Effects of Metformin and Furosemide on Rosuvastatin Pharmacokinetics in Healthy Volunteers: Implications for Their Use as Probe Drugs in a Transporter Cocktail

Abstract

Background: In a recently described probe drug cocktail for clinically relevant drug transporters containing digoxin, furosemide, metformin and rosuvastatin, mutual interactions were essentially absent except for increases in the systemic exposure of rosuvastatin. To optimize the cocktail, we further examined the dose dependence of the effects of metformin and furosemide on rosuvastatin pharmacokinetics.

Methods: This was a randomized, open label, single center, six-treatment, six-period, six-sequence crossover trial. Eighteen healthy male subjects received 10 mg rosuvastatin as reference treatment and, as test treatments, 10 mg rosuvastatin combined with 10, 50 or 500 mg metformin (T1, T2 and T3) or with 1 or 5 mg furosemide (T4 and T5). Primary pharmacokinetic endpoints were rosuvastatin C _max (maximum plasma concentration) and AUC_0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration).

Results: The relative bioavailability of rosuvastatin was essentially unchanged when administered with metformin in T1 and T2, but in T3 it increased to 152% for AUC_0-tz (90% CI 135-171%) and 154% for C _max (90% CI 132-180%). Coadministration with furosemide did not change rosuvastatin relative bioavailability in T4, but in T5 it increased slightly to 116% for AUC_0-tz (90% CI 102-132%) and 118% for C _max (90% CI 98-142%).

Conclusion: The increased systemic exposure of rosuvastatin when administered as part of the proposed transporter cocktail is most likely attributable to metformin and only to a minor degree to furosemide. Reduction of the doses of metformin and furosemide is expected to eliminate the previously described interaction. EudraCT no. 2015-003052-46, ClinicalTrials.gov identifier NCT02574845.

Fig. 1

Geometric mean plasma concentration–time profiles of rosuvastatin (10 mg) after oral dosing alone (reference), and in combination with different doses of metformin a linear and b semi-log. The doses of metformin were 10 mg (T1), 50 mg (T2) and 500 mg (T3)

Fig. 2

Geometric mean plasma concentration–time profiles of rosuvastatin (10 mg) after oral dosing alone (reference), and in combination with different doses of furosemide a linear and b semi-log. The doses of furosemide were 1 mg (T4) and 5 mg (T5)