Apricitabine (ATC) is a novel
nucleoside reverse transcriptase inhibitor undergoing phase 2/3 clinical development for the treatment of
HIV infection. In this investigation, the renal handling of ATC was evaluated in the isolated perfused rat kidney (IPK) model with follow-up in vivo studies. IPK experiments were performed to characterize the renal excretion of ATC, to probe mechanisms of ATC excretion using known inhibitors of organic
cation (
cimetidine) and organic
anion (
probenecid) transport systems, and to screen for potential
drug-drug interactions between ATC and clinically relevant medications (
dapsone,
metformin,
pentamidine,
stavudine,
tenofovir and
ritonavir). ATC demonstrated net tubular secretion in the IPK with a baseline excretion ratio (XR) of 2.1 ± 0.56. ATC XR decreased 3.6-fold in the presence of
cimetidine and 2-fold in the presence of
probenecid. Among the clinically relevant medications,
metformin produced the greatest inhibitory effect on ATC excretion. In vivo studies were conducted in rats to evaluate ATC disposition upon co-administration with compounds that showed a significant effect on ATC clearance in the IPK model. Co-administration of
cimetidine and
trimethoprim significantly reduced ATC renal clearance, but resulted in only a moderate increase in plasma exposure.
Metformin had no apparent effect on ATC clearance in rats. These findings indicate that the IPK model is more sensitive to secretory inhibition as compared to in vivo. The medications screened showed minimal effects on ATC renal excretion in the IPK, and should thus be excluded as potential in vivo interactants. Overall, this study generated important information on renal handling of ATC to support its development and commercialization.