Population Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships for Docetaxel

Abstract

The population approach has been implemented prospectively in the clinical development of docetaxel (Taxotere). Overall 640 patients were evaluable for the population PK/PD analysis. The PK analysis evidenced significant covariates explaining the inter-patient variability of docetaxel clearance and the PK/PD analysis demonstrated that the variability in clearance was a significant predictor of several safety endpoints. In patients with clinical chemistry suggestive of mild to moderate liver function impairment (SGOT and/or SGPT > 1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN), total body clearance was lowered by an average of 27%. Specific safety analyses demonstrated that these patients are at a significantly higher risk than others for the development of severe docetaxel-induced side effects. Population PK/PD data were fully integrated into the regulatory dossier and in the labeling of docetaxel worldwide. Population PK/PD models are being used to elaborate a simulation model to predict the survival of patients with non-small cell lung cancer treated with docetaxel.

OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition

“…Uptake experiments were performed with these agents in the presence or absence of rifampin as described. 39 …”

Comparison of Abiraterone Acetate and Docetaxel with Androgen Deprivation Therapy in High-risk and Metastatic Hormone-naïve Prostate Cancer: A Systematic Review and Network Meta-analysis

“…Аналогичный эффект отмечен и при сочетании с дру-гими сильными ингибиторами CYP3A4, например с ке-токоназолом -снижение клиренса доцетаксела на 40-50 %. В то же время проведение пре-и постмедикации дексаметазоном не повлияло на фармакокинетику так-сана [51]. При этом безопасность комбинации кабази-таксела с данными препаратами не оценивалась, одна-ко с учетом схожего механизма действия есть основания предполагать и схожий результат.…”

Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability

“…It has been reported that an average of 37% of obese patients undergoing bariatric surgery have NASH, which is higher than the rate observed in the general US adult population (Lazo and Clark, 2008). For both morphine and docetaxel, hepatic dysfunction is well documented to alter PK and requires dose-adjustment to avoid the occurrence of ADRs, potentially due to alteration in hepatic metabolism and transporter function (Bruno et al, 2001; Eckmann et al, 2014; Hasselström et al, 1990; Linares et al, 2009; Ozawa et al, 2008, 2009; Yoon et al, 2012). For docetaxel, several studies have attempted to assess whether doses should be adjusted based on various measures of obesity and body surface area (Griggs et al, 2012; Rudek et al, 2004; Sparreboom et al, 2007).…”