ABT‐493 (protease inhibitor discovered by AbbVie and Enanta) and ABT‐530 (NS5A inhibitor) are direct acting antivirals developed as a combination regimen for treatment of chronic hepatitis C virus genotype 1‐6 infection. Rilpivirine, a non‐nucleoside reverse transcriptase inhibitor (NNRTI), and raltegravir, a HIV‐1 integrase inhibitor are often used with other antiretroviral agents in the HIV‐HCV co‐infected population. Phase 1 drug‐drug interaction (DDI) studies were conducted to evaluate pharmacokinetics,tolerability, and safety of ABT‐493 + ABT‐530 co‐administered with rilpivirine or raltegravir.
Both rilpivirine and raltegravir DDI studies utilized open label, randomized, multiple‐dose, non‐fasting study designs. In each study, healthy adult subjects received ABT‐493 300 mg QD + ABT‐530 120 mg QD and rilpivirine 25 mg QD (N=24) or raltegravir 400 mg BID (N=12) alone or in combination.
Intensive pharmacokinetic assessments were performed for ABT‐493, ABT‐530, rilpivirine, and raltegravir on multiple days throughout the study. Effects of ABT‐493 + ABT‐530 on rilpivirine or raltegravir pharmacokinetics and vice versa were assessed by a repeated‐measures analysis using SAS. Safety was evaluated via assessment of adverse events, vital signs, ECGs and clinical laboratory tests.
Coadministration with multiple ABT‐493 and ABT‐530 doses increased rilpivirine Cmax and AUCinf by 105% and 84%, respectively, relative to rilpivirine alone; raltegravir Cmax and AUC12 were increased by 34% and 47%, respectively, relative to raltegravir alone. ABT‐493 and ABT‐530 exposure following multiple QD doses, as determined by Cmax and AUC24, were similar when coadministered with rilpivirine or Raltegravir relative to administration of ABT‐493 + ABT‐530 alone (≤13% difference). All adverse events were mild in severity and assessed as not related to study drugs. No clinically significant vital signs, ECG or laboratory measurements were observed during the course of each study.
ABT‐493 and ABT‐530 exposure were not affected by rilpivirine or raltegravir. ABT‐493 + ABT‐530 increased rilpivirine and raltegravir exposures. Consistent with rilpivirine and raltegravir label recommendations for other drugs with similar magnitude of exposure increase, no dose adjustment is needed when ABT‐493 and ABT‐530 are coadministered with rilpivirine or raltegravir.