Drug Metabolism and Pharmacokinetics最新文献

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Population pharmacokinetic analysis of sirolimus in Japanese pediatric and adult subjects receiving tablet or granule formulations 西罗莫司在接受片剂或颗粒剂治疗的日本儿童和成人受试者中的群体药代动力学分析。

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics

Pub Date : 2024-05-31 DOI: 10.1016/j.dmpk.2024.101024

Taichi Miyazaki , Daichi Hayashi , Akifumi Nozawa , Shiho Yasue , Saori Endo , Hidenori Ohnishi , Ryuta Asada , Mototoshi Kato , Akihiro Fujino , Tatsuo Kuroda , Takanobu Maekawa , Shigehisa Fumino , Naonori Kawakubo , Tatsuro Tajiri , Kenji Shimizu , Chihiro Sanada , Izumi Hamada , Yuko Ishikawa , Mayumi Hasegawa , Kashyap Patel , Michio Ozeki

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 名日本人口服西罗莫司（片剂和颗粒剂）的数据进行了群体药代动力学（PopPK）分析，其中包括健康受试者和患有难治性血管异常和其他疾病的患者。该分析包括新生儿、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。最终模型用于预测不同给药方案和相关协变量下的西罗莫司谷浓度。结果表明，西罗莫司的谷浓度会随着血红蛋白水平的升高而增加，颗粒剂的暴露量是片剂的 1.23 倍。同时服用 CYP3A4 诱导剂会使谷浓度降低 54%。PK 模拟显示，按 0.02、0.04、0.06 和 0.08 毫克/千克/天的剂量服用颗粒制剂，70% 的年龄组可达到治疗谷浓度范围（5-15 毫微克/毫升）内的目标值。总之，在 PopPK 模型中加入随时间变化的协变量（体重和年龄）可适当预测日本受试者从婴儿到成人亚群的西罗莫司浓度。因此，该PopPK模型可为西罗莫司的临床个体化用药提供参考。

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