Solid Tumors Clinical Trial
Official title:
Target Dosing of Docetaxel Through Pharmacokinetic/Pharmacodynamic Optimisation of the First Chemotherapeutic Cycle
Primary Objective
1. To develop a pharmacokinetic-pharmacodynamic (PD) model for optimisation of docetaxel
dosing
Secondary Objectives
1. To establish an exposure-toxicity (neutropenia) relationship for docetaxel
2. To determine the exposure breakpoint for docetaxel toxicity based on a neutropenia PD
model
3. To identify demographic, pathophysiological and/or phenotypic covariates predicting
docetaxel clearance
4. To prospectively validate this PK-PD model for optimisation of docetaxel dosage and
determination PK variability and toxicity
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.
;
Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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