title: Pharmacokinetics of Empagliflozin and Pioglitazone After Coadministration in Healthy Volunteers.
abstract: OBJECTIVE
  The aim was to investigate the effects of coadministration of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin with the thiazolidinedione pioglitazone.
  
  
  METHODS
  In study 1, 20 healthy volunteers received 50 mg of empagliflozin alone for 5 days, followed by 50 mg of empagliflozin coadministered with 45 mg of pioglitazone for 7 days and 45 mg of pioglitazone alone for 7 days in 1 of 2 treatment sequences. In study 2, 20 volunteers received 45 mg of pioglitazone alone for 7 days and 10, 25, and 50 mg of empagliflozin for 9 days coadministered with 45 mg of pioglitazone for the first 7 days in 1 of 4 treatment sequences.
  
  
  RESULTS
  Pioglitazone exposure (Cmax and AUC) increased when coadministered with empagliflozin versus monotherapy in study 1. The geometric mean ratio (GMR) for pioglitazone Cmax at steady state (Cmax,ss) and for AUC during the dosing interval at steady state (AUCτ,ss) when coadministered with empagliflozin versus administration alone was 187.89% (95% CI, 166.35%-212.23%) and 157.97% (95% CI, 148.02%-168.58%), respectively. Because an increase in pioglitazone exposure was not expected, based on in vitro data, a second study was conducted with the empagliflozin doses tested in Phase III trials. In study 2, pioglitazone exposure decreased marginally when coadministered with empagliflozin. The GMR for pioglitazone Cmax,ss when coadministered with empagliflozin versus administration alone was 87.74% (95% CI, 73.88%-104.21%) with empagliflozin 10 mg, 90.23% (95% CI, 66.84%-121.82%) with empagliflozin 25 mg, and 89.85% (95% CI, 71.03%-113.66%) with empagliflozin 50 mg. The GMR for pioglitazone AUCτ,ss when coadministered with empagliflozin versus administration alone was 90.01% (95% CI, 77.91%-103.99%) with empagliflozin 10 mg, 88.98% (95% CI, 72.69%-108.92%) with empagliflozin 25 mg, and 91.10% (95% CI, 77.40%-107.22%) with empagliflozin 50 mg. The effects of empagliflozin on pioglitazone exposure are not considered to be clinically relevant. Empagliflozin exposure was unaffected by coadministration with pioglitazone. Empagliflozin and pioglitazone were well tolerated when administered alone or in combination. In study 1, adverse events were reported in 1 of 19 participants on empagliflozin 50 mg alone, 4 of 20 on pioglitazone alone, and 5 of 18 on combination treatment. In study 2, adverse events were reported in 8 of 20 participants on pioglitazone alone, 10 of 18 when coadministered with empagliflozin 10 mg, 5 of 17 when coadministered with empagliflozin 25 mg, and 6 of 16 when coadministered with empagliflozin 50 mg.
  
  
  CONCLUSIONS
  These results indicate that pioglitazone and empagliflozin can be coadministered without dose adjustments. EudraCT identifiers: 2008-006087-11 (study 1) and 2009-018089-36 (study 2).
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut.
authors.forename: Sreeraj
authors.initials: S
authors.lastname: Macha
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Mattheus
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Pinnetti
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany. Electronic address: uli.broedl@boehringer-ingelheim.com.
authors.forename: Uli C
authors.initials: UC
authors.lastname: Broedl
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Woerle
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005960:Glucosides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D045162:Thiazolidinediones; C570240:empagliflozin; D000077205:Pioglitazone
keywords: SGLT2 inhibitor; diabetes; drug–drug interaction; thiazolidinedione