The Discovery of Asunaprevir (BMS-650032), An Orally Efficacious NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Scola, Paul M.; Sun, Li‐Qiang; Wang, Alan Xiangdong; Chen, Jie; Sin, Nancy L.; Venables, Brian L.; Sit, Sing‐Yuen; Chen, Yan; Cocuzza, Anthony J.; Bilder, Donna M.; D’Andrea, Stanley V.; Zheng, Barbara; Hewawasam, Piyasena; Tu, Yong; Friborg, Jacques; Falk, Paul; Hernandez, Dennis; Levine, Steven M.; Chen, Chaoqun; Yu, Fei; Sheaffer, Amy K.; Zhai, Guangzhi; Barry, Diana; Knipe, Jay O.; Han, Yong‐Hae; Schartman, Richard; Donoso, Maria; Mosure, Kathy; Sinz, Michael; Zvyaga, Tatyana; Good, Andrew C.; Rajamani, Ramkumar; Kish, Kevin; Tredup, Jeffrey; Klei, Herbert E.; Gao, Qi; Mueller, Luciano; Colonno, Richard J.; Grasela, Dennis M.; Adams, Stephen P.; Loy, James; Lévesque, Paul; Sun, Huabin; Shi, Hong; Sun, Lucy; Warner, W.; Li, Danshi; Zhu, Jialong; Meanwell, Nicholas A.; McPhee, Fiona

doi:10.1021/jm500297k

Cited by 102 publications

(105 citation statements)

References 56 publications

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“…1) was derived from the lead compound BMS-605339, which was eventually discontinued for clinical development and has been fully described elsewhere [14]. The absorption, distribution, metabolism and excretion characteristics of asunaprevir have been evaluated in several cell lines and animal species.…”

Section: Preclinical Pharmacokineticsmentioning

confidence: 99%

“…3.4. Effects of asunaprevir on cardiac conduction were not expected [14], and a dedicated study to assess the effect of asunaprevir was conducted concurrently with phase 3 studies. Supratherapeutic exposures to asunaprevir (300 mg soft-gel capsule BID) had no clinically significant effect on electrocardiographic outcomes in the cardiac evaluation study AI447-025.…”

Section: Optimization Of Asunaprevir Dosing Regimenmentioning

confidence: 99%

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Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

Eley

Garimella

et al. 2015

Clin Pharmacokinet

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Asunaprevir is a tripeptidic acylsulfonamide inhibitor of the hepatitis C virus (HCV) NS3/4A protease. Asunaprevir undergoes rapid absorption, with a time to reach maximum plasma concentration (T max) of 2-4 h and an elimination half-life (t ½) of ≈15-20 h observed in single-ascending dose studies. Steady state was achieved by day 7 in multiple-ascending dose studies. The large food effect observed with earlier formulations was mitigated by the soft-gel capsule. Asunaprevir demonstrates high apparent oral clearance and minimal renal elimination, and is eliminated primarily via cytochrome P450 (CYP) 3A4-mediated hepatic oxidative metabolism and faecal excretion. Highly preferential distribution of asunaprevir to the liver occurs via organic anion-transporting polypeptide (OATP)-mediated transport and results in low plasma concentrations. The condition of the liver affects disposition, as higher asunaprevir plasma exposures are observed in patients infected with HCV and/or hepatic impairment. Japanese patients also have higher exposure relative to North American/European patients, but comparable safety at the registrational dose. Asunaprevir has a low potential to perpetrate drug-drug interactions via CYP3A4, P-glycoprotein and OATP, but is a moderate CYP2D6 inhibitor; concomitant drugs that are substrates of CYP2D6 or P-glycoprotein and have a narrow therapeutic index should be used with care. Asunaprevir plasma exposure is strongly affected by inhibitors of OATP transport. No clinically significant interactions were observed between asunaprevir and daclatasvir or daclatasvir/beclabuvir. Asunaprevir has a complex pharmacokinetic profile and forms part of potent and well-tolerated all-oral regimens for the treatment of chronic HCV infection.

