Population Pharmacokinetics of Sildenafil in Extremely Premature Infants

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2019 Sep 3

PMID 31475367

Citations 11

Authors

Daniel Gonzalez

Matthew M Laughon

P Brian Smith

Shufan Ge

Namasivayam Ambalavanan

Andrew Atz

Gregory M Sokol

Chi D Hornik

Dan Stewart

Gratias Mundakel

Brenda B Poindexter

Roger Gaedigk

Mary Mills

Michael Cohen-Wolkowiez

Karen Martz

Christoph P Hornik

Affiliations

Soon will be listed here.

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®.

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.

Citing Articles

Pharmacotherapy for Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Past, Present, and Future.

Fike C, Aschner J Pharmaceuticals (Basel). 2023; 16(4).

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Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial.

Lang J, Hornik C, Martz K, Jacangelo J, Anand R, Greenberg R Contemp Clin Trials Commun. 2022; 30:101025.

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Pulmonary vasodilator strategies in neonates with acute hypoxemic respiratory failure and pulmonary hypertension.

Cookson M, Abman S, Kinsella J, Mandell E Semin Fetal Neonatal Med. 2022; 27(4):101367.

PMID: 35688685 PMC: 10329862. DOI: 10.1016/j.siny.2022.101367.

Population pharmacokinetic analysis of sildenafil in term and preterm infants with pulmonary arterial hypertension.

Rhee S, Shin S, Oh J, Jung Y, Choi C, Kim H Sci Rep. 2022; 12(1):7393.

PMID: 35513541 PMC: 9072418. DOI: 10.1038/s41598-022-11038-6.

The Blind Spot of Pharmacology: A Scoping Review of Drug Metabolism in Prematurely Born Children.

Mork M, Traerup Andersen J, Lausten-Thomsen U, Gade C Front Pharmacol. 2022; 13:828010.

PMID: 35242037 PMC: 8886150. DOI: 10.3389/fphar.2022.828010.

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