Lorraine D. Ralph1,2, Alison H. Thomson1,3, Nicola A. Dobbs4, Chris Twelves5
1Div of Cardiovascular & Medical Sciences, University of Glasgow, UK, 2Quintiles Ltd, Heriot-Watt University Science Park, Riccarton, Edinburgh, UK, 3Pharmacy Dept, Western Infirmary, Glasgow, UK. 4Cancer Research UK, London, UK. 5Cancer Research UK, Dept of Medical Oncology, University of Glasgow, UK.
Introduction: Epirubicin is a cytotoxic anthracycline that is active against a wide range of tumours, including early or advanced breast cancer. A limited sampling approach to estimate the pharmacokinetics of epirubicin could be useful to aid the design of future studies or for use in adaptive feedback control and dosage individualisation.
Methods: The data set comprised 105 patients with advanced or metastatic breast cancer treated with single-agent epirubicin. Epirubicin was administered as a slow bolus injection and a mean of 12 blood samples per patient were collected. The pharmacokinetics of epirubicin were described using a 3-compartment model with proportional residual error. Optimal sampling times were identified by D-optimality using ADAPTII and used to propose 10 limited sampling designs. The data set was truncated to include the sampling times for each of the designs and Bayesian estimates of CL were obtained using NONMEM. CL estimates from each limited sampling design were compared to CL estimates obtained using all the data. A data set of 200 patients was simulated to assess the sensitivity of the best limited sampling designs to errors of up to 20 % in the recording of sample times.
Results: The optimum sampling times were: end of the infusion and 18 min, 40 min, 3 h, 10 h and 48 h post-start of the infusion. The best 3-sample design included samples at 40 min, 3 h and 48 h and gave estimates of CL that were unbiased and had an imprecision of 9.1 %. The best 2-sample design included samples at 3 and 48 h and produced unbiased estimates of CL with an imprecision of 12.4 %. Poor estimates of CL were obtained if a 48 h or 24 h sample was not included. Simulations that included errors of up to 20 % in the recording of the blood sampling times had negligible effects on the bias and imprecision of CL estimates.
Conclusion: Limited sampling designs have been identified that can estimate epirubicin CL with adequate precision and bias from 2 or 3 blood samples. These designs were flexible for blood sample collection times and are robust with regard to sample time recording errors.
Reference: PAGE 12 (2003) Abstr 381 [www.page-meeting.org/?abstract=381]
Poster: poster