Enhancement of the Oral Availability of Cabazitaxel Using the Cytochrome P450 3A (CYP3A) Inhibitor Ritonavir in Mice

CYP3A型 利托那韦 卡巴齐塔塞尔 药理学 最大值 药代动力学 CYP3A4型 生物利用度 化学 口服 细胞色素P450 医学 内科学 新陈代谢 生物化学 免疫学 前列腺癌 雄激素剥夺疗法 人类免疫缺陷病毒(HIV) 癌症 抗逆转录病毒疗法 病毒载量
作者
Nancy H.C. Loos,Margarida L.F. Martins,Daniëlle de Jong,Maria C. Lebre,Matthijs M. Tibben,Jos H. Beijnen,Alfred H. Schinkel
出处
期刊:Molecular Pharmaceutics [American Chemical Society]
卷期号:20 (5): 2477-2489
标识
DOI:10.1021/acs.molpharmaceut.2c01076
摘要

There is currently great interest in developing oral taxanes due to their lower costs and greater patient friendliness. We here wanted to test whether oral ritonavir, a cytochrome P450 3A (CYP3A) inhibitor, could boost the pharmacokinetics and tissue distribution of orally administered cabazitaxel (10 mg/kg) in male wild-type, Cyp3a-/-, and Cyp3aXAV (transgenic overexpression of human CYP3A4 in liver and intestine) mice. Ritonavir was initially administered at a dose of 25 mg/kg, but lower dosages of 10 and 1 mg/kg were also studied to assess the remaining amount of boosting, aiming to minimize possible side effects. Compared to the respective vehicle groups, plasma exposure of cabazitaxel (AUC0-24h) was enhanced 2.9-, 10.9-, and 13.9-fold in wild-type mice and 1.4-, 10.1-, and 34.3-fold in Cyp3aXAV mice by treatment with 1, 10, and 25 mg/kg ritonavir, respectively. Upon treatment with 1, 10, and 25 mg/kg of ritonavir, the peak plasma concentration (Cmax) was increased by 1.4-, 2.3-, and 2.8-fold in wild-type mice, while it increased by 1.7-, 4.2-, and 8.0-fold in Cyp3aXAV mice, respectively. AUC0-24h and Cmax remained unchanged in Cyp3a-/-. Biotransformation of cabazitaxel to its active metabolites still took place when coadministered with ritonavir, but this process was delayed due to the Cyp3a/CYP3A4 inhibition. These data indicate that CYP3A is the primary limiting factor in the plasma exposure to cabazitaxel and that cabazitaxel oral bioavailability could be dramatically enhanced by coadministration of an effective CYP3A inhibitor such as ritonavir. These findings could be a starting point for the setup of a clinical study, which would be needed to verify the boosting of cabazitaxel by ritonavir in humans.
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