Twice-Daily Doravirine Overcomes the Interaction Effect from Once-Weekly Rifapentine and Isoniazid in Healthy Volunteers

Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1. Its use in combination with rifapentine (RPT), an antituberculosis (TB) antibiotic, may reduce the exposure of DOR compromising viral suppression in those living with HIV-1 co-infected with TB. We conducted a prospective, phase I, open label, two-period, fixed sequence, drug interaction study to evaluate the effect of once-weekly RPT and isoniazid (INH) on the pharmacokinetics (PKs) of DOR in healthy volunteers. DOR 100 mg was administered alone twice-daily for 4 days in period 1. In period 2, once-weekly RPT + INH were co-administered with multiple doses of DOR 100 mg twice-daily for study days 7, 14, and 21. Plasma was obtained for DOR PKs when given alone and co-administered with RPT + INH. Eleven healthy volunteers enrolled and completed the study. The geometric mean ratios and 90% confidence intervals for DOR area under the concentration-time curve from zero to 12 hours (AUC ) and C in the presence of RPT + INH compared with DOR alone were 0.71 (0.60-0.85) and 0.69 (0.54-0.89), respectively. Although exposures were moderately reduced in the presence of RPT + INH, trough DOR values were within the concentration range associated with virological suppression. These results demonstrate that a modest decrease in DOR exposure would unlikely be clinically relevant in a virally suppressed patient co-administered once-weekly RPT + INH.