Vincristine-Induced Neuropathic Pain In A Cyp3a5 Non-Expresser With Reduced Cyp3a4 Activity

Abstract

Vincristine is metabolised by CYP3A5 and CYP3A4 isoforms with CYP3A5 contributing to 75% of vincristine intrinsic clearance. Vincristine is a substrate of the P-glycoprotein (P-gp) transporter. An increase in vincristine neurotoxicity in CYP3A5 nonexpressers has been observed. The severity of neuropathy was found to be inversely correlated to vincristine metabolite concentrations. However, a clear correlation between genetic polymorphisms and vincristine toxicity has not been established. We report the case of a 21-year old African male patient who received vincristine 2 mg on 3 occasions (on 14.10, 30.10 and 06.11.14) for the treatment of pre-B acute lymphoblastic leukemia. Six weeks after the last vincristine dose the patient complained of bilateral severe burning pain in the toes and allodynia, suggestive of neuropathic pain. The patient was genotyped for CYP3A5 using a real-time PCR method as well as for ABCB1 (coding for P-gp) G2677T/A and C3435T SNPs. The results showed that the patient presented a CYP3A5*3/*3 polymorphism indicating that he did not express CYP3A5 enzyme. He was a homozygous ‘wild type’ carrier for ABCB1 SNPs. Furthermore, CYP activity was evaluated using the Geneva phenotyping cocktail including midazolam as a probe for CYP3A4. The patient had a decreased CYP3A activity which could not be explained by the concomitant medication. Similarly he had no CYP3A inhibitor in his medication at the time he received vincristine. The lack of CYP3A5 expression together with decreased CYP3A4 activity probably led to a decrease in vincristine clearance and to an increase in its plasma concentrations. It is a likely explanation for the occurrence of neurotoxicity in our patient despite the low doses of vincristine he received. In patients treated with vincristine, CYP phenotyping and genotyping could be crucial in preventing serious side effects.