Prediction of carboplatin clearance from standard morphological and biological patient characteristics

Abstract

Background: Hematologic toxicity of an antineoplastic drug, carboplatin, is largely dependent on its pharmacokinetics. Its therapeutic efficacy may be related to plasma drug exposure. Dosage adjustment based on isotopic determination of glomerular filtration rate has been proposed, but its ambulatory use is not yet conceivable. The dosage adjustment based on a patient's creatinine clearance relies on accurate measurement of urine volume per unit time and can be done with ease.

Purpose: A population pharmacokinetics study was undertaken to determine a relationship between carboplatin clearance and patient characteristics. A predictive formula was derived that was then prospectively evaluated, and its outcome was compared with that obtained by other methods available to predict carboplatin clearance.

Methods: Plasma carboplatin pharmacokinetics determined as ultrafilterable platinum in 70 patients (age range, 23-84 years) treated with different combination regimens that included carboplatin at doses ranging from 184 mg to 950 mg (1-hour intravenous infusion) for various tumor types. Data were analyzed using the nonlinear mixed effects model (NONMEM). The data from 34 patients (46 cycles) were utilized to derive the most predictive formula. The reliability of the formula was subsequently evaluated by analyzing the data obtained from 36 other patients (49 cycles).

Results: Carboplatin clearance (mL/min) was found to be best predicted by the following formula: 0.134.weight + [218.weight.(1-0.00457.age).(1-0.314.sex)]creatinine expressed in micromolar concentration (with weight in kg, age in years, and sex = 0 if male and sex = 1 if female). Prospectively, this formula predicted the carboplatin clearance with good precision (median absolute percent error of 10% [range, 0% to 30%]) and minimal bias (median percent error of 2% [range, -25% to 30%]). This method of prediction was as accurate as the one derived from the measurement of glomerular filtration rate following the injection of 51 chromium-EDTA.

Conclusion: This formula for the determination of carboplatin clearance can permit individualized determination of carboplatin dosage in adults by simply multiplying the calculated carboplatin clearance by the area under the curve for the desired dosage administration.