4.6 Article

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

期刊

CLINICAL PHARMACOLOGY & THERAPEUTICS
卷 109, 期 1, 页码 253-262

出版社

WILEY
DOI: 10.1002/cpt.1990

关键词

-

资金

  1. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HHSN275201000003I]
  2. Best Pharmaceuticals for Children Act (BPCA) Data Coordinating Center [HHSN275201700002C]
  3. National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health [T32GM086330]
  4. NICHD of the National Institutes of Health [T32GM086330]
  5. NIGMS [T32GM122741]
  6. NICHD [K23HD083465, R01HD096435]
  7. FDA [R01FD006099]
  8. National Heart, Lung, and Blood Institute (NHBLI) [K24HL143283]

向作者/读者索取更多资源

This study utilized PBPK modeling to investigate the impact of sildenafil and fluconazole on pediatric pharmacokinetics, finding that reducing sildenafil dosage can mitigate DDIs in infants.
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 similar to 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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据