Pharmacokinetics and pharmacodynamics of lobaplatin (D-19466) in patients with advanced solid tumors, including patients with impaired renal or liverfunction

The purpose of this study was to determine the influence of impaired renal and liver function on the pharmacokinetics and pharmacodynamics of lobaplat in in cancer patients. A total of 25 patients with advanced solid tumors no t amenable for standard treatment entered the study. Patients had normal or gan function or an impaired liver or renal function (two levels). The start ing dose of lobaplatin was 50 mg/m(2) i.v. given every 3 weeks. The blood a nd urine of all patients were sampled for the determination of (ultrafilter able) platinum, intact lobaplatin, creatinine, and blood cell counts, No ob jective responses were recorded, Five patients experienced no change and re ceived 4-10 cycles (median, 6 cycles) of lobaplatin. The extent and duratio n of hematological toxicity were worse in patients with impaired renal func tion. Thrombocytopenia was most prominent; grade 4 toxicity was observed in 15 patients in the first two cycles of treatment. The concentration-time c urves of ultrafilterable platinum and intact lobaplatin revealed almost ide ntical patterns. The elimination of ultrafilterable platinum [final half-li fe (t(1/2 final)) = 131 +/- 15 min; clearance (Cl) = 125 +/- 14 ml/min/1.73 m(2)] was much faster than that of total platinum (t(1/2 final) = 6.8 +/- 4.3 days, Cl = 34 +/- 11 ml/min/1.73 m2). No pharmacokinetic differences we re observed between patients with normal organ function and those with an i mpaired liver function within the investigated range. An impaired renal fun ction resulted in an increase of the t(1/2 final) due to a decrease of the total body Cl that resulted in a higher exposure of the body to the drug. T he calculated creatinine Cl was linearly correlated with the total body cle arance of ultrafilterable platinum (r = 0.91), which resulted in the dosage formula D = AUC(infinity) (1.1 Cl-Cru + 16), in which D represents dose, A UC represents area concentration-time curve, and Cl-Cru represents creatini ne Cl. The thrombocyte surviving fraction correlated well with the AUC valu e of ultrafilterable platinum (r = 0.72), It can be concluded that the hema tological toxicity and the pharmacokinetics of lobaplatin are strongly affe cted by renal function. The total body Cl of ultrafilterable platinum corre lated well with the creatinine Cl and the thrombocyte surviving fraction. I n patients with renal function, represented by a creatinine clearance great er than or equal to 30 ml/min/1.73 m(2), the derived dosage formula will en able us to calculate the dose that is expected to lead to an acceptable ext ent of thrombocytopenia in a patient with a given renal function. Prospecti ve studies with larger groups of patients are needed to prove the value of this dosage formula.