Population Pharmacokinetics of Sildenafil in Extremely Premature Infants.
AIMS: To characterize the population pharmacokinetics (PopPK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants. METHODS: We performed a multi-center, open-label trial to characterize the pharmacokinetics (PKs) of sildenafil in infants ≤28 weeks gestation and <365 postnatal days (cohort 1) or <32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a PopPK analysis and dose-exposure simulations using the software NONMEM®. RESULTS: We enrolled 34 infants (cohort 1 n=25; cohort 2 n=9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with pre-systemic conversion of sildenafil to DMS, characterized the data well. Co-administration of fluconazole (n=4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5, and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro. CONCLUSIONS: We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study.
Gonzalez, D; Laughon, MM; Smith, PB; Ge, S; Ambalavanan, N; Atz, A; Sokol, GM; Hornik, CD; Stewart, D; Mundakel, G; Poindexter, BB; Gaedigk, R; Mills, M; Cohen-Wolkowiez, M; Martz, K; Hornik, CP; Best Pharmaceuticals for Children Act - Pediatric Trials Network Steering Committee,
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