Pharmacokinetic/Pharmacodynamic/Pharmacogenetic Investigation of Vincristine and its M1 Metabolite in Kenyan Pediatric Cancer Patients

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2020-12

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Abstract

Vincristine (VCR) is an anticancer drug widely used in treating a variety of malignancies in pediatric oncology. VCR is also an integral part of chemotherapy regimens in resource-limited settings due to its relatively low cost and lack of myelosuppression. It is associated with a cumulative dose-dependent peripheral neuropathy that is highly variable. It has been established that VCR is preferentially metabolized to its major M1 metabolite by the polymorphic CYP3A5 enzyme. There is a gap in knowledge regarding the disposition of M1 especially since CYP3A5 is expressed in up to 70% of African Americans, 10-20% of Caucasians, and 90% of Kenyans which may be clinically significant. Furthermore, little information is known about VCR disposition and optimal therapeutic dosing. U.S patients treated with VCR experienced excellent treatment outcomes but significant neuropathy while Kenyan patients experienced poor treatment outcomes with little to no neuropathy. This is another gap in knowledge as there is a health disparity in clinical outcome and toxicity that stresses the need for VCR dose optimization in Kenyan pediatric cancer patients. The goal of this project was to gain a better understanding of the dispositions of VCR and M1 in Kenyan pediatric cancer patients using PK/PG/PD investigations which may contribute to the provision of rational guidance for future VCR dosing optimization. To achieve the goal of this project, we first improved the insufficient existing extraction assay to allow us simultaneously quantify VCR and M1, a pre-requisite for PK characterization and further analysis. We performed PK modeling analysis and evaluated correlations between PK, PG (CYP3A5 expression), and PD (neuropathy). The M1 metabolite was largely distributed in the tissues than the parent compound and M1 was also cleared more slowly than VCR. Both VCR and its M1 metabolite exhibited distinct PK characteristics. This was the first study to simultaneously quantify VCR and M1 from dried blot spot samples. It was also the first study to develop a population PK co-model describing the fate of both compounds in a Kenyan pediatric cancer population.

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Keywords

Vincristine, VCR M1 Metabolite, Kenyan, Pediatrics, Cancer, Dried Blood Spot, LC-MS/MS, Pharmacokinetics, Population Co-model, Covariate Co-model, Neuropathy, CYP3A5 Expression

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