Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants.
Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants.
复制标题
DOI：
10.1002/cpt.1990
复制
发表时间：
2021-01
影响因子：
6.7
通讯作者：
Pharmaceuticals for Children Act - Pediatric Trials Network Steering Committee
中科院分区：
文献类型：
--
作者：
Salerno SN;Edginton A;Gerhart JG;Laughon MM;Ambalavanan N;Sokol GM;Hornik CD;Stewart D;Mills M;Martz K;Gonzalez D;Pharmaceuticals for Children Act - Pediatric Trials Network Steering Committee
当临床DDI数据有限时，基于生理的药代动力学（PBPK）模型可以潜在地预测儿科药物-药物相互作用（DDI）。对于指征治疗肺动脉高压和预防或治疗侵袭性念珠菌病的婴儿，可同时给予西地那非和氟康唑。为了解释细胞色素P450 (CYP) 3A的发育变化，我们测定了氟康唑对CYP3A4、CYP3A5和CYP3A7的抑制常数（KI），并将其纳入西地那非及其活性代谢物n -去甲基西地那非的PBPK模型。采用西地那非联合氟康唑和不联合氟康唑治疗早产儿的药代动力学（PK）数据进行模型开发和评价。模拟的PK参数与观测值相当。在氟康唑联合给药后，观察虚拟成人和婴儿在0 - 24小时（aucs,0 - 24）血浆浓度与时间曲线下模拟稳态面积的折数变化差异（2.11倍vs 2.82倍变化）。当与氟康唑治疗剂量（每日12 mg/kg静脉注射）联合使用时，将西地那非剂量减少约60%，导致模拟auss的几何平均比率为1.01，相对于单独服用西地那非的虚拟婴儿为0-24。本研究强调了PBPK模型预测婴儿ddi的可行性，以及纳入CYP3A7参数的必要性。
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.
登录
查看更多内容
影响因子：
3.1
作者：
Claassen, Karina;Thelen, Kirstin;Willmann, Stefan
通讯作者：
Willmann, Stefan
影响因子：
4.5
作者：
Maharaj AR;Gonzalez D;Cohen-Wolkowiez M;Hornik CP;Edginton AN
通讯作者：
Edginton AN
影响因子：
3.9
作者：
Ku, Hei-Young;Ahn, Hee-Jeong;Liu, Kwang-Hyeon
通讯作者：
Liu, Kwang-Hyeon
影响因子：
3.4
作者：
Nichols, DJ;Muirhead, GJ;Harness, JA
通讯作者：
Harness, JA
影响因子：
3.9
作者：
Meyer, Michaela;Schneckener, Sebastian;Lippert, Joerg
通讯作者：
Lippert, Joerg