PI-019 - LOW POTENTIAL FOR DRUG INTERACTION BETWEEN LENACAPAVIR AND FENTANYL.

H. Sun¹, H. Le¹, S. Salerno¹, B. Murray¹; ¹Gilead Sciences, CA, USA.

Background: Fentanyl is considered a sensitive CYP3A substrate based on prior studies of its metabolism via CYP3A-mediated oxidation to norfentanyl. Subcutaneous (SC) lenacapavir (LEN) is a promising option for HIV prevention. High-dose oral LEN was classified as a moderate CYP3A inhibitor after coadministration with oral midazolam, a sensitive CYP3A substrate. Therefore, an effect of SC LEN on intravenous (IV) fentanyl pharmacokinetics (PK) might be expected. We evaluated the potential for SC LEN to affect IV fentanyl metabolism and PK, and risk of respiratory depression.

Methods: We examined human fentanyl metabolism at submicromolar concentrations, and the drug–drug interaction (DDI) potential for IV fentanyl with SC LEN in vitro. High-resolution mass spectrometry was used to identify fentanyl metabolites in hepatocytes, subcellular fractions, and recombinant enzymes; enzyme-selective inhibitors were used to determine enzymology. The fractional contribution of enzymes to fentanyl elimination in vivo was calculated using an extension to the mechanistic static DDI model. The effect of SC LEN on CYP3A was estimated via separation of the effects of oral LEN on midazolam DDI and scaling of the systemic component expected after SC LEN administration. PK–pharmacodynamic relationships with respiratory depression were evaluated.

Results: We identified 17 fentanyl metabolites, including a direct glucuronide (by UGT1A4) and hydrolysis product 4ANPP (by CES2). CYP3A enzymes were responsible for an estimated 60% of hepatic fentanyl metabolism. Weak effects (exposure ratios ≤ 1.3) of selective potent CYP3A inhibitors on fentanyl PK were reconciled through consideration of its high hepatic extraction, making it resistant to changes in metabolic rate in vivo. Based on the effects of high-dose oral LEN on oral midazolam PK, a weak interaction between SC LEN and IV fentanyl is predicted. LEN-induced changes in fentanyl PK are considered unlikely to exacerbate respiratory depression.

Conclusion: Fentanyl elimination is more diverse than previously recognized; with its high hepatic extraction, this may explain the modest clinical interactions of fentanyl with potent CYP3A inhibitors. These data support low interaction potential between SC LEN and fentanyl. Future work will focus on developing a physiologically based PK model to validate these findings.