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Effect of gemfibrozil, rifampicin, or probenecid on the pharmacokinetics of the SGLT2 inhibitor empagliflozin in healthy volunteers.
Clin Ther. 2014 Feb 01; 36(2):280-90.e1.CT

Abstract

BACKGROUND

Empagliflozin is a potent, oral, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus.

OBJECTIVE

The goal of these studies was to investigate potential drug-drug interactions between empagliflozin and gemfibrozil (an organic anion-transporting polypeptide 1B1 [OATP1B1]/1B3 and organic anion transporter 3 [OAT3] inhibitor), rifampicin (an OATP1B1/1B3 inhibitor), or probenecid (an OAT3 and uridine diphosphate glucuronosyltransferase inhibitor).

METHODS

Two open-label, randomized, crossover studies were undertaken in healthy subjects. In the first study, 18 subjects received the following in 1 of 2 randomized treatment sequences: a single dose of empagliflozin 25 mg alone and gemfibrozil 600 mg BID for 5 days with a single dose of empagliflozin 25 mg on the third day. In the second study, 18 subjects received a single dose of empagliflozin 10 mg, a single dose of empagliflozin 10 mg coadministered with a single dose of rifampicin 600 mg, and probenecid 500 mg BID for 4 days with a single dose of empagliflozin 10 mg on the second day in 1 of 6 randomized treatment sequences.

RESULTS

In the gemfibrozil study, 11 subjects were male, mean age was 35.1 years and mean body mass index (BMI) was 23.47 kg/m(2). In the rifampicin/probenecid study, 10 subjects were male, mean age was 32.7 years and mean BMI was 23.03 kg/m(2). Exposure to empagliflozin was increased by coadministration with gemfibrozil (AUC0-∞: geometric mean ratio [GMR], 158.50% [90% CI, 151.77-165.53]; Cmax: GMR, 115.00% [90% CI, 106.15-124.59]), rifampicin (AUC0-∞: GMR, 135.20% [90% CI, 129.58-141.06]; Cmax: GMR, 175.14% [90% CI, 160.14-191.56]), and probenecid (AUC0-∞: GMR, 153.47% [90% CI, 146.41-160.88]; Cmax: GMR, 125.60% [90% CI, 113.67-138.78]). All treatments were well tolerated.

CONCLUSIONS

Increases in empagliflozin exposure were <2-fold, indicating that the inhibition of the OATP1B1/1B3, OAT3 transporter, and uridine diphosphate glucuronosyltransferases did not have a clinically relevant effect on empagliflozin exposure. No dose adjustments of empagliflozin were necessary when it was coadministered with gemfibrozil, rifampicin, or probenecid. ClinicalTrials.gov identifiers: NCT01301742 and NCT01634100.

Authors+Show Affiliations

Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut. Electronic address: sreeraj.macha@boehringer-ingelheim.com.Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

