Pharmacokinetic and Pharmacodynamic Study with Lobaplatin (D-19466), a New Platinum Complex, after Bolus Administration

Abstract

Background: Lobaplatin (D-19466) is a platinum compound with greater anticancer activity in NSCLC, stomach, breast and ovarian cancer in the human tumor xeno-graft model. Preclinical studies suggested a low or absence of cross resistance to CDDP and CBDCA. Methods: During a clinical phase I trial a pharmacokinetic study was performed. The amount of platinum in plasma, plasma ultrafiltrate and urine samples was measured with atomic absorption spectometry (AAS) during a 48 hour sampling period. In total, 15 patients were studied receiving 17 treatment cycles. Pharmacokinetic parameters were determined by use of a software package TopFIT version 1.1. Toxicity data (reduction of platelets and leucocytes at the nadir) were correlated to either pharmacokinetic parameters as well as to kidney function parameters (ECC). In-vitro binding of D-19466 to plasma proteins was studied. Results: The c(t)-curves of total platinum were best described by a three compartment model. The mean residence time ranged from 5.1 to 37.8 hours in patients treated with 20 respectively 60 mg/m2. The volume of distribution was ranging from 0.64 up to 3.95 L/kg, the total plasma clearance was independent from dose with a mean of 172 ml/min. The area under the curve was increasing by dose from 2490 up to 10,000 μg h/L. The urinary excretion of total platinum during 48 hours was 27.8% of the total dose. The c(t)-curves of free platinum were best described by a two-compartment model. The mean residence time, volume of distribution as well as the total plasma clearance were independent from dose with mean values of MRT – 2.6 hours, Vdss = 0.44 L/kg and Clp = 202 ml/min. The area under the curve was increasing by dose from 2215 to 5200 μg h/L. The part of the free (unbound) platinum was calculated by comparison of the AUCs of c(t)-curves of free and total platinum and was 64% with a wide range (27-95%). In-vitro studies showed an increasing binding to proteins during time. Only a poor correlation was found between the estimated creatinine clearance and the drop of platelets and leucocytes at the nadir whereas a good correlation was found between the AUC of free as well as total platinum and reduction of platelets and leucocytes. Conclusion: In-vitro studies with D-19466 showed a slow binding to plasma proteins. This corresponds with the result that only 64% of the total platinum administered is free (= unbound) platinum. The terminal half-life of the ultrafilterable (free) platinum remains short in comparison to total platinum which includes the plasma bound platinum. There was no good correlation found between estimated creatine clearance and the drop of platelets and leucocytes at the nadir. There is no need to adjust the D-19466 dose to kidney function as far as patients are treated with normal values of creatinine.