(193al) Optimization of Vincristine Infusion Time

Vincristine (VCR) is a core chemotherapeutic drug administered to pediatric Acute Lymphoblastic Leukemia (ALL) patients. It is administered via an IV bolus injection or an infusion minibag for approximately 10 minutes. In a subgroup of population, VCR administration leads to Vincristine Induced Peripheral Neuropathy (VIPN), which is the dose-limiting toxicity. For few patients, VIPN is severe with long-term effects. Even though VCR has been used as a chemotherapeutic drug for more than 50 years now, predictors and mechanism of VIPN induction are unclear. VIPN incidence is associated with VCR cumulative dosage. Hence, we are interested in finding an optimal infusion time that would lead to a reduction in VCR dosage.

A population balance model was developed to describe the mechanism of VCR in cells in different phases. The model was a function of time and cell age. This mechanistic model was combined with pharmacokinetics of VCR. Infusion time was optimized by maximizing number of leukemia cancer cells being killed by the end of induction phase of the treatment, with VCR being administered weekly. A preliminary analysis with a simplistic model showed that a schedule of 30 minute infusion in week 1, 12 minute infusion in week 2, 30 minute infusion in week 3, and 12 minute infusion in week 4, produced a better efficacy than the usual 10 minute infusion every week. Lesser amount of drug with same efficacy as before may reduce the chances of VIPN.

Currently, rigorous analysis is being done with a more complex model. In this model, cell phase transition rates are assumed to be functions following a lognormal distribution with cell age as a variable. Detailed pharmacokinetics is incorporated as well. Initially, the model consisted of G1 phase, and S, G2, M phase lumped together, followed by mitotic arrest. A quiescence phase is added to it. Further, bone marrow toxicity is incorporated to account for killing of normal cells. In the future, we intend to eventually estimate a personalized infusion time for every patient.