Pharmacokinetics of irinotecan and its metabolites SN-38 and APC in children with recurrent solid tumors after protracted low-dose irinotecan.
Irinotecan (IRN), a topoisomerase I interactive agent, has significant antitumor activity in early Phase I studies in children with recurrent solid tumors. However, the disposition of IRN and its metabolites, SN-38 and APC, in children has not been reported. Children with solid tumors refractory to conventional therapy received IRN by a 1-h i.v. infusion at either 20, 24, or 29 mg/m2 daily for 5 consecutive days for 2 weeks. Serial blood samples were collected after doses 1 and 10 of the first course. IRN, SN-38, and APC lactone concentrations were determined by an isocratic high-performance liquid chromatography assay. A linear four-compartment model was fit simultaneously to the IRN, SN-38, and APC plasma concentration versus time data. Systemic clearance rate for IRN was 58.7 +/- 18.8 liters/h/m2 (mean +/- SD). The mean +/- SD ng/ml x h single-day lactone SN-38 area under the concentration-time curve (AUC(0-->6) was 90.9 +/- 96.4, 103.7 +/- 62.4, and 95.3 +/- 63.9 at IRN doses of 20, 24, and 29 mg/m2, respectively. The relative extent of IRN conversion to SN-38 and metabolism to APC measured after dose 1 were 0.49 +/- 0.33 and 0.29 +/- 0.17 (mean +/- SD). No statistically significant intrapatient difference was noted for SN-38 area under the concentration-time curve. Large interpatient variability in IRN and metabolite disposition was observed. The relative extent of conversion and the SN-38 systemic exposure achieved with this protracted schedule of administration were much greater than reported in adults or children receiving larger intermittent doses.
Ma
M K
MK
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Zamboni
W C
WC
Radomski
K M
KM
Furman
W L
WL
Santana
V M
VM
Houghton
P J
PJ
Hanna
S K
SK
Smith
A K
AK
Stewart
C F
CF
D000293:Adolescent; D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D000077146:Irinotecan; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018193:Neoplasms, Complex and Mixed / Q000188:drug therapy / Q000473:pathology; D018204:Neoplasms, Connective and Soft Tissue / Q000188:drug therapy / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; C100720:RPR 121056; D000077146:Irinotecan; D002166:Camptothecin