title: Effect of ketoconazole on lobeglitazone pharmacokinetics in Korean volunteers.
abstract: OBJECTIVE
  Lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, is metabolized primarily by the cytochrome P450 (CYP) 3A4 isoenzyme. Individuals concomitantly taking lobeglitazone and a CYP3A4 inhibitor may experience some adverse effects secondary to increased systemic exposure to lobeglitazone. To address such potential concern, we evaluated the effects of ketoconazole, a prototypic CYP3A4 inhibitor, on the pharmacokinetic (PK) properties and associated adverse effects of lobeglitazone.
  
  
  METHODS
  A PK drug-drug interaction study was conducted in healthy individuals between 20 and 45 years old in a randomized, open-label, 2-way crossover design. Even though the PK study was performed on a single dose of lobeglitazone, multiple ketoconazole doses were given to ensure that the full extent of inhibition of CYP3A4 was maintained during the PK sampling. All study participants received a single oral dose of lobeglitazone 0.5 mg with or without 9 oral 200-mg doses of ketoconazole pretreatment twice daily. The primary PK parameter end points (AUC and Cmax) were estimated using noncompartmental analysis, and the 90% CIs for the geometric mean ratios (ratio of lobeglitazone and ketoconazole to lobeglitazone alone) were investigated. Tolerability (adverse events, vital signs, ECG, and laboratory tests) was also assessed.
  
  
  RESULTS
  A total of 24 Korean men (mean age, 26 years; age range, 20-32 years; mean weight, 68 kg; weight range, 59-81 kg) completed the study and were evaluable for lobeglitazone PK properties and tolerability. The mean (SD) Cmax values of lobeglitazone with and without ketoconazole were 49 (7) ng/mL and 48 (6) ng/mL at 1.5 and 1.0 hours after dosing, respectively. The mean (SD) AUC∞ values were 532 (117) ng·h/mL and 405 (110) ng·h/mL, respectively. Although the Cmax was not significantly affected, the geometric mean ratio for AUC∞ was increased by a point estimate of 1.33 (90% CI, 1.23-1.44). A single oral administration of lobeglitazone 0.5 mg with or without ketoconazole pretreatment did not produce any clinically significant adverse effects on vital signs, 12-lead ECG profiles, or laboratory tests.
  
  
  CONCLUSIONS
  The administration of lobeglitazone, 0.5 mg alone or in combination with multiple doses of ketoconazole, was generally well tolerated. The systemic exposure of lobeglitazone was increased to a modest extent by pretreatment with 9 twice-daily doses of ketoconazole. Clinicaltrials.gov identifier: NCT01330563.
authors.affiliation: Department of Pharmaceutical Medicine and Regulatory Sciences, Colleges of Medicine and Pharmacy, Yonsei University, Incheon, Korea; Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Korea.
authors.forename: Eun
authors.initials: E
authors.lastname: Sil Oh
authors.affiliation: Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Korea.
authors.forename: Choon
authors.initials: C
authors.lastname: Ok Kim
authors.affiliation: Department of Pharmaceutical Medicine and Regulatory Sciences, Colleges of Medicine and Pharmacy, Yonsei University, Incheon, Korea; Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Korea.
authors.forename: Ki Hyon
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Korea.
authors.forename: Youn Nam
authors.initials: YN
authors.lastname: Kim
authors.affiliation: Chong Kun Dang Clinical Research and Clinical Epidemiology and Medical Information, CKD Pharmaceuticals, Seoul, Korea.
authors.forename: Chin
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Medicine and Regulatory Sciences, Colleges of Medicine and Pharmacy, Yonsei University, Incheon, Korea; Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Korea; Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon, Korea. Electronic address: ike.lee@yonsei.ac.kr.
authors.forename: Jangik I
authors.initials: JI
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Medicine and Regulatory Sciences, Colleges of Medicine and Pharmacy, Yonsei University, Incheon, Korea; Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Korea; Department of Pediatrics, Colleges of Medicine, Yonsei University, Seoul, Korea. Electronic address: minspark@yuhs.ac.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Park
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004347:Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D056910:Republic of Korea; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D011743:Pyrimidines; D045162:Thiazolidinediones; C546215:lobeglitazone; D007654:Ketoconazole
keywords: CYP3A4; drug interaction ketoconazole; lobeglitazone; pharmacokinetics