May 30, 2019
Time-dependent inhibition (TDI), in which a shift in inhibitory potency (IC50) is observed upon increasing incubation time, is a well-known phenomenon in CYP inhibition studies. However, to date little is known about whether a similar effect can occur in transporter inhibition studies. The 2017 FDA draft guidance on in vitro drug-drug interaction studies introduced the recommendation that a 30-minute pre-incubation be included in inhibition studies for OATB1B1 and OATP1B3 based on a limited number of studies using cyclosporin A and its primary metabolite AM11. However, the broader relevance and necessity of this pre-incubation step for other clinically relevant inhibitors and transporters remained unknown.
Potentiation of Transport Inhibition by Pre-incubation (PTIP)
In a recent publication2 in Drug Metabolism and Disposition by researchers at SOLVO Biotechnology and Novartis Institutes for Biomedical Research, a systematic evaluation of the effect of increasing pre-incubation times, termed Potentiation of Transport Inhibition by Pre-incubation (PTIP), was investigated. Cell lines expressing OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2-K transporters were studied using 30 different inhibitors with pre-incubation times of up to 3 hours.
The effect of PTIP on clinical DDI risk assessment
Even after considering the effects of non-specific binding and toxicity, the majority of PTIP observations were confirmed. The authors concluded that OCT1 and OCT2 transporters were subject to PTIP, in addition to OATP1B1 and OATP1B3. Furthermore, in several cases PTIP was shown to impact the outcome of the in vitro risk assessment for determining whether to conduct a clinical DDI study, using calculations from the current regulatory guidance documents.
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Transporter research at SOLVO Biotechnology
1. In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies Guidance for Industry, October 2017. Food and Drug Administration Center for Drug Evaluation and Research.
2. A systematic in vitro investigation of the inhibitor preincubation effect on multiple classes of clinically relevant transporters. Tatrai P., Schweigler P., Poller B., Domange N., de Wilde R., Hanna I., Gaborik Z., Huth F. (2019) Drug Metab. Dispos. P-pub ahead of print.