Vincristine Case Study

Vincristine is the primary treatment for acute lymphoblastic leukemia (ALL) in children. Common toxicities include peripheral and autonomic neuropathies, which can be life threatening. Vincristine is metabolized extensively by CYP450 3A and its PK has a significant inter-individual variation. In addition to chemotherapy treatment, children are given antifungals for prophylaxis of infections. Itraconazole, voriconazole and fluconazole are commonly used agents. The azole family is an inhibitor of the CYP3A enzyme, which may lead to increased toxicities. It is currently unknown as to whether these toxicities are caused by an increased exposure to vincristine and to what extent it is caused by azole-induced inhibition of CYP3A4.

There are many …show more content…
A CTS has five parts: a study design specification, an input-output model, a covariate distribution model, a trial execution model and a trial analysis …show more content…
These inhibitions are not correlated with these azoles but were used to assess power and parameter precision at the different extents of clearance inhibition. Optimal sampling times were determined using the D-optimal design based on the population PK model by Guilhaumou et al. A set dose of 1.4 mg/m2, capped at 2.0mg, infused over 1 hour was used in all simulations per treatment guidelines for vincristine.

Input-Output Model
This model is designed to develop the wanted results. In this study, the input-output model simulates the vincristine concentration-time profile using a non-linear mixed effect (NLME) PK model developed by Guilhaumou et al. This was chosen because it has the known bi-exponential PK of vincristine. This design used body surface area (BSA) scaling on all structural model parameters. The variability of vincristine’s clearance and residual error was calculated for using inter-occasion variability (IOV).

Covariate