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

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.

Evaluation of the drug-drug interaction potential for trazpiroben (TAK-906), a D2/D3 receptor antagonist for gastroparesis, towards cytochrome P450s and transporters.

Trazpiroben (TAK-906), a peripherally selective dopamine D2/D3 receptor antagonist, is being developed for the treatment of patients with gastroparesis. The potential of trazpiroben to act as a perpetrator or a victim for cytochrome P450 (CYP)- or transporter- mediated drug-drug interactions (DDIs) was evaluated following the latest regulatory guidelines.In vitro studies revealed that trazpiroben is metabolised mainly through a non-CYP pathway (56.7%) by multiple cytosolic, NADPH-dependent reductase, such as aldo-keto reductase and short-chain dehydrogenase/reductase including carbonyl reductases. Remaining metabolism occurs through CYP3A4 and CYP2C8 (43.3%). Trazpiroben is neither an inhibitor nor an inducer of major CYP enzymes at a clinically relevant dose. It is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/1B3, but is not an inhibitor of transporters listed in the DDI guidelines at a clinically relevant dose. This is consistent with findings from CYP3A and P-gp-based clinical assessment showing no substantial change (≤2-fold) in trazpiroben exposure when co-administered with itraconazole.Collectively, trazpiroben has low potential of enzyme-mediated DDIs and is unlikely to act as a perpetrator of transporter-mediated DDIs but there may be a potential to act as a victim of OATP1B1/1B3 DDI that will be evaluated clinically.

The effect of genetic polymorphisms in UGT2B15 on the pharmacokinetic profile of sipoglitazar, a novel anti-diabetic agent.

PURPOSE: Sipoglitazar was a novel, azolealkanoic acid derivative that possesses selective activity for the peroxisome proliferator-activated receptors (PPAR) PPARγ, PPARα, and PPARδ. The compound undergoes phase II biotransformation by conjugation catalyzed by UDP-glucuronosyltransferase (UGT). The aim of this analysis was to explore the influence of genetic polymorphism in UGT on the pharmacokinetics of sipoglitazar. METHODS: Three preliminary phase I clinical pharmacology studies were conducted in tandem in healthy human subjects. Genotyping was undertaken in a total of 82 subjects in the phase I program for the purpose of genotyping UGT polymorphisms. Plasma samples were collected for up to 48 h post-dose to characterize the pharmacokinetic profile following a single oral dose of the drug. RESULTS: Plasma concentrations of sipoglitazar and the distribution of dose-normalized individual values for area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)) before any stratification were considerably skewed with a multi-modal distribution. The proportion of variability in AUC(0-∞) explained by UGT2B15 was 66.7 % (P < 0.0001); the addition of other genetic or demographic factors was not statistically significant. Subjects homozygous for the UGT2B15 D85Y variant (UGT2B15*2/*2) were exposed to greater plasma concentrations of sipoglitazar than subjects homozygous for the wild-type allele UGT2B15*1/*1 (3.26-fold higher) or heterozygous allele UGT2B15*1/*2 (2.16-fold higher). CONCLUSIONS: These results indicate that sipoglitazar clearance is substantially modified by UGT2B15 enzyme variants, with higher exposure observed in the UGT2B15*2/*2 genotype group.

Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: modification of the core skeleton for improved solubility.

We recently reported the discovery of the novel pyrrolo[3,2-c]quinoline-4-one derivative 1 as a potent inhibitor of Hedgehog (Hh) pathway signaling. However, the PK evaluation of 1 at high dosage (100 mg/kg) revealed the C(max) value 3.63 µg/mL, likely due to poor solubility of this compound. Efforts to improve solubility by reducing the aromatic ring count of the core system led to N-methylpyrrolo[3,2-c]pyridine derivative 11. Further optimization of the 3-alkoxy group led to compound 11d with acceptable solubility and potent Hh inhibitory activity. Compound 11d suppressed transcription factor Gli1 mRNA expression in tumor-associated stromal tissue and inhibited tumor growth (treatment/control ratio, 3%) in a mouse medulloblastoma allograft model owing to the improved PK profile based on increased solubility. Compound 11d (TAK-441) is currently in clinical trials for the treatment of advanced solid tumors.

An unusual metabolic pathway of sipoglitazar, a novel antidiabetic agent: cytochrome P450-catalyzed oxidation of sipoglitazar acyl glucuronide.

Animal pharmacokinetic studies of sipoglitazar, a novel antidiabetic agent, showed that the deethylated metabolite (M-I) and the glucuronide conjugate of sipoglitazar (sipoglitazar-G) appeared to be the key metabolites in the elimination process. M-I was also measured as the main metabolite in the plasma of humans administered sipoglitazar. In vitro metabolic studies were performed to investigate the metabolic pathways from sipoglitazar to M-I in humans. The metabolic profile with human hepatocytes and hepatic microsomes indicated that M-I was not formed directly from sipoglitazar and that sipoglitazar-G was involved in the metabolism from sipoglitazar to M-I. Further studies of the metabolism of sipoglitazar-G revealed that the properties of the glucuronide conjugate and its metabolism are as follows: high-performance liquid chromatography, liquid chromatography-tandem mass spectrometry, and NMR analyses showed that sipoglitazar-G was composed of two glucuronides, sipoglitazar-G1, a ß-1-O-acyl glucuronide, and sipoglitazar-G2, an α-2-O-acyl glucuronide. The stability study of these glucuronides suggested that sipoglitazar-G1 could be converted to sipoglitazar-G2 and sipoglitazar, but sipoglitazar-G2 could not be converted to sipoglitazar-G1. The oxidative metabolic study of sipoglitazar-G1 and -G2 with human hepatic microsomes and cytochrome P450-expressing microsomes revealed that M-I was formed only from sipoglitazar-G1, not from sipoglitazar-G2, and that CYP2C8 was mainly involved in this process. From these results, it is shown that the metabolic pathway from sipoglitazar to M-I is an unusual one, in which sipoglitazar is initially metabolized to sipoglitazar-G1 by UDP-glucuronosyltransferase and then sipoglitazar-G1 is metabolized to M-I by O-dealkylation by CYP2C8 and deconjugation. Sipoglitazar-G2 is sequentially formed by the migration of the ß-site of sipoglitazar-G1.