Preclinical bioavailability-bioequivalence and toxico-kinetic profile of stable succinc acid cocrystal of temozolomide

摘要

Temozolomide (TMZ) is a frontline prodrug for the treatment of glioblastoma multiforme (brain cancer) approved by the US-FDA in 1999. A limitation with this otherwise potent and selective DNA alkylating agent is degradation of the prodrug to the inactive product 5-aminoimidazole-4-carboxamide (AIC) by incipient hydrolysis during storage. This transformation not only makes the drug less effective (due to hydrolysis of the active drug), but also causes discoloration from white to pink and tan brown colour (due to AIC contamination), which can make patients anxious and suspicious about the drug efficacy. We solved the stability issue of TMZ by preparing its succinic acid (SA) cocrystal and showed that TMZ-SA is stable for over 6 months in accelerated stability conditions of 40 degrees C, 75% RH, as confirmed by PXRD. TMZ-SA retained its white colour for over 6 months compared to the tan-brown discoloration for TMZ in less than 1 month. Based on the enhanced stability and comparable dissolution profile of TMZ-SA, we now take forward TMZ-SA pharmaceutical cocrystal to stability assessment by HPLC analysis and preclinical bioavailability and bioequivalence with the reference drug. We observed that there were no significant differences in the pharmacokinetic profile of the test cocrystal TMZ-SA compared to standard drug TMZ in Sprague Dawley rats. The bioavailability ratio was found to be in the range 102-109%. Pharmacokinetic parameters such as T-max, C-max, T-1/2, AUC and K-e are slightly superior for TMZ-SA and the toxico-kinetic profile is also better than TMZ. Most significantly, it has been shown that the active drug is released from the hydrogen-bonded cocrystal and was detected in the brain tissue of rats. Thus we report on a pharmaceutical cocrystal complying with the United States Food and Drug Administration guidance on pharmaceutical cocrystals. These results suggest that TMZ-SA cocrystal with improved physico-chemical properties is bioequivalent and has superior stability compared to the reference drug TMZ and a potential lead for an improved TMZ formulation.