Physiologically‐Based Pharmacokinetic Modeling Characterizes the CYP3A‐Mediated Drug‐Drug Interaction Between Fluconazole and Sildenafil in Infants

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 (K I) 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 (AUC ss,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 AUC ss,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. If an investigational drug is suspected to interact with concomitant medications, drug-drug interaction (DDI) studies are performed in healthy adult volunteers during drug development and are communicated in the product label. 1 For ethical reasons, pediatric DDI studies are rarely conducted unless children receive the drugs per standard of care. There are also logistic challenges

Characterization of fluorescent probe substrates to develop an efficient high-throughput assay for neonatal hepatic CYP3A7 inhibition screening

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Inhibition of drug-metabolizing enzymes by Qingfei Paidu decoction: Implication of herb-drug interactions in COVID-19 pharmacotherapy

“…P450 inhibition experiments were carried out in 200 μL reaction mixtures, which included potassium phosphate buffer (PBS, 100 mM, pH 7.4), each P450 substrate, NADPH-generating system (10 mM G-6-P, 1.0 unit/mL G-6-PDH, 1.0 mM β-NADP + and 4.0 mM MgCl 2 , HLMs or RLMs, along with inhibitor ( Li et al, 2020b ; Santori et al, 2020 ; Salerno et al, 2020 ; Fang et al, 2020 ; Zhang et al, 2020b ). Each P450 substrate and the details of P450 reactions are shown in Table S2 .…”

Pediatric Drug‐Drug Interaction Evaluation: Drug, Patient Population, and Methodological Considerations

“…However, the number of examples of the use of PBPK modeling for pediatric DDI assessment is limited. Although a few recent reports have used PBPK modeling to predict an eDDI in children, 63–66 only 1 article considered a target population younger than 2 years of age 65 . As of now, the use of PBPK modeling in pediatric regulatory submissions has primarily focused on initial dose finding for clinical trials, especially in younger children, those younger than 2 years of age 67 .…”