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Departments of Pharmaceutical Sciences [M. K. M., W. C. Z., K. M. R., S. K. H., A. K. S., C. F. S.], Hematology and Oncology [W. L. F., V. M. S.], and Molecular Pharmacology [P. J. H.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105-2794, and Department of Pharmacology [P. J. H.] and The Center for Pediatric Pharmacokinetics and Therapeutics [P. J. H., C. F. S.], University of Tennessee, Memphis, Tennessee 38163
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·h single-day lactone SN-38 area under the concentration-time
curve (AUC0
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.
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