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  19th International Workshop on
Clinical Pharmacology of Antiviral Therapy
May 22, 2018
Baltimore, USA | Baltimore Marriott Inner Harbor
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No oral cabotegravir dose adjustment expected with rifabutin
  19th International Workshop on Clinical Pharmacology of Antiviral Therapy
Mark Mascolini
Coadministered rifabutin modestly lowered plasma levels of oral cabotegravir and left cabotegravir troughs above those that maintain viral suppression with a 10-mg oral dose [1]. Simulations will be done to estimate the impact of rifabutin on long-acting injected cabotegravir.
Trials are testing long-acting injected cabotegravir after an oral dose lead-in for HIV treatment (in combination with rilpivirine) and prevention (as monotherapy) [2]. Because HIV/TB coinfection prevalence remains high in many populations, people taking cabotegravir may simultaneously take the antimycobacterial rifabutin. Cabotegravir metabolism depends mainly on UGT1A1 and partly on UGT1A9. Rifabutin is a moderate UGT inducer and so could lower levels of cabotegravir. Significant interactions limit coadministration of cabotegravir and rifampin, another mycobacterial agent [3].
GlaxoSmithKline researchers and colleagues conducted this phase 1 study in healthy adults to evaluate the impact of rifabutin on pharmacokinetics of oral cabotegravir in a two-period fixed-sequence design. In period 1 participants received 30 mg of cabotegravir once daily for 14 days. In period 2 they continued cabotegravir with 300 mg of rifabutin once daily for another 14 days. Geometric least squares mean (GLSM) ratios compared cabotegravir levels at day 14 (cabotegravir alone) and day 28 (with rifabutin).
Twelve of 15 male volunteers completed all treatments. Fourteen men were white and 1 Asian. Age averaged 43.7 years and weight 83.8 kg.
GLSM ratios (and 90% confidence intervals) showed lower cabotegravir exposure when taken with rifabutin versus alone:
-- Area under the concentration-time curve: GLSM ratio 0.79 (0.74 to 0.83)
-- Maximum concentration: GLSM ratio 0.83 (0.76 to 0.90)
-- Trough concentration: GLSM ratio 0.74 (0.70 to 0.78)
Cabotegravir clearance was faster with than without rifabutin (GLSM ratio 1.27, 90% CI 1.20 to 1.38).
The researchers detected no drug-related adverse events during treatment with cabotegravir alone. Three weeks after combined cabotegravir/rifabutin treatment ended, 1 participant had a drug-related grade 3 adverse event, elevated alanine aminotransferase. All adverse events resolved during follow-up.
The investigators concluded that rifabutin modestly reduced oral cabotegravir exposure, but concentrations remained above those linked to durable HIV suppression in a phase 2 trial [4]. They proposed that rifabutin and oral cabotegravir can be given together without dose adjustment.
1. Ford S, Lou Y, Lewis N, D'Amico R, Spreen W, Patel P. Rifabutin (RBT) decreases cabotegravir (CAB) exposure following oral co-administration. 19th International Workshop on Clinical Pharmacology of Antiviral Therapy. May 22-24, 2018. Baltimore. Abstract 12.
2. Stellbrink HJ, Hoffmann C. Cabotegravir: its potential for antiretroviral therapy and preexposure prophylaxis. Curr Opin HIV AIDS. 2018 May 8. doi 10.1097/COH.0000000000000480. https://www.ncbi.nlm.nih.gov/pubmed/29746267
3. Ford SL, Sutton K, Lou Y, et al. Effect of rifampin on the single-dose pharmacokinetics of oral cabotegravir in healthy subjects. Antimicrob Agents Chemother. 2017;61(10)pii: e00487-17. http://aac.asm.org/content/61/10/e00487-17.long
4. Margolis DA, Brinson CC, Smith GHR, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015;15:1145-1155. https://www.ncbi.nlm.nih.gov/pubmed/26201299