کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8514343 | 1556505 | 2017 | 36 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model
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کلمات کلیدی
CmaxPBPKDDIOATPAUC - AUCStatin - استاتینdrug-drug interaction - تعامل دارو و داروAbsorption - جذبmaximum plasma concentration - حداکثر غلظت پلاسماTransporters - حمل و نقلphysiologically based pharmacokinetics - فارماکوکینتیک مبتنی بر فیزیولوژی استarea under the plasma concentration-time curve - محدوده تحت منحنی زمان غلظت پلاسماPhysiologically based pharmacokinetic modeling - مدلسازی فارماکوکینتیک مبتنی بر فیزیولوژیorganic anion-transporting polypeptide - پلی اتیلن حمل و نقل آنیونی آلی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 106, Issue 5, May 2017, Pages 1439-1451
Journal: Journal of Pharmaceutical Sciences - Volume 106, Issue 5, May 2017, Pages 1439-1451
نویسندگان
Wen Lin, Tao Ji, Heidi Einolf, Surya Ayalasomayajula, Tsu-Han Lin, Imad Hanna, Tycho Heimbach, Christopher Breen, Venkateswar Jarugula, Handan He,