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

• Published in: British journal of clinical pharmacology Vol. 84; no. 9; pp. 1941 - 1949
• Main Authors: Stopfer, Peter, Giessmann, Thomas, Hohl, Kathrin, Hutzel, Sabine, Schmidt, Sven, Gansser, Dietmar, Ishiguro, Naoki, Taub, Mitchell E., Sharma, Ashish, Ebner, Thomas, Müller, Fabian
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.09.2018
• Subjects: Adult; Area Under Curve; Cross-Over Studies; Digoxin - administration & dosage; Digoxin - metabolism; Digoxin - pharmacokinetics; Dose-Response Relationship, Drug; Drug Development - methods; Drug Interactions; drug transporters; Furosemide - administration & dosage; Furosemide - metabolism; Furosemide - pharmacokinetics; Healthy Volunteers; Humans; Male; Membrane Transport Proteins - metabolism; Metformin - administration & dosage; Metformin - metabolism; Metformin - pharmacokinetics; Middle Aged; Original; pharmacokinetics; Phase I; Renal Elimination; Rosuvastatin Calcium - administration & dosage; Rosuvastatin Calcium - metabolism; Rosuvastatin Calcium - pharmacokinetics; Young Adult; drug transporters; pharmacokinetics; Phase I; drug interactions
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.13609

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.