RALTEGRAVIR
ELVITEGRAVIR
- Action to be taken: No action needed
- Rationale:Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.
ELVITEGRAVIR
- Cytochrome P450 enzyme substrate: CYP3A
- Action to be taken: Caution and monitoring, possible dose reduction.
- Rationale:
Elvitegravir undergoes primarily oxidative metabolism via CYP3A, and is secondarily glucuronidated via UGT1A1/3 enzymes. Drugs that inhibit CYP3A activity are expected to decrease the clearance of elvitegravir and increase its serum concentration. In vitro evidence suggests that cannabis can inhibit the activity of CYP3A4 and thus increase serum concentration of drugs metabolized by that enzyme. No dose adjustment of elvitegravir is required when coadministered with ketoconazole. Concentrations of ketoconazole may increase when used concomitantly with VITEKTA in combination with protease inhibitors such as ritonavir. Careful dose titration of cannabis may be required when it is added to the combination therapy of elvitegravir and ritonavir.
- Cytochrome P450 enzyme substrate: CYP3A
- Action to be taken: Caution
- Rationale: Dolutegravir is primarily metabolized by UGT1A1 with minor contribution from CYP3A. In vitro studies have shown that, dolutegravir inhibits CYP3A4 but not any of the following cytochrome P450 enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6. However at clinically relevant concentrations neither inhibition nor induction of the aforementioned CYP enzymes was observed. In vitro evidence suggests that cannabis can inhibit the activity of CYP3A4 and thus increase serum concentration of drugs metabolized by that enzyme. Co-administration of dolutegravir and other drugs that inhibit CYP3A enzymes may increase dolutegravir plasma concentration. Darunavir and lopinavir are well known inhibitors of the CYP3A4 pathway. In a randomized, open label study Lopinavir/ritonavir did not significantly affect dolutegravir exposure; whereas darunavir/ritonavir decreased dolutegravir exposure by 11–38%. However, this reduction was not deemed clinically significant. Based on the available data and the results of drug interaction trials, drug interactions of dolutegravir and CYP3A4 substrates are unexpected.
References
- Insentress(raltegravir) package insert. Merck Sharp & Dohme Corp, Whitehouse Station, NJ 2014 -2017
- Sativex package insert. GW Pharma Ltd., Cambridge, UK. 2017
- Vitekta (elvitegravir) package insert. Gilead Sciences, Inc.Foster City, CA 2014
- Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sciences. 2007;80:1415-1419
- Pellinen, P., Honkakoski, P., Stenback, F., Niemitz, M., Alhava, E., Pelkonen, O., Lang, M. A., and Pasanen, M. Cocaine N-demethylation and the metabolism-related hepatotoxicity can be prevented by cytochrome P450 3A inhibitors. Eur.J Pharmacol 1-3-1994;270(1):35-43.
- Tivicay (dolutegravir) package insert. GlaxoSmithKline. Research Triangle Park, NC 2013
- Cottrell ML, Hadzic T, Kashuba ADM. Clinical Pharmacokinetic, Pharmacodynamic and Drug-Interaction Profile of the Integrase Inhibitor Dolutegravir. Clinical pharmacokinetics. 2013;52(11):981-994. doi:10.1007/s40262-013-0093-2.
- Song I, Min SS, Borland J, et al. The effect of lopinavir/ritonavir and darunavir/ritonavir on the HIV integrase inhibitor S/GSK1349572 in healthy participants. J Clin Pharmacol. 2011 Feb;51(2):237–242.