Leukopenia following triple high-dose chemotherapy and stem cell rescue
V. Nock (1,2), A. Lindauer (3), U. Jaehde (3), C. Kloft (1)
(1) Dept. Clinical Pharmacy, Martin-Luther-Universitaet Halle-Wittenberg/Freie Universitaet Berlin, Germany (2) and Graduate Research Training Program PharMetrX (3) Dept. Clinical Pharmacy, University of Bonn, Bonn, Germany
Objectives: Myelosuppression is one of the most important dose-limiting adverse events in many anticancer regimens. In a clinical study 17 patients received a combination therapy of carboplatin (C), etoposide (E) and thiotepa (T) including a stem cell rescue consisting of peripheral blood stem cell retransfusion (PBSCT) and G-CSF treatment. The current data analysis describes the leukopenic effect of all drugs in this combination regimen following a population PK/PD modelling approach.
Methods: Population PK models for 17 patients receiving CET doses up to 1500, 2400 and 750 mg/m² body surface area, respectively, were developed. In addition, data on PBSCT on day 7 were available for 17 patients as well as information on granulocyte colony stimulating factor (G-CSF) treatment for 16. Individual PK profiles for all drugs were estimated and integrated into a PD model for myelosuppression [1] assuming an additive effect of the drugs (SLOPE) on the proliferation rate of the cells in the bone marrow. The leukopenic potency of each drug in the triple regimen was investigated. Modelling and simulation activities were performed using NONMEMTM VI (ADVAN 6, FOCE+I), statistical analyses using R 2.10.
Results: PK parameter estimates for all drugs were in accordance with previous published ones [2,3,4]. The leucocyte-time course exhibited an initial increase in leukocyte count probably due to dexamethasone administration [5] during the first few days. After the nadir was reached a steep increase in counts followed by a pronounced rebound after G-CSF administration was observed. C was estimated to have the highest influence (SLOPE=0.13 L/µmol, RSE: 35.4%) on the proliferation of progenitor cells, showing a 6.5-fold higher drug effect than E (SLOPE=0.02 L/µmol, RSE: 56.8%). Compared to the other drugs T exhibited negligible toxicity, keeping in mind that its active metabolite tepa was not taken into account.
Conclusions: Based on the successful integration of the generated individual PK profiles of the drugs in the PD model for leukopenia discrimination between the drug effect size of C, E, and T was possible. Estimation of the PD parameters was precise. First results suggest an improvement of the model by integration of the stem cell rescue in order to better describe this dose-limiting toxicity and guide future chemotherapy.
References:
[1] LE Friberg et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 20: 4713-21 (2002)
[2] A Lindauer et al. Population pharmacokinetics of high-dose carboplatin in children and adults. Ther Drug Monit 32: 159-68 (2010)
[3] B You et al. Etoposide pharmacokinetics and survival in patients with small cell lung cancer: A multicenter study. J Lungcancer 62: 261-272 (2008)
[4] A Huitema et al. Population pharmacokinetics of thioTEPA and its active metabolite TEPA in patients undergoing high-dose chemotherapy. Br J Clin Pharmacol 51: 61-70 (2001)
[5] B Jilma et al. Glucocorticoids Dose-Dependently Increase Plasma Levels of Granulocyte Colony Stimulating Factor in Man. J Clin Endocrinol Metab 83: 1037-1040 (1998)
