritonavir was shown to be a potent inhibitor of P glycoprotein (P-gp) and MRP2 (21). Inhibition of P-gp by a ritonavir-boosted protease inhibitor could lead to increased absorption in the gut (22). On the other hand, an increase in the level of tenofovir exposure due to inhibition of MRP2, an efflux transporter from the renal proximal tubule cells, resulting in decreased renal excretion, was also speculated (21).…”

Steady‐state amprenavir and tenofovir pharmacokinetics after coadministration of unboosted or ritonavir‐boosted fosamprenavir with tenofovir disoproxil fumarate in healthy volunteers

“…The reduction in TFV C min and AUC was less during the TDF 1 FPV/RTV period relative to the TDF 1 unboosted FPV period, possibly because the P-gpinhibitory effect of RTV may have partially counteracted the P-gp-induction effect of APV. TPV and NFV also induce intestinal P-gp [36,37], while ATV and LPV markedly inhibit P-gp [38], contributing to their TFV exposureelevating effects.…”

“…The reduction in TFV C min and AUC was less during the TDF 1 FPV/RTV period relative to the TDF 1 unboosted FPV period, possibly because the P-gpinhibitory effect of RTV may have partially counteracted the P-gp-induction effect of APV. TPV and NFV also induce intestinal P-gp [36,37], while ATV and LPV markedly inhibit P-gp [38], contributing to their TFV exposureelevating effects.It is unclear why TDF coadministration would increase APV concentrations, as TDF does not affect cytochrome P450 3A4 (CYP3A4) metabolism [9], the primary metabolic pathway for APV, nor does it affect P-gp [39,40], for which APV is a substrate. The increase in APV plasma concentrations during TDF coadministration is in contrast to the reduction in ATV and LPV concentrations seen when unboosted ATV, ATV/RTV or LPV/RTV is given with TDF [13,26,28], which is postulated to occur because of a physicochemical reaction these PIs have with TDF at the time of their absorption in the intestine [11].…”