The pharmacokinetics of oral trazpiroben (TAK-906) after organic anion transporting polypeptide 1B1/1B3 inhibition: A phase I, randomized study.
Clin Transl Sci
; 15(6): 1532-1543, 2022 06.
Article
em En
| MEDLINE
| ID: mdl-35460165
ABSTRACT
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 (11) 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Rifampina
/
Transportadores de Ânions Orgânicos
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Adult
/
Humans
Idioma:
En
Revista:
Clin Transl Sci
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos