Fostemsavir interaction study flags strong CYP3A inducers, statins, oral contraceptives

18 October 2019. Related: Conference reports, PK and drug interactions.

Mark Mascolini, natap.org

Fostemsavir, an HIV attachment inhibitor now being studied for heavily pretreated people, has few meaningful interactions with other antiretrovirals or with medications commonly used for HIV-related comorbidities. [1]

There are four exceptions: dose adjustments are recommended for most statins and for ethinyl estradiol-based hormonal therapies, such as oral contraceptives. Strong CYP3A inducers, such as rifampin, will be contraindicated with fostemsavir, as will the dual-drug elbasvir/grazoprevir for HCV.

Now in a phase 3 trial combined with other antiretrovirals [2], fostemsavir binds to HIV gp120 near the CD4 binding site and thus blocks HIV attachment to the CD4 receptor on T cells. Fostemsavir is an oral prodrug of temsavir, which is metabolised primarily by an esterase-mediated hydrolysis pathway and partly via a CYP3A4-medicated oxidative pathway. ViiV Healthcare researchers and collaborators collected data from 11 drug-drug interaction studies to inform potential use of fostemsavir with other antiretrovirals and with drugs frequently used by people with HIV infection.

This analysis determined that strong CYP3A inducers like rifampin, as well as the anti-HCV combination agent elbasvir/grazoprevir, are contraindicated with fostemsavir. Because temsavir is partly metabolized by CYP3A4, strong CYP3A inducers significantly lower temsavir plasma concentrations and may impair virologic response to fostemsavir. Temsavir inhibits the transporter OATP1B1/3, and that could lead to higher grazoprevir concentrations and thus to elevated liver enzymes

Dose modifications may be needed when fostemsavir gets taken with three groups of agents:

1. Estrogen-based therapies such as oral contraceptives (ethinyl estradiol dose should be at or below 30 ug).
2. Statins (temsavir inhibits OATP1B1/3 and BCRP and thus affects pharmacokinetics of certain statins; use lowest possible starting statin dose, monitor for adverse events such as myopathy, and limit daily doses of certain statins, such as rosuvastatin </= 20 mg).
3. Drugs that prolong QT interval (use fostemsavir with caution with drugs that pose a risk of torsades de pointes, in people with pre-existing cardiac disease, or in older patients).

Analysed data indicate that no dose adjustment will be needed when fostemsavir is taken with other drugs frequently used by people with HIV:

1. Drugs that increase gastric pH, such as famotidine.
2. Strong CYP3A inhibitors, such as ritonavir and cobicistat.
3. Moderate CYP3A inducers, such as rifabutin and etravirine.
4. Other antiretrovirals including nucleosides, nonnucleosides, protease inhibitors, integrase inhibitors, CCR5 antagonists, or entry inhibitors including the monoclonal antibody ibalizumab, which is licensed for people with multidrug-resistant HIV.
5. Opioid-dependence therapies such as methadone and buprenorphine.

References

1. Moore KP et al. Fostemsavir drug-drug interaction profile, an attachment inhibitor and oral prodrug of temsavir, for heavily treatment experienced HIV-1 infected patients. IDWeek, October 2-6, 2019, Washington, DC. Abstract 2500.
   http://natap.org/2019/IDWeek/IDWeek_30.htm (natap report)
   
2. ClinicalTrials.gov. Attachment inhibitor comparison in heavily treatment experienced patients. ClinicalTrials.gov identifier NCT02362503.