E Chatelut(1,2), V Brunner(1), C Chevreau(1), A Pujol(1), H Roché(1), V Paschel(1), G Houin(2), R Bugat(1,2), P Canal(1)
(1) Centre Claudius Regaud and (2) Université Paul Sabatier, 31052 Toulouse, France
Carboplatin, a nonnephrotoxic but myelosuppressive antineoplastic analog of cisplatin, is an alternative for patients who cannot tolerate cisplatin toxicity. For carboplatin, the area under the plasma ultrafilterable (uf) concentration versus time curve (AUC) correlates well with hematologic toxicity and therapeutic outcome. Since renal glomerular filtration accounts for the majority of the plasma clearance of uf carboplatin, Calvert et al [J Clin Oncol 7:1748, 1989] proposed a simple dosing equation to achieve a target AUC for each patient using a determination of his glomerular filtration rate (GFR) by injection of 51Cr-EDTA. However its ambulatory use is limited due to the isotopic determination of the GFR. Moreover the measurement of the creatinine clearance, based on urine collection, remains questionable and the numerous mathematical equations and nomograms proposed to predict the creatinine clearances do not predict accurately the uf plasma clearance of carboplatin (CL).
We conducted a population pharmacokinetic study (46 cycles, 6 blood samples per cycle) in 34 patients (M/F 23/11) treated with different combination regimens including carboplatin at doses ranging from 180 to 655 mg (1 hr iv infusion) for various tumor types. The patient characteristics were : age from 24 to 82 (median 62), and serum creatinine levels from 64 to 356 µM. Plasma uf platinum levels were determined by flameless atomic absorption spectrophotometry. Data were analysed using Nonlinear Mixed Effects Model (NONMEM) according to a two compartment linear mammillary model. A constant coefficient of variation model was used for the residual and the inter-individual variabilities. The effect of the following co-variables on CL were investigated: age, sex, height, weight (WT), body surface area, serum creatinine, serum proteins, serum albumin, cisplatin pretreatment.
The interpatient variability was large: CL ranged from 2.3 to 11.7 l/hr. CL (l/hr) was found to be best predicted by the formula:
0.00802*WT + (13.1 *WT *(1 – 0.00457 *AGE) *(1 – 0.314 * SEX))/creatinine (µM)
with WT in kg, age in years, and sex = 0 if male and sex = 1 if female.
The calculated CL according to this formula was closely correlated to the observed CL: CLcalc = 0.87 * CLobs + 0.50 ; r=0.93, p<0.00001. The percentage of error [(calculated CL – observed CL/observed CL) x100] ranged between -28.4 and 26.7% (mean: -4.2% ± 3.4% with 95% confidence interval) .
The first part of the formula corresponds to the non-renal elimination which is mainly due to the covalent protein binding of carboplatin. The second part corresponds to the renal elimination : as it has been shown by Cokcroft and Gault [Nephron 16:31, 1976], WT, sex, and age must be taken into account with the creatinine level to predict the GFR. This formula is currently evaluated in a prospective study and should allow to individualize very easily the carboplatin dose in adult.
Reference: PAGE 3 (1994) Abstr 874 [www.page-meeting.org/?abstract=874]
Poster: oral presentation