The purpose of this study was to determine the influence of impaired renal and liver function on the pharmacokinetics and pharmacodynamics of
lobaplatin in
cancer patients. A total of 25 patients with advanced solid
tumors not amenable for standard treatment entered the study. Patients had normal organ function or an impaired liver or renal function (two levels). The starting dose of
lobaplatin was 50 mg/m2 i.v. given every 3 weeks. The blood and urine of all patients were sampled for the determination of (ultrafilterable)
platinum, intact
lobaplatin,
creatinine, and blood cell counts. No objective responses were recorded. Five patients experienced no change and received 4-10 cycles (median, 6 cycles) of
lobaplatin. The extent and duration of hematological toxicity were worse in patients with impaired renal function.
Thrombocytopenia was most prominent; grade 4 toxicity was observed in 15 patients in the first two cycles of treatment. The concentration-time curves of ultrafilterable
platinum and intact
lobaplatin revealed almost identical patterns. The elimination of ultrafilterable
platinum [final half-life (t1/2 final) = 131+/-15 min; clearance (Cl) = 125+/-14 ml/min/1.73 m2] was much faster than that of total
platinum (t1/2 final = 6.8+/-4.3 days, CI = 34+/-11 ml/min/1.73 m2). No pharmacokinetic differences were observed between patients with normal organ function and those with an impaired liver function within the investigated range. An impaired renal function resulted in an increase of the t1/2 final due to a decrease of the total body Cl that resulted in a higher exposure of the body to the
drug. The calculated
creatinine Cl was linearly correlated with the total body clearance of ultrafilterable
platinum (r = 0.91), which resulted in the dosage formula D = AUCinfinity (1.1 Cl(CrU) + 16), in which D represents dose, AUC represents area concentration-time curve, and Cl(CrU) represents
creatinine Cl. The thrombocyte surviving fraction correlated well with the AUC value of ultrafilterable
platinum (r = 0.72). It can be concluded that the hematological toxicity and the pharmacokinetics of
lobaplatin are strongly affected by renal function. The total body Cl of ultrafilterable
platinum correlated well with the
creatinine Cl and the thrombocyte surviving fraction. In patients with renal function, represented by a
creatinine clearance > or =30 ml/min/1.73 m2, the derived dosage formula will enable us to calculate the dose that is expected to lead to an acceptable extent of
thrombocytopenia in a patient with a given renal function. Prospective studies with larger groups of patients are needed to prove the value of this dosage formula.