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Background: Fostemsavir is a prodrug of temsavir, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells. This study assessed the impact of fostemsavir on the pharmacokinetics (PK) of the opioids methadone (R-, S-, and total) or buprenorphine/norbuprenorphine when coadministered.
Methods: AI438068 was a Phase 1, open-label study in subjects on methadone maintenance therapy (40 - 120 mg QD, Part 1, N=16) or buprenorphine/naloxone maintenance therapy (8/2 - 24/6 mg QD, Part 2, N=16). HIV- and HBV-positive subjects were excluded; a positive test for HCV antibodies with documentation of anti-HCV therapy was acceptable. In Part 1, subjects received methadone on Day 1 and methadone QD with fostemsavir 600 mg BID on Days 2-9. In Part 2, subjects received buprenorphine/naloxone on Day 1 and buprenorphine/naloxone QD with fostemsavir 600 mg BID on Days 2-9. Serial blood samples were collected up to 24 hours post-dose Day 1 and Day 9. Plasma concentrations were quantified by validated LC/MS/MS methods. Geometric mean ratios (GMRs) and 90% confidence intervals (CI) were derived for dose-normalized methadone (R-, S-, total), buprenorphine and norbuprenorphine PK using linear mixed-effects models. The effect of fostemsavir was deemed clinically insignificant if the 90% CI fell within 0.70-1.43 for methadone and 0.50-2.00 for buprenorphine and norbuprenorphine. Adverse events were monitored throughout the study, including signs of withdrawal or toxicity.
Results: Methadone exposures (R-, S-, and total) increased 9-15% and buprenorphine/norbuprenorphine exposures increased 24-39% when coadministered with fostemsavir. In subjects on a stable regimen of methadone or buprenorphine/naloxone, coadministration of fostemsavir was safe and generally well tolerated with no reported symptoms of overdose or withdrawal.

AnalyteCmax GMR (90% CI)AUC(TAU) GMR (90% CI)C24 GMR (90% CI)
R-methadone1.15 (1.11, 1.20)1.13 (1.07, 1.19)1.09 (1.01, 1.17)
S-methadone1.15 (1.10, 1.19)1.15 (1.09, 1.21)1.10 (1.02, 1.19)
total methadone1.15 (1.11, 1.19)1.14 (1.09, 1.20)1.10 (1.02, 1.18)
buprenorphine1.24 (1.06, 1.46)1.30 (1.17, 1.45)1.39 (1.18, 1.63)
norpbuprenorphine1.24 (1.03, 1.51)1.39 (1.16, 1.67)1.36 (1.10, 1.69)
[Cmax, AUC(TAU), and C24 GMR (90% CI)]


Conclusions: Methadone and buprenorphine may be coadministered with fostemsavir without dose adjustment. Consistent with recommendations for other antiretrovirals, monitoring for clinical signs of sedation with buprenorphine may be warranted.

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