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

Mukker, Jatinder Kaur; Dukes, George E.; Tolkoff, Max; Wang, Lisi; Almansa, Cristina; Huh, Susanna Y.; Nishihara, Masateru; Ramsden, Diane; Chen, Chunlin

doi:10.1111/cts.13274

Cited by 4 publications

(2 citation statements)

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“…Previous in vitro and animal studies demonstrated that trazpiroben selectively antagonizes D 2 /D 3 receptors with limited central nervous system penetrance, and also shows low affinity for the hERG potassium channel 16,17 . With respect to human studies, trazpiroben was well tolerated in phase 1 clinical trials (NCT03237156) and during phase 1 clinical pharmacology studies 18–22 . A phase 2a study (NCT03268941) assessed the safety profile, pharmacokinetics (PK), and pharmacodynamics of trazpiroben in patients with gastroparesis, with pharmacodynamics evaluated by the effect of trazpiroben on prolactin levels and gastric function 23 .…”

Section: Introductionmentioning

confidence: 99%

“…16,17 With respect to human studies, trazpiroben was well tolerated in phase 1 clinical trials (NCT03237156) and during phase 1 clinical pharmacology studies. [18][19][20][21][22] A phase 2a study (NCT03268941) assessed the safety profile, pharmacokinetics (PK), and pharmacodynamics of trazpiroben in patients with gastroparesis, with pharmacodynamics evaluated by the effect of trazpiroben on prolactin levels and gastric function. 23 This phase 2a study showed significantly improved volume-to-fullness following the nutrient drink test, and improved American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary (ANMS GCSI-DD) symptom scores with trazpiroben, further supporting its development to treat gastroparesis.…”

Section: Introductionmentioning

confidence: 99%

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Randomized clinical trial: A phase 2b controlled study of the efficacy and safety of trazpiroben (TAK‐906) for idiopathic or diabetic gastroparesis

Tack

McCallum

Kuo

et al. 2023

Neurogastroenterology Motil

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BackgroundPrevious clinical studies of trazpiroben, a dopamine D2/D3 receptor antagonist for long‐term treatment of moderate‐to‐severe idiopathic and diabetic gastroparesis, have shown improved symptoms of fullness. This study assessed trazpiroben efficacy, safety, and tolerability in adults with idiopathic and diabetic gastroparesis versus placebo.MethodsThis global, multicenter, double‐blind, parallel‐group, phase 2b study (NCT03544229) enrolled eligible adults aged 18–85 years with symptomatic idiopathic or diabetic gastroparesis. Randomized participants received either oral placebo or trazpiroben 5, 25, or 50 mg, administered twice daily over 12 weeks, and completed the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index‐Daily Diary. Change in weekly composite score from baseline to week 12 (primary endpoint) and treatment‐emergent adverse events were assessed. Data were summarized descriptively.Key ResultsOverall, 242 participants were enrolled (mean [standard deviation] age 55.7 [14.2] years; 75.6% female); 193 completed the study. No significant differences in change from baseline in weekly average of the daily diary composite score occurred at week 12 between placebo (least‐squares mean [standard error] −1.19 [0.12]) and trazpiroben (5, 25, and 50 mg: −1.11 [0.22], −1.17 [0.12], and −1.21 [0.12], respectively). Overall, 41.4% of participants receiving trazpiroben reported treatment‐emergent adverse events (placebo, 39.7%). No serious events were considered trazpiroben‐related; no life‐threatening or fatal events were reported.Conclusions & InferencesThere was no clinically meaningful difference in efficacy between trazpiroben and placebo in treating gastroparesis, based on the primary endpoint analysis. Trazpiroben was well tolerated with no new safety concerns identified, strengthening evidence supporting its favorable safety profile.NCT number: NCT03544229.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Randomized clinical trial: A phase 2b controlled study of the efficacy and safety of trazpiroben (TAK‐906) for idiopathic or diabetic gastroparesis

Tack

McCallum

Kuo

et al. 2023

Neurogastroenterology Motil

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

Mukker

Dukes

Tolkoff

et al. 2022

Clinical Translational Sci

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Trazpiroben is a dopamine D 2 /D 3 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 (C max ) of plasma trazpiroben were higher in participants receiving treatment B than those receiving treatment A (AUC ∞ , 168.5 vs. 32.68 ng*h/ml; C max , 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. | 1533 THE PKs OF TRAZPIROBEN AFTER OATP1B1/1B3 INHIBITION Received a single oral dose of trazpiroben 25 mg immediately following a single i.v. dose of rifampin 600 mg (n = 6) Allocated to treatment sequence AB (n = 6) Received a single oral dose of trazpiroben 25 mg (n = 6) Received a single oral dose of trazpiroben 25 mg immediately following a single i.v. dose of rifampin 600 mg (n = 6) Received a single oral dose of trazpiroben 25 mg (n = 6) Enrollment Allocation Analyzed (n = 12) a Follow-up (14 days ± 2 days) • Lost to follow-up (n = 0) Follow-up Analysis

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The Role of Coproporphyrins As Endogenous Biomarkers for Organic Anion Transporting Polypeptide 1B Inhibition–Progress from 2016 to 2023

Lai

2023

Drug Metab Dispos

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Since the initial clinical study investigating CP-I and CP-III as endogenous biomarkers for OATP inhibition DDIs published in 2016, significant progress has been made in confirming the usefulness of the CPs, particularly the CP-I, as biomarkers in assessing OATP inhibition DDIs. CP-I exhibits selectivity towards OATP1B activity in human subjects with genetic variants of OATP1B1. Its sensitivity to a broad spectrum of clinical OATP1B inhibitors has been established, from weak to vigorous. Dose-dependent CP-I changes in healthy human subjects show agreement with DDI magnitudes of probe substrates by rifampin treatment. PBPK models have been established for concentration changes of plasma CP-I with OATP inhibitors, demonstrating the usefulness of supporting the quantitative translation of the effect of CP-I levels into the DDI risk assessment of potential OATP inhibitors. As plasma CP-I's sensitivity, specificity, and selectivity have been validated in humans, monitoring CP-I levels in single and multiple clinical phase I dose escalation studies is recommended for early assessment of DDI risks and understanding the full dose-response of an investigational drug to OATP inhibitions. A decision tree is proposed to preclude the need to conduct a dedicated DDI study by administering a probe substrate drug to human subjects.

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

Cited by 4 publications

References 44 publications

Randomized clinical trial: A phase 2b controlled study of the efficacy and safety of trazpiroben (TAK‐906) for idiopathic or diabetic gastroparesis

Randomized clinical trial: A phase 2b controlled study of the efficacy and safety of trazpiroben (TAK‐906) for idiopathic or diabetic gastroparesis

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

The Role of Coproporphyrins As Endogenous Biomarkers for Organic Anion Transporting Polypeptide 1B Inhibition–Progress from 2016 to 2023

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