Target Dosing of Docetaxel Through Pharmacokinetic/Pharmacodynamic Optimisation of the First Chemotherapeutic Cycle

Rationale

Poor tolerance of standard docetaxel dosage regimens used as a single agent in Asians has been clearly demonstrated by our group in 2 separate studies. Neutropenia emerged as the most prominent manifestation of chemotherapy toxicity [12, 20]. While this has been attributed to the lower docetaxel CL derived in our Asian patients, an optimal dosage regimen taking into account the extensive genetic polymorphisms associated with CYP3A4 has yet to be established. The use of ketoconazole as a potent CYP3A4 modulator to reduce pharmacokinetic variability of docetaxel did show >2-fold reduction in docetaxel dosage, but inter-individual variability in CL was not significantly reduced. There was also poor correlation of docetaxel CL to midazolam phenotyping of CYP3A4 with the addition of ketoconazole to the regimen [23]. Since the use of an additional modulator failed to achieve the desired reduction in pharmacokinetic variability, the idea of using low-dose docetaxel to predict its own pharmacokinetic parameters appeared feasible, safe and an appealing approach.

The more acute toxicities of docetaxel, such as neutropenia, stomatitis, neurological toxicities and fluid retention are more frequently associated with the 3 weekly than weekly dosing schedule. This study is designed so that the less toxic weekly schedule is used for PK/PD correlation. This information would be utilized to derive an optimal dosage for the 3 weekly regimen that follows since cumulative myelosuppression was not observed with previous weekly docetaxel for metastatic breast cancer [31].

Currently patients with impaired liver function manifested by elevated baseline ALT/AST more than 1.5 more than the institutional limits of normal are not treated with the recommended dose of docetaxel because of impaired clearance of docetaxel. Theoretically, these patients may benefit from docetaxel treatment, but the dose will need to be individualized based on hepatic drug clearance to avoid toxicity. To determine the clinical usefulness of our strategy of predicting docetaxel clearance and individualised dosing based on clearance and a PD model, patients with a certain extent of liver dysfunction will be included into the study. They will be divided into 3 groups according to the level of AST/ALT and SAP, total bilirubin, and initial weekly doses as well as q3weekly doses will be lower than the recommended doses for patients with normal liver function. Previous investigators have reported the feasibility of using the erythromycin breath test as an in vivo probe for CYP3A activity and docetaxel clearance in patients with liver dysfunction (Baker SD et al Evaluation of CYP3A activity as a predictor covariate for docetaxel clearance Proceedings of ASCO 2004; 128: 2006abs).

2.4 Hypothesis

The hypothesis for this study is that PK/PD guided dosing of docetaxel will reduce the variability in docetaxel PK while achieving the maximum exposure desired within acceptable limits of toxicity. At this juncture, this is a novel approach in oncology to fully exploit the potential of using low-dose docetaxel as its own probe drug to individualise and optimise dosage for subsequent chemotherapy treatment without having to use other agents to modulate or predict drug metabolism and clearance.