Population pharmacokinetic parameter estimation to assess the impact of dose on etoposide pharmacokinetics
Reif S. (1), Kloft C. (1), Jetter A. (2), Fuhr U. (2), Siegert W. (3), McLeod H. (4), Schunack W. (1), Jaehde U. (1,5)
(1) Dept. Clinical Pharmacy, Institute of Pharmacy, Freie Universitaet Berlin; (2) Institute of Pharmacology, Universitaet zu Koeln; (3) Dept. Hematology and Oncology, Charité Virchow Hospital, Humboldt-Universitaet zu Berlin; (4) Dept. Medicine & Therapeutics, Institute of Medical Sciences, University of Aberdeen; (5) Dept. Clinical Pharmacy, Institute of Pharmacy, Universitaet Bonn
Objectives: To perform a population pharmacokinetic study in order to evaluate the effect of dose and various patient specific factors on pharmacokinetic parameters of etoposide in a heterogeneous patient population.
Methods: Patients suffering from different types of tumors were treated with etoposide at the following dosage levels administered as a 1 h intravenous infusion: (1) 50 mg (absolute dose), (2) 100 mg/m², (3) 200 mg/m², (4) 400 mg/m², and (5) 600 mg/m². Serial blood samples were drawn (2-6 per patient) up to 24 h after the end of infusion and etoposide was quantified in plasma by HPLC. Pharmacokinetic data analysis was performed using P-Pharm™. A two-compartment model was assumed for pharmacokinetic parameter estimation. The influence of potential individual predictors including etoposide dose on pharmacokinetic parameters of etoposide was assessed by using multiple linear regression models.
Results: Up to now, 57 patients were included in a preliminary population pharmacokinetic study. Mean estimates and their coefficients of variation (CV%) of the primary population pharmacokinetic parameters clearance (CL), volume of distribution in the central compartment (Vc), and the distribution rate constants k12 and k21 were (with covariates) 40.2 mL/min (13.6%), 11.3 L (13.3%), 0.08 1/h (24.5%), and 0.23 1/h (22.4%), respectively. CL was shown to significantly increase with increasing serum creatinine clearance, whereas Vc was positively correlated with body surface area and etoposide dose. 42% and 76% of the interindividual variability of CL and Vc, respectively, were explained by including these covariates in the population pharmacokinetic model.
Conclusions: First results suggest a significant influence of etoposide dose on Vc but not on etoposide CL. Studies are ongoing to refine the population pharmacokinetic model that might be useful in dosage individualization