Vincristine in childhood leukaemia: no pharmacokinetic rationale for dose reduction in adolescents

Abstract

Aim: To investigate whether there is any pharmacokinetic rationale for the common practice of administering vincristine to adolescents at relatively lower doses than those to younger children. Methods: A total of 98 children, aged 1.3–17.3 y, with acute lymphoblastic leukaemia (ALL) were studied on day 1 of induction therapy. Plasma samples were drawn before and 10, 30, 360 and 1380 min after injection of vincristine 2.0 mg/m2 (maximum dose 2.0 mg) and analysed by high‐performance liquid chromatography. Results: The median value (and range) for distribution half‐life was 6.4 min (0.8–11.8), elimination half‐life 1014 min (258–2570), volume of distribution 445 L/m2 (137–1241) and total body clearance 362 ml/min/m2 (134–2553). No correlation was found between age and any of these pharmacokinetic parameters. The area under the concentration time curve (AUC) was significantly correlated to age (p= 0.002; ρ– 0.31), as expected from the dosage of vincristine. The lower AUC in children with a body surface area > 1 m2, which is reached at 8–9 y of age, indicates that they received a less intense treatment because of the capping of the vincristine dose at 2.0 mg. Conclusions: Vincristine pharmacokinetics were not age dependent in this paediatric population. Thus, we found no pharmacokinetic rationale for dose reduction in adolescents. The common practice of limiting the vincristine dose to 2.0 mg should be carefully reconsidered.

Selective Metabolism of Vincristine in Vitro by Cyp3a5

“…Early vincristine clinical studies showed up to 11-fold variability in drug exposure (dose-corrected area under the curve) among adult patients (Van den Berg et al, 1982). More recent pediatric clinical pharmacokinetic studies also reported a 19-fold difference in the dosecorrected area under the curve (Frost et al, 2003). Understanding determinants of the variation in vincristine exposure may allow identification of patient-specific risk factors for neurotoxicity or individualized dosing strategies to decrease the risk of patient relapse.…”

Effect of CYP3A5 Expression on Vincristine Metabolism with Human Liver Microsomes

“…Multiple, large-scale clinical trials of acute lymphoblastic leukemia patients report that AfricanAmerican children consistently have lower survival rates than Caucasian children (Pollock et al, 2000;Lange et al, 2002). Furthermore, in pharmacokinetic studies, the exposure to vincristine can vary 19-fold between patients (Van den Berg et al, 1982;Frost et al, 2003). This pattern suggests a genetic contribution to interpatient variability in exposure and prompted our investigation into the role of the genetically polymorphic enzyme CYP3A5 in vincristine metabolism.…”

Severe Neurotoxicities in a Case of Charcot-Marie-Tooth Disease Type 2 Caused by Vincristine for Acute Lymphoblastic Leukemia

“…Drugs interfering with this enzyme, for example, itraconazole, quinidine, nifedipine, and cyclosporine A might increase VCR level. 9 In fact, enhanced VCR neurotoxicities by itraconazole have been reported in both adults and children. 10 However, drug-enhanced VCR neurotoxicities will recover in relatively short-term period.…”