Pharmacokinetics of irinotecan and its metabolites in pediatric cancer patients: a report from the children's oncology group.
OBJECTIVE
To develop a population pharmacokinetic model of irinotecan and its major metabolites in children with cancer and to identify covariates that predict variability in disposition.


METHODS
A population pharmacokinetic model was developed using plasma concentration data from 82 patients participating in a multicenter Pediatric Oncology Group (POG) single agent phase II clinical trial. Patients between 1 and 21 years of age with solid tumors refractory to standard therapy received irinotecan, 50 mg/m(2), as a 60-min intravenous infusion for 5 consecutive days every 3 weeks. Blood samples were collected and analyzed for irinotecan and three metabolites (SN-38, SN-38G, and APC). The population model was developed with NONMEM. Clearance and volume were scaled allometrically using corrected body weight. Exponential error models were used to describe the interindividual variance in pharmacokinetic parameters, and the residual error was described with a proportional model. Significant covariate effects were identified graphically using S-PLUS and were added to the base-model. The final model was evaluated by simulating data from two other POG trials.


RESULTS
The best structural model for irinotecan and its metabolites consisted of six-compartments: two compartments for irinotecan and SN-38, and one each for APC and SN-38G. Age and bilirubin were found to be significant covariates affecting SN-38 clearance. SN-38 clearance was greater in patients less than 10 years of age and lower in patients with a total serum bilirubin >0.6 mg/dL. Simulations revealed that the model was able to predict drug and metabolite exposure (AUC) for patients receiving the same or similar doses (30-65 mg/m(2)) of irinotecan.


CONCLUSIONS
This population model accurately describes the pharmacokinetics of irinotecan and its primary metabolites. The model, which includes age and bilirubin as covariate effects on SN-38 clearance, is the first population model to describe the pharmacokinetics of irinotecan and its major metabolites in children.
Thompson
Patrick A
PA
Texas Children's Cancer Center and Hematology Service, Texas Children's Hospital, Baylor College of Medicine, 6621 Fannin St. 1510.00, Houston, TX 77030-2399, USA. pathomps@txccc.org
Gupta
Manish
M
Rosner
Gary L
GL
Yu
Alexander
A
Barrett
Jeffrey
J
Bomgaars
Lisa
L
Bernstein
Mark L
ML
Blaney
Susan M
SM
Mondick
John
J
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D005965:Glucuronates / Q000097:blood / Q000493:pharmacokinetics*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D015337:Multicenter Studies as Topic; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
D000970:Antineoplastic Agents; D001663:Bilirubin; D002166:Camptothecin; D051544:Cytochrome P-450 CYP3A; D005965:Glucuronates; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme; C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; C100720:RPR 121056; C510163:CYP3A4 protein, human