Para-aminosalicylic acid significantly reduced tenofovir exposure in human subjects; mismatched findings from in vitro to in vivo translational research.

Abstract

AIM\nTenofovir and para-aminosalicylic acid (PAS) may be co-prescribed to treat patients with concomitant infections of human immunodeficiency virus and Mycobacterium tuberculosis bacteria. Both drugs are known to have remarkable renal uptake transporter-mediated clearance. Owing to the lack of clinical studies on drug-drug interaction between the two drugs, we conducted a translational clinical study to investigate the effect of PAS on tenofovir pharmacokinetics.\n\n\nMETHODS\nInitially, we studied in vitro renal uptake transporter-mediated drug-drug interactions using stably transfected cells with human organic anion transporters (organic anion transporter 1 and 3 [OAT1 and OAT3]). Later, we estimated clinical drug interactions using static and physiologically based pharmacokinetic (PBPK) modeling. Finally, we investigated the effects of PAS-calcium formulation (PAS-Ca) on tenofovir disoproxil fumarate pharmacokinetics in healthy male Korean subjects.\n\n\nRESULTS\nPAS inhibited OAT1- and OAT3-mediated tenofovir uptake in vitro. The PBPK drug-drug interaction model suggested a 1.26-fold increase in tenofovir peak plasma concentration when co-administered with PAS. By contrast, an open-label, randomized, crossover clinical trial evaluating the effects of PAS-Ca on tenofovir pharmacokinetics showed significantly altered geometric mean ratio (90% confidence intervals) of maximum plasma concentration (Cmax ) and area under the curve (AUC0-inf ) by 0.33 (0.28-0.38) and 0.29 (0.26-0.33), respectively.\n\n\nCONCLUSIONS\nOur study findings suggest that the PAS-Ca formulation significantly reduced systemic exposure to tenofovir through an unexplained mechanism, which was contrary to the initial prediction. Caution should be exercised while predicting in vivo PK profiles from in vitro data, particularly when there are potential confounders such as pharmaceutical interactions.