title: Pharmacokinetic drug-drug interaction study of ranolazine and metformin in subjects with type 2 diabetes mellitus.
abstract: Ranolazine and metformin may be frequently co-administered in subjects with chronic angina and co-morbid type 2 diabetes mellitus (T2DM). The potential for a drug-drug interaction was explored in two phase 1 clinical studies in subjects with T2DM to evaluate the pharmacokinetics and safety of metformin 1000 mg BID when administered with ranolazine 1000 mg BID (Study 1, N = 28) or ranolazine 500 mg BID (Study 2, N = 25) as compared to metformin alone. Co-administration of ranolazine 1000 mg BID with metformin 1000 mg BID resulted in 1.53- and 1.79-fold increases in steady-state metformin Cmax and AUCtau , respectively; co-administration of ranolazine 500 mg BID with metformin 1000 mg BID resulted in 1.22- and 1.37-fold increases in steady-state metformin Cmax and AUCtau , respectively. Co-administration of ranolazine and metformin was well tolerated in these T2DM subjects, with no serious adverse events or drug-related adverse events leading to discontinuation. The most common adverse events were nausea, diarrhea, and dizziness. These findings are consistent with a dose-related interaction between ranolazine and metformin, and suggest that a dose adjustment of metformin may not be required with ranolazine 500 mg BID; whereas, the metformin dose should not exceed 1700 mg of total daily dose when using ranolazine 1000 mg BID.
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Zack
authors.affiliation: DaVita Clinical Research, Minneapolis, MN, USA.
authors.forename: Jolene
authors.initials: J
authors.lastname: Berg
authors.affiliation: SeaView Research, Inc., Miami, FL, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Juan
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Pannacciulli
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Martine
authors.initials: M
authors.lastname: Allard
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Mildred
authors.initials: M
authors.lastname: Gottwald
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Yongwu
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Cardiovascular Research Foundation, New York, NY, USA.
authors.forename: Ori
authors.initials: O
authors.lastname: Ben-Yehuda
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Phil
authors.initials: P
authors.lastname: Jochelson
mesh_terms: D000328:Adult; D000368:Aged; D000787:Angina Pectoris / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D000818:Animals; D019540:Area Under Curve; D016466:CHO Cells; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002908:Chronic Disease; D015897:Comorbidity; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D000075102:Organic Cation Transporter 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019338:Polypharmacy; D000069458:Ranolazine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014481:United States
chemical_list: D002317:Cardiovascular Agents; D007004:Hypoglycemic Agents; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; D008687:Metformin; D000069458:Ranolazine
keywords: chronic angina; drug interactions; metformin; pharmacokinetics; ranolazine; type 2 diabetes mellitus