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Clinical Trial
. 2017 Sep 22;61(10):e00487-17.
doi: 10.1128/AAC.00487-17. Print 2017 Oct.

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

S L Ford  1 , K Sutton  2 , Y Lou  3 , Z Zhang  3 , A Tenorio  2 , C Trezza  2 , P Patel  2 , W Spreen  4
Affiliations
Clinical Trial

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

S L Ford et al. Antimicrob Agents Chemother. .

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.).

Keywords: HIV-1; cabotegravir; drug-drug interactions; integrase strand transfer inhibitors; pharmacokinetics; rifampin.

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Figures

FIG 1
FIG 1
CAB concentration in plasma-time profiles following administration with and without RIF. Concentration values are means ± SD. CAB, cabotegravir; RIF, rifampin.
FIG 2
FIG 2
Study design. All subjects received the same study medication throughout the trial. Both CAB 30 mg and RIF 600 mg were administered to subjects on day 21. CAB, cabotegravir; QD, once daily; RIF, rifampin.
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