YH12852, a Potent and Selective Receptor Agonist of 5-hydroxytryptamine, Increased Gastrointestinal Motility in Healthy Volunteers and Patients With Functional Constipation.

Gastrointestinal (GI) motility disorders are common, decreases quality of life, and imposes a substantial economic burden. YH12852 is a novel agonist of 5-hydroxytryptamine for the treatment of GI motility disorders. This phase I/IIa study assessed the tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of YH12852. In the multiple dose (MD) cohort, healthy subjects and patients with functional constipation were randomized and received orally YH12852 at 0.3, 0.5, 1, 2, or 3 mg or prucalopride 2 mg or their matching placebo, once daily for 14 days after breakfast. In the multiple low-dose cohort (MLD), healthy subjects randomly received once-daily oral doses of YH12852 at 0.05 or 0.1 mg for 14 days after breakfast. Questionnaires, gastric emptying breath test for PDs, and plasma samples for PKs were collected. In the MD cohort, a total of 56 subjects (29 healthy volunteers and 27 patients with functional constipation) were randomized, of whom 48 completed the study. In the MLD cohort, a total of 16 healthy subjects were randomized, and 15 subjects completed the study. YH12852 increased the average weekly frequency of spontaneous bowel movements and loosened the stool. In addition, YH12852 increased quality of life satisfaction, and decreased severity of constipation symptom and GI symptoms. YH12852 was safe and well-tolerated up to 3 mg and showed nearly dose proportional PKs. In conclusion, YH12852 was safe and enhanced GI motility. YH12852 can be developed as an effective treatment option for GI motility disorders, including functional constipation. Further studies are warranted to confirm this possibility.

Pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers: a randomized, open-label, 3-period, crossover, multiple-dose study.

PURPOSE: Rosuvastatin is indicated for hypercholesterolemia or dyslipidemia and metformin mainly for type 2 diabetes. These 2 drugs are frequently prescribed in combination due to the high comorbidity of the 2 diseases. However the nature of pharmacokinetic interaction between the 2 drugs has not been previously investigated. The purpose of our study was to investigate the pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers. METHODS: This was a randomized, open-label, 6-sequence, 3-period, crossover, multiple-dose study. Eligible subjects, aged 20 to 50 years and within 20% of the ideal body weight, received 1 of the following 3 treatments for each period once daily for 5 consecutive days with a 10-day washout period between the treatments: monoadministration of rosuvastatin 10 mg tablet, monoadministration of metformin 750 mg tablet, and coadministration of rosuvastatin 10 mg tablet with metformin 750 mg tablet. Blood samples were collected up to 72 hours after the last dose and pharmacokinetic parameters for rosuvastatin and metformin were compared between combination and monotherapy. Adverse events were investigated and evaluated based on subject interviews and physical examinations. FINDINGS: Among the 36 enrolled subjects, 31 completed the study. The coadministration of rosuvastatin with metformin produced a significant pharmacokinetic interaction in rosuvastatin Css,max, with the 90% CI for the geometric mean ratio (coadministration:monoadministration) being 110.27% to 136.39% (P = 0.0029), whereas no significant interaction was observed in rosuvastatin AUCtau, yielding the 90% CI of 104.41% to 118.95%. When metformin was coadministered with rosuvastatin, no significant pharmacokinetic interaction was observed for Css,max and AUCtau of metformin, yielding the 90% CIs of the geometric mean ratio for coadministration to monoadministration as 87.38% to 102.54% and 86.70% to 99.08%, respectively. Overall, 19 mild and 1 moderate adverse events occurred in 12 subjects, with no significant differences in the incidence among the 3 treatments. IMPLICATIONS: Although the Css,max of rosuvastatin was significantly influenced by coadministration with metformin, the degree of interaction seen was considered clinically insignificant, with no significant interaction observed in the other pharmacokinetic measures between the 2 drugs. These results imply that drug effects of rosuvastatin and metformin will also not be significantly influenced by coadministration of the 2 drugs. All treatments were well tolerated and no serious adverse events occurred. ClinicalTrials.gov identifier: NCT01526317.