Optimization of a drug transporter probe cocktail: potential screening tool for transporter-mediated drug-drug interactions

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Details zur Publikation

Autor(en): Stopfer P, Giessmann T, Hohl K, Hutzel S, Schmidt S, Gansser D, Ishiguro N, Taub ME, Sharma A, Ebner T, Müller F
Zeitschrift: British Journal of Clinical Pharmacology
Jahr der Veröffentlichung: 2018
Band: 84
Heftnummer: 9
Seitenbereich: 1941-1949
ISSN: 0306-5251


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.


FAU-Autoren / FAU-Herausgeber

Müller, Fabian Dr.
Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie


Autor(en) der externen Einrichtung(en)
Boehringer Ingelheim Pharma GmbH & Co. KG
Nippon Boehringer Ingelheim Co Ltd.


Zitierweisen

APA:
Stopfer, P., Giessmann, T., Hohl, K., Hutzel, S., Schmidt, S., Gansser, D.,... 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://dx.doi.org/10.1111/bcp.13609

MLA:
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 84.9 (2018): 1941-1949.

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Zuletzt aktualisiert 2018-12-11 um 10:53