Using Metabolite Data to Develop Patient Centric Specification for Amide Impurity in Vildagliptin Tablets
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abstract
Many specified impurities in vildagliptins finished product have been disclosed in the literature that are above their qualification threshold. We used the impurity B (amide impurity) as a case example to explore whether existing literature can be leveraged to determine the safe level of impurity and thereby develop a patient-centric specification (PCS) for impurities. No-observed-adverse-effect level (NOAEL) was derived from rate metabolism information and converted to human equivalent dose (HED). The HED was estimated as 6.5 mg/day. The high qualification levels are supported by repeat dose toxicity studies performed in rats, mice and dogs. Maximum theoretical amount (MTA) was correlated with the maximum observed amount (MOA) to verify whether the exposure was due to impurity and/or metabolite. MOA/MTA was found 1 suggesting that metabolism contributed to the amount excreted in feces and therefore could be used to further justify a higher specification limit than the usual one of 0.5%. Quite often the drug metabolism and degradation pathways overlap, resulting in the formation of identical constituents. Therefore, metabolism data can be leveraged for deriving safe levels of degradation impurities and develop PCS for impurities.
