Department of Pharmacy & Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
J Clin Pharmacol. 2020 Mar;60(3):340-350. doi: 10.1002/jcph.1532. Epub 2019 Oct 9.
Oral administration of docetaxel is an attractive alternative for conventional intravenous (IV) administration. The low bioavailability of docetaxel, however, hinders the application of oral docetaxel in the clinic. The aim of the current study was to develop a population pharmacokinetic (PK) model for docetaxel and ritonavir based on the phase 1 studies and to support drug development of this combination treatment. PK data were collected from 191 patients who received IV docetaxel and different oral docetaxel formulations (drinking solution, ModraDoc001 capsule, and ModraDoc006 tablet) coadministered with ritonavir. A PK model was first developed for ritonavir. Subsequently, a semiphysiological PK model was developed for docetaxel, which incorporated the inhibition of docetaxel metabolism by ritonavir. The uninhibited intrinsic clearance of docetaxel was estimated based on data on IV docetaxel as 1980 L/h (relative standard error, 11%). Ritonavir coadministration extensively inhibited the hepatic metabolism of docetaxel to 9.3%, which resulted in up to 12-fold higher docetaxel plasma concentrations compared to oral docetaxel coadministered without ritonavir. In conclusion, a semiphysiological PK model for docetaxel and ritonavir was successfully developed. Coadministration of ritonavir resulted in increased plasma concentrations of docetaxel after administration of the oral formulations of ModraDoc. Furthermore, the oral ModraDoc formulations showed lower variability in plasma concentrations between and within patients compared to the drinking solution. Comparable exposure could be reached with the oral ModraDoc formulations compared to IV administration.
口服多西他赛是一种有吸引力的替代传统静脉注射（IV）给药的方法。然而，多西他赛的生物利用度低，限制了口服多西他赛在临床上的应用。本研究的目的是建立基于 I 期研究的多西他赛和利托那韦的群体药代动力学（PK）模型，为该联合治疗的药物开发提供支持。PK 数据来自 191 名接受 IV 多西他赛和不同口服多西他赛制剂（口服液、ModraDoc001 胶囊和 ModraDoc006 片剂）与利托那韦联合给药的患者。首先建立了利托那韦的 PK 模型。随后，建立了半生理 PK 模型来描述多西他赛，其中纳入了利托那韦对多西他赛代谢的抑制作用。基于 IV 多西他赛的数据，估计未受抑制的多西他赛内在清除率为 1980 L/h（相对标准误差，11%）。利托那韦联合给药广泛抑制多西他赛的肝代谢至 9.3%，与未联合利托那韦的口服多西他赛相比，导致多西他赛血浆浓度增加 12 倍。总之，成功建立了多西他赛和利托那韦的半生理 PK 模型。利托那韦联合给药可增加口服 ModraDoc 制剂后多西他赛的血浆浓度。此外，与口服液相比，口服 ModraDoc 制剂在患者间和患者内的血浆浓度变异性更低。与 IV 给药相比，口服 ModraDoc 制剂可达到相似的暴露量。
