Population pharmacokinetics of sildenafil in extremely premature infants.
AIMS: To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants.
METHODS: We performed a multicentre, open-label trial to characterize the PK 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 population PK 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 presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration 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.
British journal of clinical pharmacology
Administration, Oral; Cohort Studies; Cytochrome P-450 CYP3A; Fluconazole; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Intravenous; Models, Biological; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
pharmacokinetics; premature infants; sildenafil
Gonzalez D, Laughon MM, Smith PB, et al. Population pharmacokinetics of sildenafil in extremely premature infants. Br J Clin Pharmacol. 2019;85(12):2824-2837. doi:10.1111/bcp.14111