Stopfer Peter, Giessmann Thomas, Hohl Kathrin, Sharma Ashish, Ishiguro Naoki, Taub Mitchell E, Jungnik Arvid, Gansser Dietmar, Ebner Thomas, Müller Fabian
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.
Eur J Drug Metab Pharmacokinet. 2018 Feb;43(1):69-80. doi: 10.1007/s13318-017-0427-9.
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.
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 (maximum plasma concentration) and AUC (area under the plasma concentration-time curve from time zero to the last quantifiable concentration).
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 (90% CI 135-171%) and 154% for C (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 (90% CI 102-132%) and 118% for C (90% CI 98-142%).
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.
在最近描述的一种用于临床相关药物转运体的探针药物组合中，包含地高辛、呋塞米、二甲双胍和瑞舒伐他汀，除瑞舒伐他汀的全身暴露增加外，基本不存在相互作用。为优化该组合，我们进一步研究了二甲双胍和呋塞米对瑞舒伐他汀药代动力学影响的剂量依赖性。
这是一项随机、开放标签、单中心、六治疗组、六周期、六序列交叉试验。18名健康男性受试者接受10mg瑞舒伐他汀作为对照治疗，作为试验治疗，接受10mg瑞舒伐他汀分别联合10、50或500mg二甲双胍（T1、T2和T3）或联合1或5mg呋塞米（T4和T5）。主要药代动力学终点为瑞舒伐他汀Cmax（最大血浆浓度）和AUC（从时间零点至最后可定量浓度的血浆浓度-时间曲线下面积）。
在T1和T2中，瑞舒伐他汀与二甲双胍合用时相对生物利用度基本不变，但在T3中，AUC的相对生物利用度增至152%（90%CI 135 - 171%），Cmax的相对生物利用度增至154%（90%CI 132 - 180%）。在T4中，瑞舒伐他汀与呋塞米合用时相对生物利用度未改变，但在T5中，AUC的相对生物利用度略有增加至116%（90%CI 102 - 132%），Cmax的相对生物利用度增至118%（90%CI 98 - 142%）。
当作为拟议的转运体组合的一部分给药时，瑞舒伐他汀全身暴露增加最可能归因于二甲双胍，仅在较小程度上归因于呋塞米。预计降低二甲双胍和呋塞米的剂量可消除先前描述的相互作用。欧洲临床试验注册号EudraCT no. 2015 - 003052 - 46，美国国立医学图书馆临床试验标识符NCT02574845。
