The pharmacokinetics of oral trazpiroben (TAK‐906) after organic anion transporting polypeptide 1B1/1B3 inhibition: A phase I, randomized study

• Published in: Clinical and translational science Vol. 15; no. 6; pp. 1532 - 1543
• Main Authors: Mukker, Jatinder K., Dukes, George, Tolkoff, Max, Wang, Lisi, Almansa, Cristina, Huh, Susanna Y., Nishihara, Mitsuhiro, Ramsden, Diane, Chen, Chunlin
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.06.2022; John Wiley and Sons Inc; Wiley
• Subjects: Bile; Bioavailability; Biomarkers; By products; Dopamine; Dopamine D2 receptors; Dopamine D3 receptors; Drug dosages; FDA approval; Gastroesophageal reflux; Intravenous administration; Metabolism; Nervous system; Oral administration; Organic anion transporting polypeptide; Ostomy; Pharmacokinetics; Polypeptides; Polypharmacy; Potassium; Rifampin; Urine; United States > US
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/cts.13274

Trazpiroben is a dopamine D2/D3 receptor antagonist under development for the treatment of gastroparesis. This phase I, open‐label, randomized, two‐way crossover study (NCT04121078) evaluated the effect of single‐dose intravenous rifampin, a potent inhibitor of the organic anion transporting polypeptides (OATPs) 1B1 and 1B3, on the pharmacokinetics and safety of trazpiroben in healthy adults. The utility of coproporphyrin (CP) I and CPIII as biomarkers of OATP inhibition was also assessed. Overall, 12 participants were enrolled and randomized (1:1) into one of two treatment sequences (AB and BA). Participants received either a single oral dose of trazpiroben 25 mg (treatment A) or a single oral dose of trazpiroben 25 mg immediately after a single 30‐min intravenous infusion of rifampin 600 mg (treatment B). After a washout period of at least 7 days, participants received the other treatment. Geometric mean area under the curve from time 0 extrapolated to infinity (AUC∞) and maximum serum concentration (Cmax) of plasma trazpiroben were higher in participants receiving treatment B than those receiving treatment A (AUC∞, 168.5 vs. 32.68 ng*h/ml; Cmax, 89.62 vs. 14.37 ng/ml); corresponding geometric mean ratios (90% confidence interval) showed 5.16 (4.25–6.25) and 6.24 (4.62–8.42)‐fold increases in these parameters, respectively. In this study, trazpiroben was confirmed as a substrate of OATP1B1/1B3, and therefore co‐administration of trazpiroben with moderate to strong inhibitors of OATP1B1/1B3 is not recommended. This is also the first assessment of the utility of CPI and CPIII as endogenous biomarkers of OATP1B1/1B3 inhibition after a single intravenous dose of rifampin.