Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents

Abstract

Due to variation in drug distribution, metabolism and elimination processes between patients, systemic exposure to chemotherapeutic agents may be highly variable from patient to patient after administration of similar doses. This pharmacokinetic variability may explain in part the large variability in therapeutic response seen in patients receiving chemotherapy. Patients receiving high exposures of a chemotherapeutic agent may show a better response to therapy but are also at higher risk for toxicity, while patients with lower exposures may have a reduced therapeutic response but also a lower risk of experiencing side-effects. The optimal exposure in a patient results in an adequate therapeutic response with low risk of adverse effects. Relationships between systemic exposure and toxic or therapeutic effects have been demonstrated for several anticancer drugs. These relationships may be used to optimize the administration of chemotherapeutic agents applying pharmacokinetically guided dosing (PKGD). However, measurement of plasma drug levels for dosing are not regularly performed with these agents. This thesis deals with PKGD of the four chemotherapeutic agents cyclophosphamide, thiotepa, carboplatin (as administered in the high-dose CTC regimen) and paclitaxel. To be able to implement this dosing strategy in clinical practice, we firstly worked on a fast and robust bioanalytical method for the quantification of cyclophosphamide and thiotepa and their relevant active metabolites using HPLC-MS/MS. Furthermore, we performed extensive population pharmacokinetic analysis to accurately describe the time-course of cyclophosphamide (and multiple metabolites), thiotepa (and its metabolite tepa), carboplatin and paclitaxel concentrations in plasma using non-linear regression methods. These models formed the basis for the Bayesian dosing strategy we applied for the PKGD strategy. Factors influencing the pharmacokinetic profile of cyclophosphamide, thiotepa and carboplatin were also established: Co-medicated agents such as phenytoin and aprepitant, as well as serum creatinine levels and obesity appeared to influence the pharmacokinetics of cyclophosphamide, thiotepa and/or carboplatin. Moreover, we established relationships between toxicity (irreversible alopecia and veno-occlusive disease of the liver (VOD)) and exposure to cyclophosphamide, thiotepa and carboplatin (or metabolites), which stress the importance of pharmacokinetically guided dosing in the CTC regimen in reducing or preventing the occurrence of these toxicities. Finally, pharmacokinetically guided dosing strategies for cyclophosphamide, thiotepa, carboplatin and paclitaxel were developed and validated in a prospective manner. In the CTC scheme, a total of 46 patients received adapted doses of cyclophosphamide, thiotepa and carboplatin based on their individual pharmacokinetic profile. A total of 25 patients with non-small cell lung cancer received multiple individualized paclitaxel administrations. The studies proved that the pharmacokinetically guided dosing strategy results in an effective reduction of interindividual variability in exposure to the compounds or their metabolites and is feasible in clinical practice. Whether the dosing strategy also results in reduction of toxicity and/or improvement of therapeutic outcome remains to be determined from larger studies, preferably in a randomized setting. In conclusion, a very significant therapeutic gain may be achievable by individualized dosing of chemotherapeutic agents to produce a uniformly high, effective yet safe drug exposure in each patient.