Coadministration of DRV/c with 3HP should be avoided.
PK & SAFETY OF DARUNAVIR/COBICISTAT WITH ONCE-WEEKLY ISONIAZID/RIFAPENTINE
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Study Design
This was an open-label, fixed sequence, 2-period crossover study in healthy volunteers. Participants received DRV/c 800 mg/150 mg once-daily alone for 4 days, then continued DRV/c once-daily for Days 5-19 with weekly 3HP coadministration on Days 5, 12, and 19. Intensive PK assessments were performed over 24 hours on Days 4 (DRV/c alone), 14 (DRV/c 48-72 hours after 3HP), and 19 (DRV/c simultaneously with 3HP). PK parameters were determined using noncompartmental methods (Phoenix WinNonlin). Geometric mean ratios (GMR) with 90 confidence intervals (CIs) were calculated and compared between phases using mixed effects models.
Study Results
A total of 13 participants were enrolled (10 males; 8 white, 3 black, 2 others; 2 Hispanic/Latino; median range age 25 21-45 years and weight 70.7 62-85.1 kg). PK results are summarized in the Table. Relative to DRV/c alone, DRV AUC0-24h, C0h, Cmax, and C24h were significantly decreased with 3HP coadministration, with more marked decreases ~48-72 hours after RPT administration (Day 14) in comparison to simultaneous administration (Day 19). CLss/F was increased and V/F differed depending on the timing of 3HP administration, suggesting induction and changes in bioavailability, respectively, with 3HP. On Day 14, several individual C0h (6/13) and C24h (8/13) were below the DRV EC50 (0.055 ug/mL). On Day 19, 0/10 C0h and 1/10 C24h fell below the DRV EC50, and 2/10 C24h were just above this threshold (0.068 and 0.069 ug/mL). Nearly all AEs related to study drugs were mild or moderate in severity; one grade 3 direct bilirubin increase occurred and was deemed possibly related to DRV/c and INH and probably related to RPT.
Study Conclusions
DRV exposures were decreased with 3HP coadministration vs. DRV alone. Multiple trough concentrations fell below the DRV EC50. Temporal relationships between 3HP coadministration and the extent of induction or mixed inhibition/induction of DRV metabolism were apparent. Coadministration of DRV/c with 3HP should be avoided.
References
Brooks KM, et al.. Pk & safety of darunavir/cobicistat with once-weekly isoniazid/rifapentine. Conference On Retroviruses And Opportunistic Infections. . G01; 2022.
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