Effect of Rifampin on the Single-Dose Pharmacokinetics of Oral Cabotegravir in Healthy Subjects

Abstract

Drug-drug interactions between antiretroviral medications and rifampin complicate the treatment of HIV and tuberculosis coinfection. This study evaluated the effect of rifampin on the pharmacokinetics of oral cabotegravir, an integrase strand transfer inhibitor being investigated for long-acting treatment and prevention of HIV-1 infection. This was a phase I, single-center, open-label, fixed-sequence crossover study in healthy adults. The objective was to evaluate the effect of steady-state rifampin on the single-dose plasma pharmacokinetics of cabotegravir. Subjects received a single oral dose of cabotegravir (30 mg) on day 1 followed by plasma sampling on days 1 to 8. Treatment with once-daily oral rifampin (600 mg) occurred on days 8 to 28. Subjects received a second dose of 30 mg cabotegravir on day 21 followed by pharmacokinetic sampling on days 21 to 28. Fifteen subjects were enrolled and completed the study. Rifampin decreased the cabotegravir area under the concentration-time curve from 0 h to infinity and the half-life by 59% and 57%, respectively, whereas oral clearance was increased 2.4-fold. The maximum concentration of cabotegravir in plasma was unaffected by coadministration with rifampin. All adverse events were mild in severity, with chromaturia attributed to rifampin observed in all subjects. Rifampin induction of cabotegravir metabolism resulted in increased cabotegravir oral clearance and significantly decreased cabotegravir exposures. Rifampin is expected to increase cabotegravir clearance following long-acting injectable administration. Concomitant administration of rifampin with oral and long-acting formulations of cabotegravir is not recommended currently without further study. (This study has been registered at ClinicalTrials.gov under registration no. NCT02411435.)

Single-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites Alone and in Combination with Gemfibrozil, Itraconazole, or Rifampin in Healthy Subjects: A Randomized, Parallel-Group, Open-Label Study

“…Chromaturia, reported in three subjects in group E (rifampin ? ozanimod), is a well-documented and benign side effect of rifampin [14,15]. S1P receptor modulators may cause a transient decrease in heart rate (HR) and AV conduction delays upon initiation of dosing [16].…”

Pharmacokinetic and pharmacodynamic considerations of rifamycin antibiotics for the treatment of tuberculosis

“…It can also be used with efavirenz without dose modifications and with raltegravir or dolutegravir, provided the integrase inhibitor dose is doubled to twice daily. Rifampicin reduces cabotegravir and bictegravir concentrations significantly, more work is needed to determine whether or not these DDI can be overcome with dose modifications [18]. Rifampicin and rifapentine reduce exposure to almost all known protease inhibitors and co-administration is not recommended, with the exception of lopinavir/ritonavir, where the use of double doses can be considered, with close monitoring, in settings where rifabutin is not available [19,20].…”

Effect of a High‐Fat Meal on the Pharmacokinetics of the HIV Integrase Inhibitor Cabotegravir

“…Cabotegravir had no significant effect on the pharmacokinetics (PK) of midazolam, a sensitive cytochrome P450 3A4 probe substrate, a levonorgestrel/ethinyl estradiol–containing oral contraceptive, or the nonnucleoside reverse‐transcriptase inhibitor rilpivirine . Rifampin significantly reduced cabotegravir exposures, therefore, potent enzyme inducers should not be coadministered with cabotegravir …”

“…8,10,11 Rifampin significantly reduced cabotegravir exposures, therefore, potent enzyme inducers should not be coadministered with cabotegravir. 12 Single-dose oral cabotegravir 30 mg is readily absorbed with a median time to peak plasma concentration (t max ) of 2 hours and has a plasma apparent terminal-phase half-life (t 1/2 ) of approximately 38.5 hours under fasted conditions and an area under the concentration-time curve from time 0 to infinity (AUC 0-Ý ) of 146 μg•h/mL. 12,13 Previous studies demonstrated that a moderate-fat meal (30% fat, ß670 calories) did not significantly affect the PK of cabotegravir administered at 10-and 30-mg doses, respectively, using early prototype formulations (Supplemental Data).…”

“…12 Single-dose oral cabotegravir 30 mg is readily absorbed with a median time to peak plasma concentration (t max ) of 2 hours and has a plasma apparent terminal-phase half-life (t 1/2 ) of approximately 38.5 hours under fasted conditions and an area under the concentration-time curve from time 0 to infinity (AUC 0-Ý ) of 146 μg•h/mL. 12,13 Previous studies demonstrated that a moderate-fat meal (30% fat, ß670 calories) did not significantly affect the PK of cabotegravir administered at 10-and 30-mg doses, respectively, using early prototype formulations (Supplemental Data). Furthermore, the time to maximal drug concentration (t max ) and half-life of cabotegravir 30 mg given with a moderate-fat meal were a median of 3.0 hours (range, 1.0-6.0) and a geometric mean of 38.6 hours (95% confidence interval, 35.0-42.7), respectively (Supplemental Data).…”