Population Pharmacokinetic Parameters of Doxorubicin, Ifosamide and Etoposide in Small Cell Lung Cancer Patients
Gilles Freyer(1), Brigitte Tranchand(2), Blandine Ligneau(1), Claude Ardiet(2), Pierre-Jean Souquet(3), Isabelle Court-Fortune(3), Robert Riou(3), Paul Rebattu(4), Véronique Trillet-Lenoir(1,6), Jean-Pierre Boissel(5,6), Pascal Girard(5,6).
(1)Medical Oncology Unit, Centre Hospitalier Lyon-Sud, Pierre-Bénite.(2)Pharmacology Unit, Centre Léon Bérard , Lyon.(3) Lyon-Saint Etienne Thoracic Oncology Group (GLOT). (4)Department of Medicine, Centre Léon Bérard, Lyon. (5) Pharmacology Unit, Hôpital Louis Pradel, Lyon.(6). DRED EA 643, Lyon, France.
Purpose: (i) To determine the population pharmacokinetic (PK) parameters of Doxorubicin (Dox), Etoposide (Eto) and Ifosfamide (Ifo) in small cell lung cancer (SCLC) patients; (ii) to assess the potential relationship between those parameters;(iii) to estimate the impact of individual morphological and biological covariates on patients? PK parameters and (iv) to study the potential prognostic value of PK parameters on patients? overall survival.
Patients and methods: Twenty-four patients with either limited to the thorax or extensive SCLC entered the study. All but one received at least two courses of the 3 day-AVI (Dox 50 mg/m² day 1, Eto 120 mg/m² day 1,2,3, Ifo 2500 mg/m² day 1,2) regimen. Individual blood samples were collected at each course and data on 47 courses were available. Data were analyzed with the Non Linear Mixed Effect Model (NONMEM) program. Dox, Eto and Ifo plasma concentrations were studied with multi-compartment (3, 2 and 2, respectively) models. Inter-individual and inter-occasion (course-to-course) variability was estimated. The impact of individual covariates (Age, Sex, Stage of the disease, Weight, Height, Body-Surface Area, Serum Creatinine, Total Protidemia, LDH, ASAT, ALAT, Alkaline Phosphatase, Gamma-GT, Bilirubin) on PK parameters was also assessed. Correlations between individual PK parameters of Dox, Eto and Ifo were explored by using Pearson?s correlation coefficient. Exploratory analyses were performed to determine the possible impact of PK parameters on tumor response and patients?survival.
Results: Exhaustive data were available in each patient. Doxo Clearance (Cl) and Volume of Distribution (Vd) were 54.3 l/h and 11.8 l (Inter-individual variability : 17.2% and 19.2%). Eto Cl and Vd were 2.53 l/h and 5.39 l (Inter-individual variability : 20.4% and 15.2%). Ifo Cl and Vd were 6.42 l/h and 27.8 l (Inter-individual variability : 37% and 26.8%). Course-to-course variability was much lower than inter-individual variability. No correlation was observed between the respective PK parameters of each drug. Since individual covariates were tested, only Serum Creatinine correlated with Eto Cl and Vd. Self-induction of the metabolism of Ifosfamide and hence Cl increase from day 1 to day 2 (21.9%) was apparent. The percentage of Cl increase at day 2 correlated with Cl value at day 1 (r= - 0.61, p<0.001).Trends on PK-PD relationships will be presented at the meeting.
Conclusion: Assessment of potential relationships between individual systemic exposure of chemotherapy and therapeutic endpoints (tumor response, toxicity and survival) will be required to adjust drugs dosages to individual PK parameters rather than questionable Body-Surface Area. In this case the 3 component drugs of the AVI regimen should be monitored simultaneously.