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Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions.
Br J Clin Pharmacol. 2018 09; 84(9):1941-1949.BJ

Abstract

AIMS

Previous pharmacokinetic characterization of a transporter probe cocktail containing digoxin (P-gp), furosemide (OAT1, OAT3), metformin (OCT2, MATE1, MATE2-K) and rosuvastatin (OATP1B1, OATP1B3, BCRP) in healthy subjects showed increases in rosuvastatin systemic exposure compared to rosuvastatin alone. In this trial, the doses of metformin and furosemide as putative perpetrators were reduced to eliminate their drug-drug interaction (DDI) with rosuvastatin.

METHODS

In a randomized, open-label, single-centre, five-treatment, five-period crossover trial, 30 healthy male subjects received as reference treatments separately 0.25 mg digoxin, 1 mg furosemide, 10 mg metformin and 10 mg rosuvastatin, and as test treatment all four drugs administered together as a cocktail. Primary pharmacokinetic endpoints were AUC0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration) and Cmax (maximum plasma concentration) of each probe drug.

RESULTS

Geometric mean ratios and 90% confidence intervals of test (cocktail) to reference (single drug) for AUC0-tz were 96.4% (88.2-105.3%) for digoxin, 102.6% (93.8-112.3%) for furosemide, 97.5% (93.5-101.6%) for metformin and 105.0% (96.4-114.4%) for rosuvastatin, indicating lack of interaction. The same analysis for Cmax and for pharmacokinetic parameters of urinary excretion of all cocktail components also indicated no DDI.

CONCLUSIONS

Digoxin (0.25 mg), furosemide (1 mg), metformin (10 mg) and rosuvastatin (10 mg) exhibit no mutual pharmacokinetic interactions and are well tolerated administered as a cocktail. The cocktail is thus optimized and has the potential to be used as a screening tool for clinical investigation of transporter-mediated DDI.

Authors+Show Affiliations

Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co. Ltd., Chuo-ku, Kobe City, Japan.Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany. Friedrich-Alexander-Universität Erlangen-Nürnberg, Institute of Experimental and Clinical Pharmacology and Toxicology, Fahrstr. 17, 91054, Erlangen, Germany.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29665130

Citation

Stopfer, Peter, et al. "Optimization of a Drug Transporter Probe Cocktail: Potential Screening Tool for Transporter-mediated Drug-drug Interactions." British Journal of Clinical Pharmacology, vol. 84, no. 9, 2018, pp. 1941-1949.
Stopfer P, Giessmann T, Hohl K, et al. Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions. Br J Clin Pharmacol. 2018;84(9):1941-1949.
Stopfer, P., Giessmann, T., Hohl, K., Hutzel, S., Schmidt, S., Gansser, D., Ishiguro, N., Taub, M. E., Sharma, A., Ebner, T., & Müller, F. (2018). Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions. British Journal of Clinical Pharmacology, 84(9), 1941-1949. https://doi.org/10.1111/bcp.13609
Stopfer P, et al. Optimization of a Drug Transporter Probe Cocktail: Potential Screening Tool for Transporter-mediated Drug-drug Interactions. Br J Clin Pharmacol. 2018;84(9):1941-1949. PubMed PMID: 29665130.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions. AU - Stopfer,Peter, AU - Giessmann,Thomas, AU - Hohl,Kathrin, AU - Hutzel,Sabine, AU - Schmidt,Sven, AU - Gansser,Dietmar, AU - Ishiguro,Naoki, AU - Taub,Mitchell E, AU - Sharma,Ashish, AU - Ebner,Thomas, AU - Müller,Fabian, Y1 - 2018/06/21/ PY - 2018/01/09/received PY - 2018/03/21/revised PY - 2018/04/02/accepted PY - 2018/4/18/pubmed PY - 2019/10/15/medline PY - 2018/4/18/entrez KW - Phase I KW - drug interactions KW - drug transporters KW - pharmacokinetics SP - 1941 EP - 1949 JF - British journal of clinical pharmacology JO - Br J Clin Pharmacol VL - 84 IS - 9 N2 - AIMS: Previous pharmacokinetic characterization of a transporter probe cocktail containing digoxin (P-gp), furosemide (OAT1, OAT3), metformin (OCT2, MATE1, MATE2-K) and rosuvastatin (OATP1B1, OATP1B3, BCRP) in healthy subjects showed increases in rosuvastatin systemic exposure compared to rosuvastatin alone. In this trial, the doses of metformin and furosemide as putative perpetrators were reduced to eliminate their drug-drug interaction (DDI) with rosuvastatin. METHODS: In a randomized, open-label, single-centre, five-treatment, five-period crossover trial, 30 healthy male subjects received as reference treatments separately 0.25 mg digoxin, 1 mg furosemide, 10 mg metformin and 10 mg rosuvastatin, and as test treatment all four drugs administered together as a cocktail. Primary pharmacokinetic endpoints were AUC0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration) and Cmax (maximum plasma concentration) of each probe drug. RESULTS: Geometric mean ratios and 90% confidence intervals of test (cocktail) to reference (single drug) for AUC0-tz were 96.4% (88.2-105.3%) for digoxin, 102.6% (93.8-112.3%) for furosemide, 97.5% (93.5-101.6%) for metformin and 105.0% (96.4-114.4%) for rosuvastatin, indicating lack of interaction. The same analysis for Cmax and for pharmacokinetic parameters of urinary excretion of all cocktail components also indicated no DDI. CONCLUSIONS: Digoxin (0.25 mg), furosemide (1 mg), metformin (10 mg) and rosuvastatin (10 mg) exhibit no mutual pharmacokinetic interactions and are well tolerated administered as a cocktail. The cocktail is thus optimized and has the potential to be used as a screening tool for clinical investigation of transporter-mediated DDI. SN - 1365-2125 UR - https://www.unboundmedicine.com/medline/citation/29665130/Optimization_of_a_drug_transporter_probe_cocktail:_potential_screening_tool_for_transporter_mediated_drug_drug_interactions_ L2 - https://doi.org/10.1111/bcp.13609 DB - PRIME DP - Unbound Medicine ER -