Miyazaki Taichi, Hayashi Daichi, Nozawa Akifumi, Yasue Shiho, Endo Saori, Ohnishi Hidenori, Asada Ryuta, Kato Mototoshi, Fujino Akihiro, Kuroda Tatsuo, Maekawa Takanobu, Fumino Shigehisa, Kawakubo Naonori, Tajiri Tatsuro, Shimizu Kenji, Sanada Chihiro, Hamada Izumi, Ishikawa Yuko, Hasegawa Mayumi, Patel Kashyap, Xie Yehua, Ozeki Michio
Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
Innovative and Clinical Research Promotion Center, Gifu University Hospital, Gifu, Japan.
Drug Metab Pharmacokinet. 2024 Dec;59:101024. doi: 10.1016/j.dmpk.2024.101024. Epub 2024 May 31.
A population pharmacokinetic (PopPK) analysis was conducted using data from 215 Japanese administered oral sirolimus (tablet and granule) including healthy subjects and patients with intractable vascular anomalies and other diseases. The analysis included neonates, infants, and adults, and identified covariates that influence sirolimus pharmacokinetics (PK). The final model was used to predict sirolimus trough concentrations for various dosing regimens and covariates of interest. The results showed that sirolimus trough concentrations were predicted to increase with higher levels of hemoglobin, and that the granule formulation had a 1.23-fold higher exposure than the tablet formulation. Coadministration of CYP3A4 inducers was found to decrease trough concentrations by 54 %. The PK simulations showed that administration of the granule formulation at doses of 0.02, 0.04, 0.06, and 0.08 mg/kg/day in ages <3 months, 3 to <6 months, 6 to <12 months, and ≥1 year, respectively, resulted in >70 % target attainment within the therapeutic trough concentration range (5-15 ng/mL). In conclusion, incorporation of time-varying covariates (body weight and age) into the PopPK model appropriately predicted sirolimus concentrations in Japanese subjects from infants to adult sub-populations. This PopPK model would therefore be able to provide a reference for clinical individualization of sirolimus dosing.
利用215名接受口服西罗莫司（片剂和颗粒剂）的日本受试者（包括健康受试者以及患有难治性血管异常和其他疾病的患者）的数据进行了群体药代动力学（PopPK）分析。该分析纳入了新生儿、婴儿和成人，并确定了影响西罗莫司药代动力学（PK）的协变量。最终模型用于预测各种给药方案和感兴趣的协变量下的西罗莫司谷浓度。结果显示，预测西罗莫司谷浓度会随着血红蛋白水平升高而增加，且颗粒剂配方的暴露量比片剂配方高1.23倍。发现联合使用CYP3A4诱导剂会使谷浓度降低54%。PK模拟表明，分别在年龄<3个月、3至<6个月、6至<12个月和≥1岁的受试者中，以0.02、0.04、0.06和0.08mg/kg/天的剂量给予颗粒剂配方，在治疗谷浓度范围（5 - 15ng/mL）内实现目标浓度的比例>70%。总之，将时变协变量（体重和年龄）纳入PopPK模型可适当预测日本从婴儿到成人亚群体中西罗莫司的浓度。因此，该PopPK模型能够为西罗莫司给药的临床个体化提供参考。
