New Recommendation: Evaluate NMEs for OCT1 Transporter-Mediated DDI Potential

Brian Ogilvie, Ph.D., Vice President of Scientific Consulting at XenoTech, presented a case study on the importance of the hepatic OCT1 transporter in the disposition of sumatriptan in August 2017 at the University of Rhode Island College of Pharmacy’s Transports in Drug Discovery and Development conference.

Ogilvie recommended that drug development teams evaluate drug candidates as inhibitors and substrates of OCT1. He reached this conclusion based on analysis of research published by Matthaei, et al., in 2016 — and in relevant literature elsewhere — that indicated that OCT1 polymorphisms affect sumatriptan’s and other drugs’ pharmacokinetics (PK) significantly.

Patient-to-patient variability in the activity of this hepatic transporter can result in slower than expected liver uptake, with correspondingly slower hepatic metabolism. The sumatriptan case is an illustration of how any drug that inhibits OCT1 — or relies on it for transport into the liver for therapeutic action or for clearance — has the potential to be involved in OCT1-related drug-drug interactions (DDIs) or pharmacogenetic (PGx) effects.

Neither the 2012 USFDA guidance nor the draft 2017 USFDA in vitro DDI guidance recommended any evaluation of drug candidates as inhibitors or substrates of OCT1. However, in August 2018, the International Transporter Consortium (ITC) released the white paper, “Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance,” offering some of the same evidence Ogilvie presented the year before.

The paper recommends prospective evaluation of OCT1 for all drug candidates — and possibly, retrospective studies on other transporters, such as intestinal transporter OATP2B1 — for potential mediation of clinically important DDIs and interpatient variability.

While the white paper provides more detail, here is a summary of the main points relating to OCT1:

• OCT1 is the most highly expressed OCT in the human liver and can play a major role in liver uptake. This facilitative transporter is located on the sinusoidal side of hepatocytes and transports weak bases.
• Clinically relevant observations have been published, such as the impact of decreased OCT1 transporter function on sumatriptan pharmacokinetics. Sumatriptan has low bioavailability and is mainly metabolized by liver monoamine oxidase A (MAO-A). Approximately 60 percent of the sumatriptan metabolites are excreted in urine, while 40 percent are excreted in the feces. If OCT1 uptake by the liver decreases, metabolism is subsequently reduced and serum levels may rise above the therapeutic range. 
• Five common human OCT1 polymorphisms with reduced or deficient function are described. These polymorphisms result in strong or nearly complete decreases in activity and should not be ignored since up to 9 percent of Caucasians are homozygous for null alleles. 
• The ITC recommends evaluating a drug candidate for OCT1 substrate and inhibition potential in a manner similar to that of OATP1B1 and OATP1B3, using the decision trees proposed in the draft 2017 USFDA in vitro DDI guidance. The white paper’s authors note that the cutoff values are likely to change as new data are collected. 
• The ITC now considers inhibition of hepatic OCT1 as a perpetrator of clinical DDIs and recommends the evaluation of drug candidates for potential OCT1-mediated interactions. Clinically relevant observations from the impact of decreased transporter activity resulting from reduced OCT1 function (polymorphisms) include: 
  • Reduced hepatic uptake with no change in systemic pharmacokinetics 
    • Metformin: Among other activities, this commonly prescribed oral antihyperglycemic decreases hepatic glucose production. Reduced hepatic uptake decreases efficacy despite reaching serum levels that are expected to be therapeutic. 
  • Decreased hepatic uptake leading to increased systemic exposure due to reduced intrahepatic metabolism and excretion 
    • Fenoterol: β₂ agonist medication for severe asthma withdrawn from the market in the 1990s
      • Two-fold increase in systemic exposure (i.e., area under the curve (AUC)) was observed 
    • Tramadol: opioid pain medication
      • Two-fold increase in exposure to the O-desmethyl active metabolite (an OCT1 substrate) was observed 
    • Ondansetron and tropisetron: antiemetics often used in chemotherapy
      • Two- to four-fold increase in exposure was observed (odansetron overdose can cause prolonged cardiac QT intervals, leading to the potentially fatal arrhythmia torsades de pointes) 
    • Sumatriptan: migraine and cluster headaches
      • Two-fold increase in exposure was observed (overdose can cause sulfhemoglobinemia, resulting in green blood, and serious adverse cardiovascular events have also been reported)
    • Morphine/codeine: opioid pain medications
      • Variability in exposure, exact values not reported 
  • DDIs with strong and specific inhibitors of OCT1 may produce effects similar to the effects of OCT1 polymorphisms

The potential significance of these effects underscores the critical importance of including OCT1 in drug transporter studies.

For more information on OCT1 and other transporters now considered to be of interest to drug developers for predicting DDIs, read the ITC white paper or contact XenoTech.

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