Background: ISA, the active moiety of the water soluble prodrug isavuconazonium sulfate, is a novel triazole in clinical development for treatment of invasive fungal infections (caused by Aspergillus, Candida or rare moulds). ISA is a substrate and moderate inhibitor of CYP3A4. LPV/RTV are indicated for the treatment of HIV-1 and are substrates of CYP3A4. RTV is a strong inhibitor of CYP3A4 and inducer of multiple enzymes including CYP3A4. Concurrent doses of ISA and LPV/RTV could affect the PK of both drugs. We assessed the PK effects of multiple doses of ISA on LPV/RTV, and multiple doses of LPV/RTV on ISA.
Methods: This was an open-label, multiple-dose, three-arm, Phase 1 study in healthy subjects aged 18–55 years. Patients were randomized to one of three treatment arms: Arm 1: 200 mg ISA TID on Days 1–2 and 200 mg ISA QD on Days 3–13 Arm 2: LPV/RTV BID on Days 1–12 and LPV/RTV QD on Day 13 Arm 3: A combination of ISA and LPV/RTV at the same doses on the same days. Primary PK parameters were area under the concentration-time curve during the interval between consecutive doses (AUCtau) and maximum drug concentration (Cmax) at Day 13.
Results: Fifty-five patients received ≥1 dose of study drug treatment (safety analysis set) and 51 were included in the PK analysis set. Three subjects discontinued due to an AE (one in the LPV/RTV arm [diarrhea] and two in the combination arm [vomiting, nightmare]). The geometric mean ratio (GMR, %) of ISA AUCtau and Cmax for ISA + LPV/RTV vs ISA alone were 196 (90% confidence interval [CI]: 164, 235) and 174 (90% CI: 146, 208), respectively. The GMR of LPV AUCtau and Cmax for LPV/RTV + ISA vs LPV/RTV alone were 73 (90% CI: 56, 96) and 77 (90% CI: 62, 95), respectively. The GMR of RTV AUCtau and Cmax for LPV/RTV + ISA vs LPV/RTV alone were 69 (90% CI: 48, 98) and 67 (90% CI: 46, 97), respectively. A similar proportion of subjects experienced AEs across treatment groups (61% in the ISA alone arm, 74% in the LPV/RTV arm and 72% in the combination arm). Gastrointestinal AEs were more common in the combination and LPV/RTV alone arms versus the ISA alone arm (61% and 63% vs 17%, respectively).
Conclusion: Coadministration of ISA and LPV/RTV resulted in ~2-fold increase in exposure of ISA and a decrease in LPV and RTV exposure (27% and 31%, respectively).