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, M. M., Smith, P., Ge, S., Ambalavanan, N., Atz, A., Sokol, G. M., Hornik, C. D., Stewart, D., Mundakel, G., Poindexter, B. B., Gaedigk, R., Mills, M., Cohen-Wolkowiez, M., Martz, K., Hornik, C. P., . Population pharmacokinetics of sildenafil in extremely premature infants. British journal of clinical pharmacology 85, 2824-2837 (2019).