Impact of body-size measures on irinotecan clearance: alternative dosing recommendations.
OBJECTIVE
To evaluate relationships between various body-size measures and irinotecan (CPT-11) clearance and metabolism in cancer patients, and to provide future dosing recommendations for this agent.


METHODS
Pharmacokinetic data were obtained from 82 adult patients (50 men, 32 women; median age, 54 years) receiving CPT-11 as a 90-minute intravenous infusion (dose range, 175 to 350 mg/m(2)). In each patient, plasma samples were collected at timed intervals in the first administration of a 3-week schedule, and CPT-11 and its metabolite, SN-38, were measured by a liquid chromatographic assay.


RESULTS
The mean (+/- SD) CPT-11 clearance was 33.6 +/- 10.8 L/h, with an interindividual variability (IIV) of 32.1%. When clearance was adjusted for body-surface area (BSA), the IIV was similar (34.0%). In addition, in a multiple linear regression analysis, none of the studied measures (BSA, lean body mass, [adjusted] ideal body weight, and body mass index) was a significant covariate (P >.13; r(2) <.014) in our population. Similarly, BSA did not significantly contribute to variability in the relative extent of conversion to SN-38 (P =.26).


CONCLUSIONS
BSA is not a predictor of CPT-11 clearance or SN-38 pharmacokinetics and does not contribute to reducing kinetic variability. These findings provide a rationale for the conduct of a comparative phase III study between BSA-based dosing and flat or fixed dosing of CPT-11.
Mathijssen
Ron H J
RH
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), 3008 AE Rotterdam, the Netherlands.
Verweij
Jaap
J
de Jonge
Maja J A
MJ
Nooter
Kees
K
Stoter
Gerrit
G
Sparreboom
Alex
A
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001824:Body Constitution; D001830:Body Surface Area; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015999:Multivariate Analysis; D009426:Netherlands; D012189:Retrospective Studies
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin