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Avoid CYP, P-gp, UGT Inducers With HIV Capsid Inhibitor Lenacapavir
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CROI 2021, Conference on Retroviruses and
Opportunistic Infections, March 6-10, 2021
Mark Mascolini
Initial drug-drug interaction studies in healthy volunteers indicate that the unique anti-HIV drug lenacapavir should not be given with strong UGT1A1 inhibitors or with potent inducers of CYP, P-gp, or UGT [1]. Strong inhibitors of CYP3A and P-gp boost lenacapavir levels, Gilead Sciences researchers found, but not enough to require dose adjustments.
Lenacapavir inhibits HIV replication by disrupting unraveling of the capsid sheath that protects HIV RNA once the virus invades a cell. The novel antiretroviral also thwarts production of new virus on the cell surface and fouls up assembly of the protective capsid after newly formed HIV emerges from infected cells. Formerly called GS-6207, lenacapavir may be suitable for every-6-month subcutaneous dosing [2]. A phase 1b trial determined that resistance to lenacapavir is rare and provoked by a single mutation [3]. Gilead is currently developing this novel agent as part of a long-acting antiretroviral regimen.
A standard facet of every drug-development program, drug-drug interaction studies aim to tell which other agents will affect concentrations of the study drug-and how the study drug will affect other agents-according to which metabolizing enzymes and transporters the drugs use.
Toward those ends, Gilead researchers tested lenacapavir with strong inhibitors of CYP3A (voriconazole 400 mg twice daily), CYP3A and P-gp (darunavir 800 mg once daily, cobicistat 150 mg once daily), and CYP3A, P-gp, and UGT1A1 (atazanavir 300 mg once daily, cobicistat). Healthy volunteers took these probe drugs until they reached steady-state concentrations, then they added lenacapavir. Thirty people took voriconazole plus 300 mg of lenacapavir, 30 took darunavir/cobicistat plus lenacapavir, 30 took only cobicistat plus lenacapavir, and 30 took atazanavir/cobicistat plus lenacapavir. Another 30 people took 300 mg of lenacapavir alone once.
Strong CYP3A and P-gp inhibition with darunavir/cobicistat doubled lenacapavir exposure (area under the concentration-time curve, AUC). The research team considered that change not clinically relevant and proposed that lenacapavir can be given at the standard dose with strong CYP3A and P-gp inhibitors like darunavir/cobicistat. Lenacapavir AUC rose 30% with only strong CYP3A inhibition (voriconazole), 130% with CYP3A and P-gp inhibition (cobicistat), and 300% with CYP3A, P-gp, and UGT inhibition (atazanavir/cobicistat). The Gilead team classified the last of those three interactions as "moderate."
In the next part of the study, 25 participants each took 300 mg of lenacapavir alone or with a strong inducer of CYP3A, P-gp, and UGT (rifampin 600 mg once daily), a moderate inducer of CYP3A, P-gp, and UGT (efavirenz 600 mg once daily), and a single 40-mg dose of famotidine, the H2 blocker used to treat ulcers and gastroesophageal reflux.
Rifampin cut lenacapavir exposure (AUC) 85%, a finding leading the researchers to advise avoiding giving lenacapavir and strong inducers like rifampin together. Taking a single dose of famotidine 2 hours before lenacapavir "dramatically" boosted gastric pH. Results of the efavirenz-lenacapavir interaction study are pending.
In the third part of this analysis volunteers took pitavastatin 2 mg on day 1, rosuvastatin 5 mg on day 4, tenofovir alafenamide (TAF) 25 mg on day 7, and midazolam 2.5 mg on day 10. In that order, these drugs are sensitive substrates of OATP, BCRP and OATP, P-gp, and CYP3A. On day 11, participants started lenacapavir 600 mg twice daily for 2 days, then every 3 days. While taking lenacapavir, volunteers took pitavastatin on day 15, rosuvastatin on day 18, TAF on day 21, and midazolam on day 24.
Lenacapavir proved a moderate inhibitor of CYP3A, approximately tripling midazolam AUC. In comparison, lenacapavir bumped up TAF AUC 1.5-fold, rosuvastatin AUC 1.3-fold, and pitavastatin AUC 1.1-fold. The researchers advised caution when giving lenacapavir with sensitive CYP3A substrates like midazolam. The interactions of lenacapavir with TAF, rosuvastatin, and pitavastatin indicate that lenacapavir can be given with drugs that are sensitive substrates of P-gp, BCRP, or OATP.
The Gilead team stated it main conclusions like this:
- Without additional data, lenacapavir should not be given with strong UGT1A1 inhibitors.
- Potent inducers of CYP, P-gp, or UGT should be avoided with lenacapavir.
- Caution is in order when giving lenacapavir with sensitive CYP3A substrates, but not with substrates of P-gp, BCRP, or OATP.
- No dose adjustment is needed when giving lenacapavir with strong inhibitors of CYP3A or P-gp.
- Lenacapavir can be given with gastric acid reducers.
References
1. Begley R, Lutz J, Dvory-Sobol H, et al. Clinical evaluation of drug interactions with oral lenacapavir and probe drugs. CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021. Abstract 89.
2. Pharmaphorum.com. Data sets up 2021 filings for Gilead’s twice-a-year HIV drug lenacapavir. November 19, 2020.
https://pharmaphorum.com/news/data-sets-up-2021-filings-for-gileads-twice-a-year-hiv-drug-lenacapavir/
3. Mascolini M. Lenacapavir resistance analysis in a phase 1b clinical proof-of-concept study: Resistance to HIV capsid inhibitor rare and linked to single mutation. HIV Drug Therapy/Glasgow 2020, October 5-8, 2020. https://www.natap.org/2020/GLASGOW/GLASGOW_56.htm
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