Population pharmacokinetics of doxorubicin, etoposide and ifosfamide in small cell lung cancer patients: results of a multicentre study

Aims To determine the population pharmacokinetic (PK) parameters of doxorub icin (Dox), etoposide (Eto) and ifosfamide (Ifo) in small cell lung cancer (SCLC) patients, to assess the potential relationship between those paramet ers and to estimate the impact of individual morphological and biological c ovariates on patients' PK parameters. Methods Twenty-four patients with either SCLC limited to the thorax or exte nsive SCLC entered the study. All but one received at least two 3 day cours es of the standard AVI (Dox 50 mg m(-2) day 1, Eto 120 mg m(-2) day 1,2,3, Ifo 2000 mg m(-2) day 1,2) regimen. Individual blood samples were collected during each course and data on 47 courses were available. Data were analys ed with the NONMEM program. Dox, Eto and Ifo plasma concentrations were stu died with multicompartment (3, 2 and 2, respectively) models. Inter-individ ual and interoccasion (course-to-course) variabilities were estimated. The influence of individual covariates (age, sex, stage of the disease, weight, height, body-surface area, serum creatinine, total protein, LDH, ASAT, ALA T, alkaline phosphatase, gamma-GT, bilirubin) on PK parameters was also ass essed. Correlations between individual PK parameters of Dox, Eto and Ifo we re explored by using Pearson's correlation coefficient. Results Multiple data were available for each patient. Dox clearance (CL) a nd volume of distribution (V-d) were 32.0 l h(-1) and 9.3 l (Inter-individu al variability: 17.2% and 19.2%). Eto CL (l h(-1)) and V-d were, respective ly, 3.34-0.0083* serum creatinine (mu mol l(-1)) and 6.38 l (interindividua l variability: 15.6% and 18.7%). Ifo CL and V-d at day 1 were 5.6 l h(-1) a nd 26.0 l (interindividual variability: 10.1% and 17.2%, respectively). Est imation of course-to-course variability improved the precision of PK models in some cases. No correlation was observed between the respective PK param eters of each drug. Of individual covariates tested, only serum creatinine correlated with Eto CL (r = -0.37, P < 0.001). Self-induction of the metabo lism of Ifo was apparent (mean CL increase from day 1 to day 2 : 42%) and i ndividually correlated with the CL value at day 1 (r = -0.61, P < 0.001). Conclusions Assessment of potential relationships between individual system ic exposure of chemotherapy and therapeutic endpoints (tumour response, tox icity and survival) will be required to adjust drugs dosages based on indiv idual PK parameters rather than questionable body-surface area. However, al l three drugs in the AVI regimen should be monitored simultaneously.