Pharmacokinetics of free and total platinum species after rapid and prolonged infusions of aqua (1,1-bis(aminomethyl)cyclohexane) sulfatoplatinum (II) (spiroplatin) during a phase I trial.
The pharmacokinetics of the second generation platinum complex aqua(1,1-bis-(aminomethyl)cyclohexane)sulphatoplatinum(II) (spiroplatin, TNO-6) were studied during a phase I evaluation. Thirty patients received 49 cycles of spiroplatin by short term (less than or equal to 10-min), 1-, 3- or 6-h infusion. Dosages given ranged from 5 to 40 mg/m2. Platinum determinations were performed by atomic absorption spectrometry. Up to 5 days after administration platinum concentrations in plasma decayed triexponentially. Pharmacokinetic parameters of total platinum in plasma after short-term and prolonged infusion were similar in terms of terminal half-life (3.7 +/- 1.1 and 3.6 +/- 0.5 days), AUC/dose (548 +/- 106 and 616 +/- 278 min.m2/l), volume of distribution (20 +/- 6 and 27 +/- 81) and total body clearance (2.9 +/- 1.0 and 3.4 +/- 1.8 ml/min), whereas peak plasma concentrations were two times lower after prolonged infusion. The cumulative urinary platinum excretion after short-term infusion was 20 +/- 6%, 30 +/- 6% and 47 +/- 7% of the administered dose after 6, 24 and 120 h, respectively. These values are comparable to those after administration of cisplatin. The half-life of ultrafilterable platinum was 4.4 +/- 0.7 min. The curves of free and total platinum diverged rapidly, reflecting the high reactivity of spiroplatin towards plasma proteins. This high reactivity, most likely caused by the abundant presence of aquated compounds in the injection fluid, may also account for severe and unpredictable nephrotoxicity induced by spiroplatin.
van der Vijgh
W J
WJ
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Elferink
F
F
Vermorken
J B
JB
ten Bokkel Huinink
W W
WW
Klein
I
I
Gall
H E
HE
Simonetti
G
G
McVie
J G
JG
Pinedo
H M
HM
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000493:pharmacokinetics; D004341:Drug Evaluation; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000378:metabolism / Q000652:urine; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010984:Platinum / Q000097:blood / Q000652:urine; D013997:Time Factors
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010984:Platinum; C040757:spiroplatin; D002945:Cisplatin