Een farmacokinetiek studie van vincristine bij het gelijktijdig gebruik van anti-schimmelmedicijnen bij kinderen die behandeld worden voor acute lymfatische leukemie (ALL).

Vincristine (VCR) is an important component in the treatment of acute lymphoblastic leukemia (ALL) in children. Proper dosing of vincristine is required to maximize disease control while avoiding toxicity. Peripheral and autonomic neuropathies are the most common side effects which can be life-threatening. Vincristine pharmacokinetics are time- and dose-dependent and considerable intra- and interpatient variation have previously been reported. Vincristine is predominantly metabolized in the liver by the cytochrome P450 (CYP) 3A family of enzymes and eliminated by an efflux pump, P-glycoprotein (P-gp). Inhibition of CYP3A4 by several drugs, such as azole antifungals, could increase vincristine exposure and potentiate the side effects caused by vincristine. Since in paediatric oncology patients azoles are increasingly being used for prophylaxis and treatment of fungal infections, guidelines for the co-administration of vincristine and azole therapy are necessary. The azoles used for antifungal prophylaxis are itraconazole, voriconazole and fluconazole. Several case reports suggest that co-administration of azoles and vincristine lead to increased toxicity, but this has not been studied specifically. It is not known whether these side-effects are related to a higher exposure of vincristine, and to what extent this exposure is increased. Information of the increase in plasma levels of vincristine during concomitant azole therapy may lead to evidence-based dosing guidelines for the effective and safe co-administration of these drugs, assuming that lower dose-levels of vincristine are needed.

The aim of this study is to provide evidence based dosing guidelines for vincristine in combination with azoles. Therefore we will study the pharmacokinetics of vincristine with and without concomitant azole therapy in pediatric patients with acute lymphoblastic leukemia.

Sampling will be performed around 2 VCR administrations during induction and intensification phase of the standard treatment of ALL (DCOG-ALL-10 protocol).

Toxicity will be assessed during 4 weeks following the last sampling.

No intervention, observation of blood levels of vincristine.