No oral cabotegravir dose adjustment expected with rifabutin
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.
References
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
Source:
NATAP
