TAKE INTO CONSIDERATION CLINICALLY RELEVANT TRANSPORTER POLYMORPHISMS
TAKE HOME MESSAGES FORM THE ITC PAPERS part 6
A number of Transporter polymorphisms has been described in literature, but Giacomini et al. highlight two: SLCO1B1 c.521T>C and ABCG2 c.421C>A. These polymorphisms (i) are associated with the PK and PD profiles of drugs at genome-wide level significance, (ii) are associated with drug disposition, efficacy or toxicity, based on candidate gene studies and (iii) show altered functionality in in vitro studies. A strategy is laid out to assess transporter polymorphisms in drug development. The main steps are 1) determining whether the drug candidate is a BCRP or OATP1B1 substrate, 2) determine the role these transporters play in the disposition or PD effect of the compound and 3) conducting a clinical DDI study with an inhibitor of the transporter(s). Based on the information from these studies, a pharmacongenomic study can be considered. While the authors focus on OATP1B1 and BCRP polymorphisms, the effect of polymorphisms in other transporters are being actively investigated and the authors caution that these may need to be considered when evaluating a drugs safety and efficacy.
Reference:
Giacomini, K.M., et al., International transporter consortium commentary on clinically important transporter polymorphisms. Clin
Pharmacol Ther, 2013. 94(1): p. 23-6.
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