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.

WHEN SHOULD I STUDY TRANSPORTERS?

TAKE HOME MESSAGES FROM THE ITC PAPERS part 4

This question is often asked and not easy to answer. Tweedie et al. lay out a strategy that is driven by the clinical plan and consists of three phases:

I – Discovery to First Time in Human (FTIH)

The first phase of the transporter strategy is to review the therapeutic area, patient population, potential co-medications, routes of administration, the development plan, etc. Based on this review some early screens could be considered to support lead optimization, e.g. OATP1B1 and BCRP inhibition in the case of expected co-medications with statins.

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1.THERE ARE A NUMBER OF ADDITIONAL TRANSPORTERS YOU SHOULD SERIOUSLY CONSIDER

TAKE HOME MESSAGES FROM THE ITC PAPERS: part 2

In 2010 the ITC presented 7 transporters it considered clinically relevant, now often referred to as the ’ITC-7’: OAT1, OAT3, OCT2, OATP1B1, OATP1B3, P-gp and BCRP. Hillgren et al. summarize a number of transporters of emerging importance:

MATEs: MATEs are expressed in the liver (MATE1) and kidney (MATE1, MATE2-K) and are involved in the transport of cationic and zwitterionic molecules like Metformin and Cimetidine. Due to their important role in renal excretion of drugs the ITC suggests adding MATEs to the OAT1/3 and OCT2 decision trees, i.e. inhibition of MATEs should be studied for each new molecular entity (NME), whereas substrate studies should be performed for compounds showing more than 25% renal, active secretion.

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