Abstract
Physiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. In infants for whom treatment of pulmonary hypertension and prevention or treatment of invasive candidiasis are indicated, sildenafil with fluconazole may be given concurrently. To account for developmental changes in cytochrome P450 (CYP) 3A, we determined and incorporated fluconazole inhibition constants (KI) for CYP3A4, CYP3A5, and CYP3A7 into a PBPK model developed for sildenafil and its active metabolite, N-desmethylsildenafil. Pharmacokinetic (PK) data in preterm infants receiving sildenafil with and without fluconazole were used for model development and evaluation. The simulated PK parameters were comparable to observed values. Following fluconazole co-administration, differences in the fold change for simulated steady-state area under the plasma concentration vs. time curve from 0 to 24 hours (AUCss,0–24) were observed between virtual adults and infants (2.11-fold vs. 2.82-fold change). When given in combination with treatment doses of fluconazole (12 mg/kg i.v. daily), reducing the sildenafil dose by ~ 60% resulted in a geometric mean ratio of 1.01 for simulated AUCss,0–24 relative to virtual infants receiving sildenafil alone. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 253-262 |
| Number of pages | 10 |
| Journal | Clinical pharmacology and therapeutics |
| Volume | 109 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2021 |
Funding
This Pediatric Trials Network (PTN) study was funded under Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) contract HHSN275201000003I (Principal Investigator [PI]: Daniel K. Benjamin, Jr.). The Best Pharmaceuticals for Children Act (BPCA) Data Coordinating Center was funded under HHSN275201700002C (PI: Ravinder Anand). S.N.S. was supported by the National Institute of General Medical Sciences (NIGMS) and the NICHD of the National Institutes of Health under award T32GM086330. J.G.G. received research support from an NIGMS-funded T32 program under award T32GM122741. D.G. received research support from the NICHD (K23HD083465 and R01HD096435). M.M.L. received research support from the FDA (R01FD006099) and the National Heart, Lung, and Blood Institute (NHBLI) (K24HL143283). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A special thanks to Leonard Collins for developing the HPLC-MS/MS assay for 6?-hydroxytestosterone. The assay measuring sildenafil and DMS concentrations in the clinical PK samples was developed by Robert M. Wurm, BS, at OpAns, LLC (Durham, NC). This Pediatric Trials Network (PTN) study was funded under Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) contract HHSN275201000003I (Principal Investigator [PI]: Daniel K. Benjamin, Jr.). The Best Pharmaceuticals for Children Act (BPCA) Data Coordinating Center was funded under HHSN275201700002C (PI: Ravinder Anand). S.N.S. was supported by the National Institute of General Medical Sciences (NIGMS) and the NICHD of the National Institutes of Health under award T32GM086330. J.G.G. received research support from an NIGMS\u2010funded T32 program under award T32GM122741. D.G. received research support from the NICHD (K23HD083465 and R01HD096435). M.M.L. received research support from the FDA (R01FD006099) and the National Heart, Lung, and Blood Institute (NHBLI) (K24HL143283). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
