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Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine.
Clin Pharmacokinet. 2020 Jun 05 [Online ahead of print]CP

Abstract

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 (AUC0-tz) by 248% and maximum plasma concentration (Cmax) by 1025%. Probenecid increased furosemide AUC0-tz by 172% and Cmax 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 (AUC0-tz unaltered, Cmax + 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.

Authors+Show Affiliations

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.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.CTC North GmbH & Co KG, University Medical Centre Hamburg Eppendorf, Hamburg, 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, Japan.Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA.Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA.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.Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.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.Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany. Peter.Stopfer@boehringer-ingelheim.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32504272

Citation

Wiebe, Sabrina T., et al. "Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine." Clinical Pharmacokinetics, 2020.
Wiebe ST, Giessmann T, Hohl K, et al. Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine. Clin Pharmacokinet. 2020.
Wiebe, S. T., Giessmann, T., Hohl, K., Schmidt-Gerets, S., Hauel, E., Jambrecina, A., Bader, K., Ishiguro, N., Taub, M. E., Sharma, A., Ebner, T., Mikus, G., Fromm, M. F., Müller, F., & Stopfer, P. (2020). Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine. Clinical Pharmacokinetics. https://doi.org/10.1007/s40262-020-00907-w
Wiebe ST, et al. Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine. Clin Pharmacokinet. 2020 Jun 5; PubMed PMID: 32504272.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine. AU - Wiebe,Sabrina T, AU - Giessmann,Thomas, AU - Hohl,Kathrin, AU - Schmidt-Gerets,Sven, AU - Hauel,Edith, AU - Jambrecina,Alen, AU - Bader,Kerstin, AU - Ishiguro,Naoki, AU - Taub,Mitchell E, AU - Sharma,Ashish, AU - Ebner,Thomas, AU - Mikus,Gerd, AU - Fromm,Martin F, AU - Müller,Fabian, AU - Stopfer,Peter, Y1 - 2020/06/05/ PY - 2020/6/7/entrez JF - Clinical pharmacokinetics JO - Clin Pharmacokinet N2 - 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 (AUC0-tz) by 248% and maximum plasma concentration (Cmax) by 1025%. Probenecid increased furosemide AUC0-tz by 172% and Cmax 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 (AUC0-tz unaltered, Cmax + 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. SN - 1179-1926 UR - https://www.unboundmedicine.com/medline/citation/32504272/Validation_of_a_Drug_Transporter_Probe_Cocktail_Using_the_Prototypical_Inhibitors_Rifampin,_Probenecid,_Verapamil,_and_Cimetidine L2 - https://dx.doi.org/10.1007/s40262-020-00907-w DB - PRIME DP - Unbound Medicine ER -
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