HTB

No clinically relevant reduction in oral cabotegravir when co-administered with rifabutin  

Polly Clayden, HIV i-Base

Rifabutin (RBT) can be given with oral cabotegravir (CAB) without dose adjustment, according to data presented at the 19th International Workshop on Clinical Pharmacology. A modest decrease in plasma CAB following long-acting (LA) administration with RBT is expected.

CAB is in development as a LA injectable formulation with an oral CAB 30 mg lead-in for treatment and prevention of HIV.

Significant interaction between oral CAB and rifampicin (RIF) limits their use together. RBT is chemically similar to RIF but considered a weaker inducer of UGTs and CYP3A. CAB is metabolised primarily by UGT1A1, with minor contribution by UGT1A9.  

This study evaluated the effect of RBT on the pharmacokinetics (PK) of oral CAB in HIV negative participants. It was phase I, single-centre, open label, two period, fixed-sequence, drug interaction study conducted by the originator manufacturer ViiV Healthcare.

Fifteen male participants with a median age of 44 years and weight of 84 kg received oral CAB 30mg once daily for 14 days and then co-administered with RBT 300mg once daily for 14 days. Twelve participants completed as planned. Serial PK sampling was performed on days 14 and 28.

Comparing CAB + RBT to CAB alone, the GLS mean ratios were: AUC0–24, Cmax, and Ctrough were 0.79 ug*h/mL (90% CI 0.74 to 0.83), 0.83 ug/mL (90% CI 0.76 to 0.90) and 0.74 ug/mL (90% CI 0.70 to 0.78), respectively.

RBT increased CAB oral clearance by 27% following repeat dose co-administration and reduced AUC0–24, Cmax, and Ctrough by 21%, 17% and 26% respectively.

Eleven participants reported 24 adverse events – most were grade 1 and occurred during CAB + RBT co-administration.

The investigators concluded that a 27% increase in clearance does not preclude co-administration of RBT + CAB LA. Simulations will inform strategies for LA regimens and alternative dosing schedules with RBT.

Reference

Ford S et al. Rifabutin
 (RBT) decreases cabotegravir (CAB) exposure following oral co-administration. 19th International Workshop on Clinical Pharmacology. Baltimore. 22–24 May 2018. Oral abstract 12.
http://regist2.virology-education.com/presentations/2018/Antiviralpk/29_patel.pdf (PDF)

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