Fostemsavir + Darunavir/Ritonavir = Precautionary

Study Design

This was an open-label, single sequence, multiple dose, three-cohort study in 42 healthy subjects (n=14 per cohort) to analyze the drug-drug interactions between fostemsavir (formerly BMS 663068, prodrug for temsavir) and boosted darunavir (DRV) and/or etravirine (ETR).Dosing in each cohort was on days 1-4, 7-16 and 17-26, with a 2-day washout on day 5 and 6. Treatment was as follows:Cohort 1: Fostemsavir 600mg BID on days 1-4, then DRV/ritonavir 600mg/100mg BID on days 7-16, followed by fostemsavir + DRV/r on days 17-26.Cohort 2: Fostemsavir 600mg BID on days 1-4, then ETR 200mg BID on days 7-16, followed by fostemsavir + ETR on days 17-26.Cohort 3: Fostemsavir 600mg BID on days 1-4, then DRV/r+ETR on days 7-16, followed by fostemsavir + DRV/r + ETR on days 17-26.Geometric mean ratios and 90% confidence intervals were calculated against predefined no effects limits of 0.75 - 1.7 for ETR and DRV, and 0.80 - 1.25 for fostemsavir use.

Study Results

Treatment and comparison (n)PK parameter, adjusted geometric meansCmax ratioAUCtau ratioC12 ratioFostemsavir + DRV/r vs Fostemsavir(Cohort 1)1.52(1.28-1.82)1.63(1.42-1.88)1.88(1.09-3.22)Fostemsavir + ETR vs Fostemsavir(Cohort 2)0.52(0.45-0.59)0.50(0.44-0.57)0.48(0.32-0.72)Fostemsavir + DRV/r + ETR vs Fostemsavir(Cohort 3)1.53(1.32-1.77)1.34(1.17-1.53)1.33(0.98-1.81)ETR decreased the Cmax, AUCtau and C12 each by ~50%, consistent with CYP3A induction by ETR. Compared to fostemsavir alone, co-administration of fostemsavir, DRV/r and ETR resulted in increased Cmax, AUCtau and C12 by 53%, 34% and 33%, respectively, of fostemsavir. Co-administration of fostemsavir and DRV/r resulted in increased Cmax, AUCtau and C12 by 52%, 63% and 88%, respectively. There was minimal PK effect on DRV/r, ETR and DRV/r + ETR, changes were within the predefined no-effect limits. The authors state that fostemsavir can be co-administered with DRV/r or DRV/r + ETR without dose adjustment. Monitoring is recommended. Co-administration of fostemsavir and ETR (without DRV/r) is not recommended.

Study Conclusions

References

Landry IS, X Tao, J Anderson, et al. Hiv-1 attachment inhibitor prodrug bms-663068: interactions with drv/r and/or etr. Conference On Retroviruses And Opportunistic Infections. Seattle, WA. ; 2015.