Daniel Gonzalez1, Matthew M Laughon2, P Brian Smith3,4, Shufan Ge1, Namasivayam Ambalavanan5, Andrew Atz6, Gregory M Sokol7, Chi D Hornik3,4,8, Dan Stewart9, Gratias Mundakel10, Brenda B Poindexter11, Roger Gaedigk12, Mary Mills4, Michael Cohen-Wolkowiez3,4, Karen Martz13, Christoph P Hornik3,4. 1. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 2. Department of Pediatrics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 3. Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA. 4. Duke Clinical Research Institute, Durham, NC, USA. 5. Division of Neonatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. 6. Department of Pediatrics, Medical University of South Carolina Children's Hospital, Charleston, SC, USA. 7. Section of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. 8. Department of Pharmacy, Duke University Medical Center, Durham, NC, USA. 9. University of Louisville Norton Children's Hospital, Louisville, KY, USA. 10. Kings County Hospital Center/SUNY Downstate Medical Center, Brooklyn, NY, USA. 11. Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 12. Department of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy-Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA. 13. Emmes Corporation, Rockville, MD, USA.
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.
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.
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