<i>In vitro</i>
 and clinical evaluation of OATP-mediated drug interaction potential of sacubitril/valsartan (LCZ696)

Ayalasomayajula, Surya; Han, Yamei; Langenickel, Thomas; Malcolm, Karl; Hanna, Imad; Alexander, Natalya; Natrillo, Adrienne; Goswami, Budhaditya; Hinder, Markus; Sunkara, Gangadhar

doi:10.1111/jcpt.12408

Cited by 23 publications

(20 citation statements)

References 20 publications

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“…Therefore, pharmacokinetic drug-drug interactions with inhibitors, inducers, or substrates of CYP450 enzymes are unlikely. In-vitro inhibition of organic anion transporter protein (OATP) 1B1 [halfmaximal inhibitory concentration (IC50), 1.9 lM], OATP1B3 (IC50, 3.8 lM) [47], and OAT3 (IC50, 0.8 lM) by sacubitril was observed at clinically relevant concentrations. Sacubitrilat and valsartan were found to be a substrate of OAT3 in vitro; however, a clinically relevant drug-drug interaction at therapeutic doses is unlikely to happen (data on file).…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

“…A total of 13 clinical pharmacology studies were conducted to evaluate the pharmacokinetic and/or pharmacodynamic drug-drug interaction potential with medicines that may be co-administered with sacubitril/valsartan in patients with HFrEF [25,29,[47][48][49]. The mechanistic pharmacokinetic drug interaction potential of sacubitril/valsartan was evaluated with CYP3A4, CYP2C9, CYP2C19, CYP2D6, and other CYP enzyme substrates (carvedilol, omeprazole, warfarin, and amlodipine); P-gp (digoxin); OATP1B1/OATP1B3 (atorvastatin and simvastatin); and OAT3 (furosemide).…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

“…More importantly, coadministration with CYP and OATP1B1/1B3 inhibitors could increase the exposure to statins, thereby increasing the risk of statin-related adverse events including myopathy and rhabdomyolysis [70]. In-vitro inhibition of OATP1B1 (IC50, 1.9 lM) and OATP1B3 (IC50, 3.8 lM) by sacubitril indicates a potential for drug-drug interactions following co-administration of sacubitril/valsartan and statins [47]. Two studies determining the pharmacokinetic drug-drug interaction potential of sacubitril/valsartan with statins (atorvastatin 80 mg QD and simvastatin 40 mg QD) were conducted in healthy subjects [29,47].…”

Section: Statinsmentioning

confidence: 99%

“…In-vitro inhibition of OATP1B1 (IC50, 1.9 lM) and OATP1B3 (IC50, 3.8 lM) by sacubitril indicates a potential for drug-drug interactions following co-administration of sacubitril/valsartan and statins [47]. Two studies determining the pharmacokinetic drug-drug interaction potential of sacubitril/valsartan with statins (atorvastatin 80 mg QD and simvastatin 40 mg QD) were conducted in healthy subjects [29,47]. Multiple-dose administration of sacubitril/valsartan (200 mg BID) with atorvastatin 80 mg QD increased the steady-state C max and AUC of atorvastatin (by 74 and 34%, respectively) and its active metabolites o-hydroxyatorvastatin (by 68 and 22%, respectively) and p-hydroxyatorvastatin (by 108 and 26%, respectively) measured on day 5 [29].…”

Section: Statinsmentioning

confidence: 99%

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Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor–Neprilysin Inhibitor

et al. 2017

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Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a twofold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, *1.9-fold for sacubitrilat, and *1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while *1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug-drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum plasma concentration (*2.0-fold) and area under the plasma concentration-time curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the plasma concentration-time curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the plasma concentration-time curves, while the area under the plasma concentrationtime curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the plasma concentration-time curves of valsartan and sacubitrilat *2.1-fold.The in-text citations in the tables were misaligned with the references in the original article. The full article with all the corrections is republished here.The online version of the original article can be found under

