Comparative pharmacokinetics of cisplatin and three analogues in mice and humans.

Pharmacokinetics of cisplatin, spiroplatin, ethylenediaminemalonatoplatinum(II) (JM-40), and carboplatin was studied in BALB/c x DBA/2 F1 mice receiving 10% lethal doses of 15.5, 6.8, 100, and 165 mg/kg, respectively. Blood samples were collected for up to 5 days after a single i.v. bolus injection. Total platinum in plasma and non-protein-bound free platinum in plasma ultrafiltrate were determined by flameless atomic absorption spectrometry. Parent JM-40 and carboplatin were determined by high performance liquid chromatography. Calculated pharmacokinetic parameters (peak concentrations, half-lives, areas under the curve) were compared with the corresponding values in patients at the maximal tolerated dose. Peak plasma concentrations were 2.4- to 20-fold higher in mice than in humans. Initial and terminal half-lives in mice were up to 6 times shorter than in patients. However, the areas under the plasma concentration versus time curves (AUCs) were found to agree. The ratios of the AUCs of free platinum in patients (AUCp) and mice (AUCm) measured over the first part of the plasma concentration versus time curve were 1.2, 0.3, 1.1, and 0.9 for cisplatin, spiroplatin, JM-40, and carboplatin, respectively. These values changed to 1.3, 0.3, 2.5, and 1.0 when the time interval was extended to free platinum levels just above the detection limit. Ratios of the AUCs of total platinum in patients and mice measured over 5 days were 2.7, 2.6, 4.2, and 1.8, respectively. Using a ratio of 1 for free platinum originating from JM-40, the retrospectively calculated maximal tolerated dose from AUCp at low dosages was 1021 mg/m2 (n = 7; range, 836-1282), compared to 1200 mg/m2 as found in the phase I trial. This suggests that the AUCp/AUCm ratio of free platinum over the first part of the concentration versus time curve can possibly be used to predict the maximal tolerated dose of platinum analogues in humans, during the early stage of phase I studies.

[1]  H. Pinedo,et al.  On-line differential pulse polarographic detection of carboplatin in biological samples after chromatographic separation. , 1986, Analytical chemistry.

[2]  M. Gore,et al.  HIGH-DOSE CARBOPLATIN (JM8) IN PATIENTS WITH LUNG-CANCER - A PHASE-I STUDY , 1986 .

[3]  J. Mcvie,et al.  Phase I study of ethylenediamine platinum(II) malonate (NSC 146 068), a second generation platinum analogue. , 1986, Cancer research.

[4]  G. Curt,et al.  Cancer chemotherapy: Progress and expectations, 1984 , 1984, Cancer.

[5]  F. Schabel,et al.  Increasing the therapeutic response rates to anticancer drugs by applying the basic principles of pharmacology , 1984, Pharmacology & therapeutics.

[6]  H. Pinedo,et al.  Pharmacokinetics of free and total platinum species after short-term infusion of cisplatin. , 1984, Cancer treatment reports.

[7]  W. Wolf,et al.  Renal toxicity studies of protein-bound platinum(cis). , 1981, Chemico-biological interactions.

[8]  J. Bull,et al.  Kinetics of cis‐dichlorodiammineplatinum , 1979, Clinical pharmacology and therapeutics.

[9]  N. Hill,et al.  Clinical studies of Platinum Coordination compounds in the treatment of various malignant diseases. , 1975, Cancer chemotherapy reports.

[10]  M Slavik,et al.  Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. , 1975, Cancer research.

[11]  H. H. Lloyd,et al.  Implications of biochemical, cytokinetic, pharmacologic, and toxicologic relationships in the design of optimal therapeutic schedules. , 1970, Cancer chemotherapy reports.

[12]  B. Chabner,et al.  Potential roles for preclinical pharmacology in phase I clinical trials. , 1986, Cancer treatment reports.

[13]  S. Marsoni,et al.  Relation of preclinical toxicology to findings in early clinical trials. , 1986, Cancer treatment reports.

[14]  K. Takahashi,et al.  Antitumor activity and toxicity of serum protein-bound platinum formed from cisplatin. , 1985, Japanese journal of cancer research : Gann.

[15]  H. Pinedo,et al.  Analysis of antitumour [1,1-bis(aminomethyl)cyclohexane]platinum(II) complexes derived from spiroplatin by high-performance liquid chromatography with differential pulse amperometric detection. , 1985, Journal of chromatography.

[16]  J. Mcvie,et al.  Clinical Experience with 1, 1-Diaminomethylcyclohexane (Sulphato) Platinum (II) (TNO-6) , 1984 .

[17]  S. Carter,et al.  The Development and Clinical Testing of New Anticancer Drugs at the National Cancer Institute — Example cis-Platinum (II) Diamminedichloride (NSC 119 875) , 1974 .

[18]  A. Guarino,et al.  Procedures for preclinical toxicologic evaluation of cancer chemotherapeutic agents: protocols of the laboratory of toxicology. , 1973, Cancer chemotherapy reports. Part 3.