Pharmacokinetics of daunorubicin and daunorubicinol in infants with leukemia treated in the interfant 99 protocol
Background. There is an extreme paucity of pharmacokinetic data for anticancer agents in infants. Therefore, we aimed at characterizing the pharmacokinetics for daunorubicin in infants and examined their relationship to age, body weight, and body surface area. Procedure. Leukemia patients treated according to the Interfant 99 protocol received 30 mg/m2 daunorubicin, with dose reduction to 3/4 for patients 6-12 months old and 2/3 for patients <6 months, respectively. Plasma samples from 21 patients (aged 0.05-1.88 years) were collected and analyzed for daunorubicin and daunorubicinol. Samples from 12 children (age 1.6-18.8 years), who received daunorubicin in an earlier investigation, were used for pharmacokinetic model building using the software NONMEM. Results. Plasma concentration time profiles could be described using a two compartment model. Daunorubicin clearance was 43.9 L hr-1m-2±65% and central volume of distribution 16.4 Lm-2±46%, whereas apparent clearance of daunorubicinol was 19.1 L hr-1m-2±32% and apparent volume of distribution 228 Lm-2±80% (mean± interindividual variability). No age-dependency in any of the BSA-normalized pharmacokinetic parameters was observed. Consequently, due to the empirical dose reduction in infants the overall exposure to daunorubicinol in infants was smaller than would be expected from older children. Patients aged <6 months experienced more infections in the induction phase than the group aged 6-12 months at diagnosis. Other toxicities were similar in both groups. Conclusion. We observed no indication of an age-dependency in the pharmacokinetics of daunorubicin.
|Keywords||Daunorubicin, Infants, Leukemia, Pharmacokinetics, acute lymphoblastic leukemia, adolescent, adult, article, asparaginase, child, clinical article, compartment model, controlled study, cyclophosphamide, cytarabine, daunorubicin, daunorubicinol, dexamethasone, distribution volume, drug clearance, drug distribution, drug dose reduction, drug efficacy, female, human, infection, liver toxicity, male, mucosal disease, nephrotoxicity, neurotoxicity, preschool child, priority journal, school child, tioguanine, treatment response, vincristine|
|Persistent URL||dx.doi.org/10.1002/pbc.22266, hdl.handle.net/1765/19401|
|Journal||Pediatric Blood & Cancer|
Hempel, G, Relling, M.V, de Rossi, G, Stary, J, de Lorenzo, P, Valsecchi, M.G, … Pieters, R. (2010). Pharmacokinetics of daunorubicin and daunorubicinol in infants with leukemia treated in the interfant 99 protocol. Pediatric Blood & Cancer, 54(3), 355–360. doi:10.1002/pbc.22266