Pharmacokinetically guided dose escalation of carboplatin in epithelial ovarian cancer: Effect on drug-plasma AUC and peripheral blood drug-DNA adduct levels

Background: Platinum based drugs are active agents in epithelial ovarian ca ncer and increased platinum drug dose intensity is thought to lead to impro ved survival, because of the largely untested assumption that increased dos e intensity results in an increased interaction of the platinum drug with i ts target, DNA. In a previously reported phase I trial (Lind et al., J Clin Oncol 1996; 14: 800-5), carboplatin dose intensity was increased by the us e of G-CSF to support the bone marrow and using pharmacokinetically-guided carboplatin dosing. The objectives of this study were to validate the carbo platin dosing formula during high dose intensity therapy and evaluate the r elationship between systemic carboplatin exposure and Pt-DNA adduct levels in peripheral blood leucocytes. Patients and methods: A total of 17 patients were studied over four levels of dose intensification. The carboplatin dose was calculated using the 'Cal vert formula'. Levels of drug-target interaction in peripheral blood leukoc ytes were measured using an immunoassay based on a monoclonal antibody that recognises DNA-platinum adducts. Pharmacokinetic measurements were carried out using a previously validated single sample method. Results: The area under the curve of concentration of unbound carboplatin i n plasma versus time (AUC) for target AUC values of 5, 7 and 9 mg/ml.min we re: 5.6 +/- 1.0, 7.3 +/- 0.7 and 9.8 +/- 0.5 mg/ml.min (mean +/- S.D.). The re was a good correlation between target and achieved dose intensities (r(2 ) = 0.899) and the slope of the linear regression line was 0.95 (+/- 0.09 S D) not significantly different to 1.0 (P > 0.6). The levels of immunoreacti ve DNA adducts were not detectable at a target AUC of 5 mg/ml.min but incre ased progressively at the higher AUC levels. Accumulation of adducts betwee n courses was not detected. Conclusions: Pharmacokinetically-based carboplatin dosing during high inten sity therapy accurately predicted the dose required to achieve a target AUC and resulted in consistent patient exposure to active drug. During the dos e escalation study, peripheral blood leucocyte DNA platinum-DNA adduct leve ls were positively related to drug dose and drug AUC.