Fostemsavir versus Buprenorphine
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Study Design
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.
Study Results
Methadone exposures (R-, S-, and total) increased 9-15% and buprenorphine/ norbuprenorphine exposures increased 24-39% when coadministered with fostemsavir.
R-methadone Cmax GMR, AUC GMR and C24 GMR were 1.15 (1.11, 1.20), 1.13 (1.07, 1.19), and 1.09 (1.01, 1.17) respectively. S-methadone Cmax GMR, AUC GMR and C24 GMR were 1.15 (1.10, 1.19), 1.15 (1.09, 1.21), and 1.10 (1.02, 1.19) respectively. Total methadone Cmax, AUC and C24 were 1.15 (1.11, 1.19), 1.14 (1.09, 1.20), and 1.10 (1.02, 1.18) respectively. Buprenorphine Cmax, AUC and C24 were 1.24 (1.06, 1.46), 1.30 (1.17, 1.45), and 1.39 (1.18, 1.63) respectively. And Norbuprenorphine Cmax, AUC and C24 were 1.24 (1.03, 1.51), 1.39 (1.16, 1.67), and 1.36 (1.10, 1.69) respectively. 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.
Study 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.
References
Sevinsky H, Magee M, Ackerman P, Chang M, Lubin S, Myers E. The effect of fostemsavir on methadone and buprenorphine pharmacokinetics. International Aids Society Conference On Hiv Science. Paris, France. 9; July 2017.
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