title: Pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers: a randomized, open-label, 3-period, crossover, multiple-dose study.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea.
authors: Donghwan
authors: D
authors: Lee
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea.
authors: Hyerang
authors: H
authors: Roh
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea.
authors: Hankil
authors: H
authors: Son
authors: Yuhan Research Institute, Yuhan Corporation, Seoul, Korea.
authors: Seong Bok
authors: SB
authors: Jang
authors: Yuhan Research Institute, Yuhan Corporation, Seoul, Korea.
authors: Seoungoh
authors: S
authors: Lee
authors: Yuhan Research Institute, Yuhan Corporation, Seoul, Korea.
authors: Su Youn
authors: SY
authors: Nam
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Korea. Electronic address: kspark@yuhs.ac.
authors: Kyungsoo
authors: K
authors: Park
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000009:adverse effects; D064368:Healthy Volunteers; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D056910:Republic of Korea; D000068718:Rosuvastatin Calcium / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D000068718:Rosuvastatin Calcium; D008687:Metformin
keywords: Drug–drug interaction; metformin; pharmacokinetics; rosuvastatin