Pharmacokinetics of elemental platinum (ultrafiltrate and total) after a thirty minute intravenous infusion of ormaplatin.
Preclinical data suggest that ormaplatin (tetrachloro-(dl-trans)-1, 2-diamminocyclohexaneplatinum) has substantial activity in cisplatin-resistant tumor models and may be less nephrotoxic than cisplatin. Based on these data we initiated a phase I clinical trial in patients with refractory metastatic cancer. This report characterizes the pharmacokinetic profile of both the total plasma concentrations of elemental platinum and the unbound ultrafiltrate concentrations of elemental platinum, following a 30 min intravenous infusion of ormaplatin. Platinum concentrations were determined by AAS, and pharmacokinetic parameters for both the total plasma concentration and the ultrafiltrate concentration of elemental platinum were determined using both compartmental and noncompartmental methods. Twenty-eight patients (14 males and 14 females; median age, 58) received ormaplatin. There was a linear relationship between Cmax and dose (r2 = 0.945) and AUC and dose (r2 = 0.976). Ormaplatin is more accurately described by a two-compartment model than by a one-compartment model. The distribution half-life (t1/2 alpha) was 0.3 h and the terminal half-life (t1/2 beta) was 39.1 h. The volume of the central compartment (V) was 68.6 L and the volume of distribution at steady state (Vdss) was 183 L. Like total plasma platinum, unbound platinum is also best characterized by a two-compartment model. The elimination of free platinum is also biphasic with a distribution half-life (t1/2 alpha) of 0.3 h and a terminal half-life (t1/2 beta) of 19.3 h. The mean volume of the central compartment (V) was 200.5 L, and the mean volume of distribution at steady state (Vdss) was 560.5 L. Clinical development of ormaplatin has been terminated due to increased frequency of neurological complications noted over other platinum agents; however, the pharmacokinetics are, in general, similar to those of other clinically used platinum compounds.
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Clinical Pharmacological Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Christian
M C
MC
Lush
R
R
Link
C J
CJ
Davis
P
P
Kohn
E
E
Sarosy
G
G
Rothenberg
M L
ML
Weiss
R B
RB
Ryan
N
N
Jacobs
J
J
Reed
E
E
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006440:Hemofiltration; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010984:Platinum / Q000097:blood*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010984:Platinum; C049777:ormaplatin