Population pharmacokinetics of sildenafil in extremely premature infants
09/2019
Journal Article
Authors:
Gonzalez, D.;
Laughon, M. M.;
Smith, P. B.;
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.
Volume:
85
Pagination:
2824-2837
Issue:
12
Journal:
Br J Clin Pharmacol
PMID:
31475367
URL:
https://www.ncbi.nlm.nih.gov/pubmed/31475367
Keywords:
Administration, Oral
Cohort Studies
Cytochrome P-450 CYP3A/blood/genetics
Fluconazole/administration & dosage/pharmacokinetics
Gestational Age
Humans
Hypertension, Pulmonary/blood/drug therapy
Infant
Infant, Newborn
Infant, Premature/*blood
Infant, Premature, Diseases/blood/drug therapy
Injections, Intravenous
*Models, Biological
Phosphodiesterase 5 Inhibitors/administration & dosage/blood/*pharmacokinetics/therapeutic use
Sildenafil Citrate/administration & dosage/blood/*pharmacokinetics/therapeutic
Abstract:
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(R). 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.
