036: Endogenous Biomarker Use in Renal Transporter-Mediated Drug Interactions: A Literature Review of Intrinsic, Extrinsic Factors & Disease Impact on Biomarker Levels

Statement of Purpose, Innovation or Hypothesis: Assessing drug interactions during clinical development may involve the liability analysis of CYP enzymes, transporters, and/or co-medications, which may impact pharmacokinetics up to a significant extent¹. Recently, novel approach of predicting transporter-mediated drug-drug interactions (DDIs) in phase I studies involves measuring plasma- and/or urine-based endogenous biomarkers². Coproporphyrin I is an established biomarker to assess hepatic transporter mediated drug interaction³. However, sparse clinical data is available for endogenous biomarkers to be utilized for renal transporter mediated drug interaction. Therefore, our literature review aims to evaluate potential renal transporter biomarkers identified in prior studies, such as pyridoxic acid (PDA) and homovanillic acid (HVA) for OAT1/3 transporters. The review focuses on intrinsic and extrinsic factors, as well as disease impacts on biomarker baseline level changes in humans.

Description of Methods & Materials: This review utilized the PubMed database. A keyword search was conducted using the following terms: (“selected biomarker-PDA/ HVA”) AND ((food) OR (drug) OR (renal impairment OR hepatic impairment OR cancer OR pediatric OR special population OR transplant)).

Data & Results: After applying the search term for PDA and HVA, there were 54 and 87 relevant articles available, respectively. Upon reviewing the articles, the number of articles that contained relevant clinical findings and baseline levels of each biomarker narrowed down to 8 and 7 respectively. For PDA, a derivative of vitamin B6, the baseline level is proportionally elevated with vitamin B6 catabolism level in both healthy volunteers and patients with diseases⁴. Additionally, vitamin B supplementation led to a 2.39-fold increase⁵, oral contraceptive use resulted in a 1.54 – 3.00-fold increase⁶, and colorectal malignancy showed a decrease in plasma from 0.946 to 1.00-fold^7,8, while rheumatoid arthritis showed a decrease of 0.727-fold in urine⁹. For Attention Deficit Hyperactivity Disorder (ADHD) patients without ADHD treating medication, their PDA baseline was 1.24-fold higher than that of healthy controls¹⁰. However, when ADHD patients taking methylphenidate, their baseline was only 1.02-fold higher than that of healthy controls¹⁰. For End Stage Renal Disease patients, their plasma baseline was elevated¹¹, whereas for chronic liver disease patients, their plasma baseline was decreased by 0.697-fold¹².

For HVA, a dopamine derivative, schizophrenia patients showed no significant difference in their plasma baseline level non-schizophrenic patients^13,14. However, first episode schizophrenia responders showed a higher HVA baseline level than non-responders, and this trend maintained 1 week after post-dose of haloperidol¹⁵. Regarding psychosis, there was no noticeable difference in plasma baseline levels of HVA between relapsers versus non-relapsers¹⁶, first-episode psychosis patients versus healthy controls¹⁷, and responders versus non-responders¹⁸. Lastly, regarding drug addiction, the baseline level of HVA in patients who were either heroin or cocaine dependent was 0.573-fold lower than in healthy controls¹⁹.

Interpretation, Conclusion or Significance: Accounting for the interplay of factors affecting baseline levels of renal transporter biomarkers is crucial for the accurate assessment of DDIs because the variability introduced by these factors can impact the interpretation and reliability of DDI assessments. Performing a comprehensive review and understanding of biomarker fluctuations in relevant patient demographics could refine DDI predictions and therapeutic strategies.

Disclosures: All authors are employees of Boehringer Ingelheim.

Citations/References: 1. Kanefendt F, Brase C, Jungmann N, Fricke R, Engelen A, Schmitz S. Pharmacokinetics of asundexian with combined CYP3A and P-gp inhibitors and an inducer: Target in vitro and in vivo studies. Br J Clin Pharmacol. 2024 Apr;90(4):1036-1049. doi: 10.1111/bcp.15981. Epub 2024 Jan 9. PMID: 38048692. 2. Chu X, Liao M, Shen H, Yoshida K, Zur AA, Arya V, Galetin A, Giacomini KM, Hanna I, Kusuhara H, Lai Y, Rodrigues D, Sugiyama Y, Zamek-Gliszczynski MJ, Zhang L; International Transporter Consortium. Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug-Drug Interaction Evaluation: Perspectives From the International Transporter Consortium. Clin Pharmacol Ther. 2018 Nov;104(5):836-864. doi: 10.1002/cpt.1216. PMID: 30347454. 3. Takita H, Scotcher D, Chu X, Yee KL, Ogungbenro K, Galetin A. Coproporphyrin I as an Endogenous Biomarker to Detect Reduced OATP1B Activity and Shift in Elimination Route in Chronic Kidney Disease. 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Additional Information/Authors: This submission is not merely a standalone piece of research; it is a continuation and expansion of our ongoing investigation into this subject. Our preceding work, which concentrated on exploring endogenous biomarker candidates for assessing renal transporters – OCT2, MATE1/2K, OAT1/3, was presented as a poster at the American College of Clinical Pharmacology 2023 Annual Meeting held in Bellevue, Washington (poster number 029). The feedback we received has enriched this current study. Thank you.