Pharmacokinetics of platinum after oral or intravenous cisplatin: a phase 1 study in 32 adult patients.
OBJECTIVE
To develop a population pharmacokinetic model for simultaneous analysis of oral/intravenous cisplatin data in order to estimate the mean population pharmacokinetic parameters, mainly the bioavailability, of cisplatin and to evaluate the influence of covariates on the pharmacokinetic variability.


METHODS
Pharmacokinetic and demographic data were collected from 32 adult patients (20 males/12 females, age range 47-76 years) receiving 30-min infusions or an oral formulation of cisplatin, 10-30 mg/m2, for various malignancies. Both total plasma and ultrafilterable or unbound platinum concentrations were determined.


RESULTS
Unbound and total platinum concentrations were ascribed to a two-compartment model, with first-order absorption and elimination. The oral bioavailability (F) population estimates were, respectively, 0.39 and 0.30 with associated intersubject variabilities (ISV) of 24% and 26%. Peak concentrations following oral dosing occurred at 1.0 h and 1.6 h for unbound and total platinum, respectively. Clearance (CL) and central distribution volume (V1) of unbound platinum were significantly related to body surface area (BSA). The CL and V1 mean estimates were, respectively, 37 l/h and 23 l with an associated ISV of 15%. The final pharmacokinetic models were validated using 1000 bootstrap samples of the original datasets.


CONCLUSIONS
Both unbound and total platinum data allowed a fair evaluation of oral cisplatin disposition, with close estimations for both absorption rates and oral bioavailability. These results also support the conventional dose adjustment of cisplatin based on BSA.
Urien
Saik
S
Laboratoire de Pharmacologie, Centre René Huguenin, 35 rue Dailly, 92210, Saint-Cloud, France. s.urien@stcloud-huguenin.org
Brain
Etienne
E
Bugat
Roland
R
Pivot
Xavier
X
Lochon
Isabelle
I
Van
Marie-Louise Vo
ML
Vauzelle
Françoise
F
Lokiec
François
F
D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012016:Reference Values
D000970:Antineoplastic Agents; D002945:Cisplatin