24491572

Citation

Macha, Sreeraj, et al. "Effect of Gemfibrozil, Rifampicin, or Probenecid On the Pharmacokinetics of the SGLT2 Inhibitor Empagliflozin in Healthy Volunteers." Clinical Therapeutics, vol. 36, no. 2, 2014, pp. 280-90.e1.
Macha S, Koenen R, Sennewald R, et al. Effect of gemfibrozil, rifampicin, or probenecid on the pharmacokinetics of the SGLT2 inhibitor empagliflozin in healthy volunteers. Clin Ther. 2014;36(2):280-90.e1.
Macha, S., Koenen, R., Sennewald, R., Schöne, K., Hummel, N., Riedmaier, S., Woerle, H. J., Salsali, A., & Broedl, U. C. (2014). Effect of gemfibrozil, rifampicin, or probenecid on the pharmacokinetics of the SGLT2 inhibitor empagliflozin in healthy volunteers. Clinical Therapeutics, 36(2), 280-e1. https://doi.org/10.1016/j.clinthera.2014.01.003
Macha S, et al. Effect of Gemfibrozil, Rifampicin, or Probenecid On the Pharmacokinetics of the SGLT2 Inhibitor Empagliflozin in Healthy Volunteers. Clin Ther. 2014 Feb 1;36(2):280-90.e1. PubMed PMID: 24491572.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of gemfibrozil, rifampicin, or probenecid on the pharmacokinetics of the SGLT2 inhibitor empagliflozin in healthy volunteers. AU - Macha,Sreeraj, AU - Koenen,Rüdiger, AU - Sennewald,Regina, AU - Schöne,Katja, AU - Hummel,Noemi, AU - Riedmaier,Stephan, AU - Woerle,Hans J, AU - Salsali,Afshin, AU - Broedl,Uli C, Y1 - 2014/02/01/ PY - 2013/10/24/received PY - 2013/12/20/revised PY - 2014/01/07/accepted PY - 2014/2/5/entrez PY - 2014/2/5/pubmed PY - 2014/10/29/medline KW - drug interactions KW - empagliflozin KW - organic anion transporters KW - uridine diphosphate glucuronosyltransferase SP - 280 EP - 90.e1 JF - Clinical therapeutics JO - Clin Ther VL - 36 IS - 2 N2 - BACKGROUND: Empagliflozin is a potent, oral, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. OBJECTIVE: The goal of these studies was to investigate potential drug-drug interactions between empagliflozin and gemfibrozil (an organic anion-transporting polypeptide 1B1 [OATP1B1]/1B3 and organic anion transporter 3 [OAT3] inhibitor), rifampicin (an OATP1B1/1B3 inhibitor), or probenecid (an OAT3 and uridine diphosphate glucuronosyltransferase inhibitor). METHODS: Two open-label, randomized, crossover studies were undertaken in healthy subjects. In the first study, 18 subjects received the following in 1 of 2 randomized treatment sequences: a single dose of empagliflozin 25 mg alone and gemfibrozil 600 mg BID for 5 days with a single dose of empagliflozin 25 mg on the third day. In the second study, 18 subjects received a single dose of empagliflozin 10 mg, a single dose of empagliflozin 10 mg coadministered with a single dose of rifampicin 600 mg, and probenecid 500 mg BID for 4 days with a single dose of empagliflozin 10 mg on the second day in 1 of 6 randomized treatment sequences. RESULTS: In the gemfibrozil study, 11 subjects were male, mean age was 35.1 years and mean body mass index (BMI) was 23.47 kg/m(2). In the rifampicin/probenecid study, 10 subjects were male, mean age was 32.7 years and mean BMI was 23.03 kg/m(2). Exposure to empagliflozin was increased by coadministration with gemfibrozil (AUC0-∞: geometric mean ratio [GMR], 158.50% [90% CI, 151.77-165.53]; Cmax: GMR, 115.00% [90% CI, 106.15-124.59]), rifampicin (AUC0-∞: GMR, 135.20% [90% CI, 129.58-141.06]; Cmax: GMR, 175.14% [90% CI, 160.14-191.56]), and probenecid (AUC0-∞: GMR, 153.47% [90% CI, 146.41-160.88]; Cmax: GMR, 125.60% [90% CI, 113.67-138.78]). All treatments were well tolerated. CONCLUSIONS: Increases in empagliflozin exposure were <2-fold, indicating that the inhibition of the OATP1B1/1B3, OAT3 transporter, and uridine diphosphate glucuronosyltransferases did not have a clinically relevant effect on empagliflozin exposure. No dose adjustments of empagliflozin were necessary when it was coadministered with gemfibrozil, rifampicin, or probenecid. ClinicalTrials.gov identifiers: NCT01301742 and NCT01634100. SN - 1879-114X UR - https://www.unboundmedicine.com/medline/citation/24491572/Effect_of_gemfibrozil_rifampicin_or_probenecid_on_the_pharmacokinetics_of_the_SGLT2_inhibitor_empagliflozin_in_healthy_volunteers_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(14)00011-3 DB - PRIME DP - Unbound Medicine ER -