Discovery and Validation of Pyridoxic Acid and Homovanillic Acid as Novel Endogenous Plasma Biomarkers of Organic Anion Transporter (OAT) 1 and OAT3 in Cynomolgus Monkeys

Self Cite

160

213

on behalf of the International Transporter ConsortiumDrug transporters can govern the absorption, distribution, metabolism, and excretion of substrate drugs and endogenous substances. Investigations to examine their potential impact to pharmacokinetic (PK) drug-drug interactions (DDIs) are an integral part of the risk assessment in drug development. To evaluate a new molecular entity as a potential perpetrator of transporters, use of well characterized and/or clinically relevant probe substrates with good selectivity and sensitivity are critical for robust clinical DDI assessment that could inform DDI management strategy in the product labeling. The availability of endogenous biomarkers to monitor transportermediated DDIs in early phases of clinical investigations would greatly benefit downstream clinical plans. This article reviews the state-of-the-art in transporter clinical probe drugs and emerging biomarkers, including current challenges and limitations, delineates methods and workflows to identify and validate novel endogenous biomarkers to support clinical DDI evaluations, and proposes how these probe drugs or biomarkers could be used in drug development.Drug transporters can modulate the absorption, distribution, metabolism, and excretion (ADME) of substrate drugs and endogenous substances, ultimately determining their exposure in systemic circulation and tissues. 1 Transporter substrate or modulator (inhibitor or inducer) drugs can become clinical victims or perpetrators of drug-drug interactions (DDIs), respectively, when the transporter in question is a substantial contributor to the pharmacokinetics (PK) of the victim drug and can be inhibited or induced in the clinical setting. For example, lapatinib, a P-glycoprotein (P-gp) inhibitor, increased digoxin exposure by 2.8-fold (TYKERB labeling at Drugs@FDA), whereas tipranavir/ ritonavir, a P-gp inducer, decreased saquinavir/ritonavir exposure by 76% (APTIVUS labeling at Drugs@FDA). Understanding DDIs is an integral part of risk assessment in drug development considering the common practice of concomitant use of multiple medications. 1-3

Section: State‐of‐the‐art In Clinical Probe Drugs and Potential Endogmentioning

confidence: 99%

Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug‐Drug Interaction Evaluation: Perspectives From the International Transporter Consortium

Chu

Liao

Shen

et al. 2018

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213

“…Renal OATs, OAT1 and OAT3, are considered to mediate tubular secretion of PDA. 32,33 Pyrimethamine is a weak OAT1 and OAT3 inhibitor at its therapeutic dose with half-maximal inhibitory concentration of 241 ± 55 µM and 9.69 ± 2.27 µM, respectively ( Figure S3). Low inhibition potency to OAT3 was consistent with our previous report.…”

Section: Inhibition Of Oat1 and Oat3 By Pyrimethaminementioning

confidence: 99%

Identification of Appropriate Endogenous Biomarker for Risk Assessment of Multidrug and Toxin Extrusion Protein‐Mediated Drug‐Drug Interactions in Healthy Volunteers

Miyake

Kimoto

Luo

et al. 2020

Endogenous biomarkers are emerging to advance clinical drug-drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2-K-mediated DDI in the kidneys. Metformin (500 mg) was also given as reference probe drug for MATE1/2-K. In addition to the previously reported endogenous biomarker candidates (creatinine and N 1methylnicotinamide (1-NMN)), N 1-methyladenosine (m 1 A) was included as novel biomarkers. 1-NMN and m 1 A presented as superior MATE1/2-K biomarkers since changes in their renal clearance (CL r) along with pyrimethamine dose were well-correlated with metformin CL r changes. The CL r of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CL r changes. Nonlinear regression analysis (CL r vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant (K i) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo K i value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro K i for MATE1 (1-NMN) and MATE2-K (1-NMN and m 1 A). It is concluded that 1-NMN and m 1 A CL r can be leveraged as quantitative MATE1/2-K biomarkers for DDI risk assessment in healthy volunteers.

“…Data indicate that the coding regions of SLC22A6 and SLC22A8 have low genetic and functional diversity and suggest that coding region variants of these transporters may not contribute substantially to interindividual differences in renal elimination of xenobiotics . Despite clinical evidence from DDI studies, which demonstrate that inhibition of these transporters significantly changes the levels of many endogenous metabolites (e.g., taurine, creatinine, indoxyl sulfate, bile acid conjugates) or victim drugs, there are few significant associations of genetic polymorphisms in SLC22A6 or SLC22A8 with drug levels or response. In fact, to our knowledge, only one study showed a significant association ( P < 0.05) of an SLC22A8 Asian‐specific nonsynonymous variant, Ile305Phe (rs11568482) with reduced renal and secretory clearance of the antibiotic, cefotaxime .…”

Section: Polymorphisms In Other Drug Transporters With Less Evidencementioning

confidence: 99%

“…Despite clinical evidence from DDI studies, which demonstrate that inhibition of these transporters significantly changes the levels of many endogenous metabolites (e.g. taurine, creatinine, indoxyl sulfate, bile acid conjugates 40–42 ) or victim drugs 43,44 , there are few significant associations of genetic polymorphisms in SLC22A6 or SLC22A8 with drug levels or response. In fact, to our knowledge, only one study showed a significant association (p<0.05) of an SLC22A8 Asian-specific non-synonymous variant, Ile305Phe (rs11568482) with reduced renal and secretory clearance of the antibiotic, cefotaxime 45 .…”

Section: Polymorphisms In Other Drug Transporters With Less Evidencementioning

confidence: 99%

Influence of Transporter Polymorphisms on Drug Disposition and Response: A Perspective From the International Transporter Consortium

Yee

Brackman

Ennis

et al. 2018

109

Advances in genomic technologies have led to a wealth of information identifying genetic polymorphisms in membrane transporters, specifically how these polymorphisms affect drug disposition and response. This review describes the current perspective of the International Transporter Consortium (ITC) on clinically important polymorphisms in membrane transporters. ITC suggests that, in addition to previously recommended polymorphisms in ABCG2 (BCRP) and SLCO1B1 (OATP1B1), polymorphisms in the emerging transporter, SLC22A1 (OCT1), be considered during drug development. Collectively, polymorphisms in these transporters are important determinants of interindividual differences in the levels, toxicities, and response to many drugs.