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Section: Drug-drug Interactionsmentioning

confidence: 99%

Section: Drug-drug Interactionsmentioning

confidence: 99%

Section: Statinsmentioning

confidence: 99%

Section: Statinsmentioning

confidence: 99%

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Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor–Neprilysin Inhibitor

et al. 2017

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“…They are extensively distributed in gastrointestinal tract, liver, kidneys and blood-brain barrier. Moreover, they can mediate the absorption and transport of multiple endogenous substances and common clinical drugs (Ayalasomayajula et al, 2016).…”

mentioning

confidence: 99%

Association between SLCO1B3 gene polymorphism and prostate cancer risk: A meta-analytic study

Shen

Liang

et al. 2018

Bangladesh J Pharmacol

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<p class="Abstract">The aim of this meta-analysis was to assess the association between SLCO1B3 gene polymorphism and prostate cancer risk. PubMed, Embase, Cochrane Library, and Web of Science from inception to September 2017 were searched. Three authors independently selected studies, extracted data and assessed risk of bias. 5 articles published from 2008 to 2013 with 840 patients were included in this meta-analysis and were from Japan, USA and China. The prostate cancer risk of SLCO1B3 (rs4149117, GG) was markedly higher than that of SLCO1B3 (rs4149117, TT/TG, RR= 0.44, 95%CI: 0.39-0.49, p<0.00001), rs4149117 (TT, RR= 0.37, 95%CI: 0.32-0.42, p<0.00001) and rs4149117 (TG, RR= 0.07, 95%CI: 0.05-0.10, p<0.00001). 2 or 5 years risk free symptoms (RFS) of prostate cancer patient with SLCO1B3 (rs4149117, GG) was markedly higher than that of SLCO1B3 (rs4149117, TT/TG) (RR= -0.17, 95% CI: -0.27--0.07, p= 0.001 and RR= -0.08, 95% CI: -0.16-0.00, p= 0.004). However, no evidence showed there existed significant statistical relationship between SLCO1B3 (rs4149117) and 10 years RFS of prostate cancer (RR= -0.07, 95% CI: -0.19-0.06, p= 0.29). These data suggest that SLCO1B3 (rs4149117, GG) enhanced the RFS of prostate cancer.</p>

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Hepatic transporter‐mediated pharmacokinetic drug–drug interactions: Recent studies and regulatory recommendations

Izat

Şahin

2021

Biopharm & Drug Disp

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Transporter‐mediated drug–drug interactions are one of the major mechanisms in pharmacokinetic‐based drug interactions and correspondingly affecting drugs' safety and efficacy. Regulatory bodies underlined the importance of the evaluation of transporter‐mediated interactions as a part of the drug development process. The liver is responsible for the elimination of a wide range of endogenous and exogenous compounds via metabolism and biliary excretion. Therefore, hepatic uptake transporters, expressed on the sinusoidal membranes of hepatocytes, and efflux transporters mediating the transport from hepatocytes to the bile are determinant factors for pharmacokinetics of drugs, and hence, drug–drug interactions. In parallel with the growing research interest in this area, regulatory guidances have been updated with detailed assay models and criteria. According to well‐established preclinical results, observed or expected hepatic transporter‐mediated drug–drug interactions can be taken into account for clinical studies. In this paper, various methods including in vitro, in situ, in vivo, in silico approaches, and combinational concepts and several clinical studies on the assessment of transporter‐mediated drug–drug interactions were reviewed. Informative and effective evaluation by preclinical tools together with the integration of pharmacokinetic modeling and simulation can reduce unexpected clinical outcomes and enhance the success rate in drug development.

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In vitro and clinical evaluation of OATP-mediated drug interaction potential of sacubitril/valsartan (LCZ696)

Abstract: Overall, the results of this study suggest that although sacubitril inhibited OATP1B1 and OATP1B3 in vitro, it does not translate into any clinically relevant in vivo effect.

Cited by 23 publications

References 20 publications

Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor–Neprilysin Inhibitor

Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor–Neprilysin Inhibitor

Association between SLCO1B3 gene polymorphism and prostate cancer risk: A meta-analytic study

Hepatic transporter‐mediated pharmacokinetic drug–drug interactions: Recent studies and regulatory recommendations

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