Population pharmacokinetics of sildenafil in extremely premature infants

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.

Keywords: pharmacokinetics; premature infants; sildenafil.

Conflict of interest statement

D.G. receives support for research from the NICHD (5K23HD083465 and 1R01HD096435). M.M.L. receives support from the US government for work in paediatric pharmacology and trials (Food and Drug Administration R01FD005101, PI: Laughon; NHLBI 1R34HL124038, PI: Laughon; NICHD Pediatric Trials Network Government Contract HHSN267200700051C, PI: Benjamin). M.C‐W. receives support for research from the National Institutes of Health (1R01‐HD076676‐01A1), the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001117), the National Institute of Allergy and Infectious Diseases (HHSN272201500006I and HHSN272201300017I), NICHD (HHSN275201000003I), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), the nonprofit organization Thrasher Research Fund (http://www.thrasherresearch.org), and from industry for drug development in adults and children (http://www.dcri.duke.edu/research/coi.jsp). C.P.H. receives salary support for research from the NICHD (5K23HD090239), the US government for his work in paediatric and neonatal clinical pharmacology (Government Contract HHSN267200700051C, PI: Benjamin, under the Best Pharmaceuticals for Children Act), and industry for drug development in children. The remaining authors have nothing to disclose.

© 2019 The British Pharmacological Society.

Figures

Figure 1

Final population pharmacokinetic model schematic for sildenafil (SIL) and its metabolite N‐desmethyl sildenafil (DMS). To incorporate presystemic conversion of SIL to DMS, simultaneous enteral SIL and equimolar DMS dosing (scaled by the relative metabolite bioavailability) was assumed.24 KA: SIL first‐order absorption rate constant; FSIL: SIL bioavailability; FDMS: relative DMS bioavailability; CL: SIL clearance (assuming complete conversion to DMS); VSIL,C: SIL central compartment volume of distribution; KA,DMS: DMS first‐order absorption rate constant; CLDMS/Fmet,DMS: DMS clearance; Fmet,DMS: fraction of SIL metabolized to DMS; Q: SIL intercompartmental clearance; and IV: intravenous

Figure 2

Sildenafil and N‐desmethyl sildenafil (DMS) plasma concentration vs time since first study dose data stratified by cohort and route of administration. Infants in cohort 1 had six standard of care sildenafil doses reported before any study doses. Cohort 2 infants received a single dose

Figure 3

Sildenafil and N‐desmethyl sildenafil (DMS) observed vs population (A) and individual (B) predictions for the final population pharmacokinetic model. Triangles and cross symbols represent enteral and intravenous administration, respectively. The solid black line represents the line of unity. The dashed line represents the linear regression fit

Figure 4

Prediction‐corrected visual predictive check for sildenafil and N‐desmethyl sildenafil (DMS) observations vs time after last dose, stratified by route of administration, and generated using the final population pharmacokinetic model. The dashed lines represent the 5th, 50th and 95th percentiles of the observed data. The solid lines represent the 5th, 50th and 95th percentiles of the predicted data. The shaded region represents the 90% confidence interval of the 5th, 50th and 95th percentiles of the predicted data. IV: intravenous

Figure 5

Simulated sildenafil concentrations over 192 h following multiple intravenous (IV; A–C) or enteral (D–F) doses of sildenafil administered every 8 hours. Pink and teal shaded regions represent the 95% prediction intervals for virtual infants with and without fluconazole, respectively. Dashed and solid lines represent 2.5th, 50th and 97.5th percentiles for virtual infants with and without fluconazole, respectively. The black lines represent the 50th (median) percentile

Figure 6

Box plots of simulated steady‐state maximum sildenafil concentrations (Cmax) following intravenous (IV; A, C) or enteral (B, D) doses of sildenafil administered every 8 h in virtual infants with (C, D) and without (A, B) fluconazole. The bottom and top of the box are the 25th and 75th percentile and the band in the middle of the box is the 50th percentile. The length of the box is the interquartile range (IQR). Upper whisker = 75th percentile +1.5 × IQR; lower whisker = 25th percentile – 1.5 × IQR. Dashed lines denote concentrations of 47, 140 and 373 ng/mL that are expected to correlate with unbound concentrations found to inhibit type 5 phosphodiesterase activity in vitro by approximately 53, 77 and 90%, respectively18