Pharmacokinetics and pharmacodynamics of lobaplatin (D-19466) in patients with advanced solid tumors, including patients with impaired renal of liver function.
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.
Welink
J
J
Department of Medical Oncology, University Hospital Vrije Universiteit, The Netherlands.
Boven
E
E
Vermorken
J B
JB
Gall
H E
HE
van der Vijgh
W J
WJ
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood / Q000652:urine; D003503:Cyclobutanes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D007674:Kidney Diseases / Q000150:complications* / Q000378:metabolism*; D008107:Liver Diseases / Q000150:complications* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010976:Platelet Count / Q000187:drug effects; D010984:Platinum / Q000097:blood / Q000652:urine; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D003503:Cyclobutanes; D009944:Organoplatinum Compounds; D010984:Platinum; D003404:Creatinine; C066228:lobaplatin