Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine.

Autor: Wiebe ST; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.; UniversitätsKlinikum Heidelberg-Medizinische Klinik, Abteilung Klinische Pharmakologie and Pharmakoepidemiologie, Heidelberg, Germany., Giessmann T; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany., Hohl K; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany., Schmidt-Gerets S; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany., Hauel E; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany., Jambrecina A; CTC North GmbH & Co KG, University Medical Centre Hamburg Eppendorf, Hamburg, Germany., Bader K; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany., Ishiguro N; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co. Ltd., Chuo-ku, Kobe, Japan., Taub ME; Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA., Sharma A; Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA., Ebner T; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany., Mikus G; UniversitätsKlinikum Heidelberg-Medizinische Klinik, Abteilung Klinische Pharmakologie and Pharmakoepidemiologie, Heidelberg, Germany., Fromm MF; Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Müller F; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.; Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Stopfer P; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany. Peter.Stopfer@boehringer-ingelheim.com.
Jazyk: angličtina
Zdroj: Clinical pharmacokinetics [Clin Pharmacokinet] 2020 Dec; Vol. 59 (12), pp. 1627-1639.
DOI: 10.1007/s40262-020-00907-w
Abstrakt: Background and Objective: A novel cocktail containing four substrates of key drug transporters was previously optimized to eliminate mutual drug-drug interactions between the probes digoxin (P-glycoprotein substrate), furosemide (organic anion transporter 1/3), metformin (organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K), and rosuvastatin (organic anion transporting polypeptide 1B1/3, breast cancer resistance protein). This clinical trial investigated the effects of four commonly employed drug transporter inhibitors on cocktail drug pharmacokinetics.
Methods: In a randomized open-label crossover trial in 45 healthy male subjects, treatment groups received the cocktail with or without single oral doses of rifampin, verapamil, cimetidine or probenecid. Concentrations of the probe drugs in serial plasma samples and urine fractions were measured by validated liquid chromatography-tandem mass spectrometry assays to assess systemic exposure.
Results: The results were generally in accordance with known in vitro and/or clinical drug-drug interaction data. Single-dose rifampin increased rosuvastatin area under the plasma concentration-time curve up to the last quantifiable concentration (AUC 0-tz ) by 248% and maximum plasma concentration (C max ) by 1025%. Probenecid increased furosemide AUC 0-tz by 172% and C max by 23%. Cimetidine reduced metformin renal clearance by 26%. The effect of single-dose verapamil on digoxin systemic exposure was less than expected from multiple-dose studies (AUC 0-tz unaltered, C max  + 22%).
Conclusions: Taking all the interaction results together, the transporter cocktail is considered to be validated as a sensitive and specific tool for evaluating transporter-mediated drug-drug interactions in drug development.
Clinical Trial Registration: EudraCT number 2017-001549-29.
Databáze: MEDLINE
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