Impact of Transporter Polymorphisms on Drug Development: Is It Clinically Significant?

Abstract

Drug transporters are becoming increasingly recognized as relevant to the drug development process. This may be a reflection of increasing target complexity and the need for high-affinity interaction with drug targets that minimize off-target side effects. Moreover, as new molecular entities (NMEs) become larger in size and amphipathic in nature, interaction with drug transporters, both uptake as well as efflux, becomes increasingly likely. In some cases transporters may limit the absorption or organ-specific entry of NMEs, whereas in other cases transporters may enhance their absorption or tissue accumulation. Indeed, in some cases, transporters may prove to be a therapeutic target. Accordingly, a better understanding of potentially clinically relevant drug transporter polymorphisms earlier in the drug development process is highly desirable. In this review we examine key transporters that are important to the absorption, distribution, and excretion of a large number of drugs in clinical use. Importantly, we provide our assessment of the potential impact of known polymorphisms in such transporters and discuss whether there is sufficient evidence to incorporate these polymorphisms in the drug development process.

Population Pharmacokinetics and Adverse Events of Erlotinib in Japanese Patients with Non-small-cell Lung Cancer: Impact of Genetic Polymorphisms in Metabolizing Enzymes and Transporters

“…The 1236C>T polymorphism is suggested to minimize ABCB1 functionality in vitro. 33) ABCB1 is highly expressed on the apical membrane of enterocytes in the entire intestine and on the bile canalicular membrane of hepatocytes, lower activity leads to higher absorption and lower elimination of erlotinib, thereby lowering CL/F. We previously reported that patients who were homozygous for the ABCB1*2 haplotype (1236TT-2677TT-3455TT) displayed higher plasma area under the curve (AUC) of erlotinib.…”

Role of Transporters in Drug Development

“…25 McLean et al provide an assessment of potential impact of known polymorphisms in drug transporters and discuss if there is sufficient evidence to incorporate these polymorphisms in the drug development process. 26 Using rosuvastatin (a substrate of OATP transporters) as an example, Riedmaier et al discuss the utility of a physiologically based pharmacokinetic (PBPK) approach in conjunction with a power calculation algorithm to evaluate the required sample size to detect the effects of OATP1B1 polymorphisms. 27 Various disease states can alter the expression and activity of drug transporters.…”

“…Interestingly, Sugiyama and colleagues have shown that, in addition to differences in allelic frequencies of OATP transporters, intrinsic ethnic variability in the activity of OATP1B1 should also be considered to fully understand the ethnic variability in the plasma exposure of statins . McLean et al provide an assessment of potential impact of known polymorphisms in drug transporters and discuss if there is sufficient evidence to incorporate these polymorphisms in the drug development process . Using rosuvastatin (a substrate of OATP transporters) as an example, Riedmaier et al discuss the utility of a physiologically based pharmacokinetic (PBPK) approach in conjunction with a power calculation algorithm to evaluate the required sample size to detect the effects of OATP1B1 polymorphisms …”

Pharmacogenomics with red cells: a model to study protein variants of drug transporter genes

“…Inter‐individual variation in the human genome due to single‐nucleotide variations (SNVs), small‐scale insertions and deletions (InDels) and copy number variations (CNVs) may result in altered pharmacokinetic and pharmacodynamic characteristics of drugs leading to a lack of therapeutic efficacy or a risk for drug‐induced toxicity [15, 16]. Variations in genes encoding drug transporters have been documented to affect responsiveness to chemotherapeutic agents [15, 17]. Rarely, sensitivity of red cells to the direct toxicity of the drugs can lead to drug‐induced haemolytic anaemia [18–21].…”