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Section: Preclinical Pharmacokineticsmentioning

confidence: 99%

Section: Optimization Of Asunaprevir Dosing Regimenmentioning

confidence: 99%

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

Eley

Garimella

et al. 2015

Clin Pharmacokinet

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“…ASV (BMS-650032), DCV (BMS-790052), BCV (BMS-791325), and BCV-M1 (a major metabolite of BCV) were synthesized at Bristol-Myers Squibb Co. (New Brunswick, NJ) (Gao et al, 2010;Gentles et al, 2014;Scola et al, 2014). Their structures are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Application of Static Models to Predict Midazolam Clinical Interactions in the Presence of Single or Multiple Hepatitis C Virus Drugs

Cheng

Chang

et al. 2016

Drug Metabolism and Disposition

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Asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are three drugs developed for the treatment of chronic hepatitis C virus infection. Here, we evaluated the CYP3A4 induction potential of each drug, as well as BCV-M1 (the major metabolite of BCV), in human hepatocytes by measuring CYP3A4 mRNA alteration. The induction responses were quantified as induction fold (mRNA fold change) and induction increase (mRNA fold increase), and then fitted with four nonlinear regression algorithms. Reversible inhibition and time-dependent inhibition (TDI) on CYP3A4 activity were determined to predict net drug-drug interactions (DDIs). All four compounds were CYP3A4 inducers and inhibitors, with ASV demonstrating TDI. The curve-fitting results demonstrated that fold increase is a better assessment to determine kinetic parameters for compounds inducing weak responses. By summing the contribution of each inducer, the basic static model was able to correctly predict the potential for a clinically meaningful induction signal for single or multiple perpetrators, but with over prediction of the magnitude. With the same approach, the mechanistic static model improved the prediction accuracy of DCV and BCV when including both induction and inhibition effects, but incorrectly predicted the net DDI effects for ASV alone or triple combinations. The predictions of ASV or the triple combination could be improved by only including the induction and reversible inhibition but not the ASV CYP3A4 TDI component. Those results demonstrated that static models can be applied as a tool to help project the DDI risk of multiple perpetrators using in vitro data.

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“…Recently, potent non-nucleotide NS5B inhibitors targeting the palm site of the HCV RNA-dependent RNA polymerase were evaluated alongside inhibitors of other key HCV enzymes, including NS5A, NS3/4A, and NS5B (the thumb site), for possible use in combination therapy (Gao et al, 2010;Gentles et al, 2014;Scola et al, 2014). During optimization to improve the metabolic stability of these NS5B inhibitors featuring a 6-substituted furo [2,3-b]pyridine core, multiple isosteric replacements of a t-butyl moiety were explored including a bicyclo[1.1.1.…”

Section: Introductionmentioning

confidence: 99%

Phosphocholine Conjugation: An Unexpected In Vivo Conjugation Pathway Associated with Hepatitis C NS5B Inhibitors Featuring A Bicyclo[1.1.1]Pentane

Zhuo

Cantone

Wang

et al. 2016

Drug Metabolism and Disposition

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, exhibited low turnover in incubations with liver S9 or hepatocytes (rat, human), with hydroxylation of the bicyclic moiety being the only metabolic pathway observed. In subsequent disposition studies using bile duct-cannulated rats, the metabolite profiles of bile samples revealed, in addition to multiple products of bicyclopentane oxidation, unexpected metabolites characterized by molecular masses that were 181 Da greater than those of compound 1 or 2. Further liquid chromatography/multiple-stage mass spectrometry and nuclear magnetic resonance analysis of the isolated metabolite of compound 1 demonstrated the presence of a phosphocholine (POPC) moiety bound to the methine carbon of the bicyclic moiety through an ester bond. The POPC conjugate of the nonstructural protein 5B inhibitors was assumed to result from two sequential reactions: hydroxylation of the bicyclic methine to a tertiary alcohol and addition of POPC by cytidine-diphosphocholine: 1,2-diacylglycerol cholinephosphotransferase, an enzyme responsible for the final step in the biosynthesis of phosphatidylcholine. However, this pathway could not be recapitulated using cytidinediphosphocholine-supplemented liver S9 or hepatocytes because of inadequate formation of the hydroxylation product in vitro. The observation of this unexpected pathway prompted concerns about the possibility that compounds 1 and 2 might interfere with routine phospholipid synthesis. These results demonstrate the participation in xenobiotic metabolism of a process whose function is ordinarily limited to the synthesis of endogenous compounds.

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The Discovery of Asunaprevir (BMS-650032), An Orally Efficacious NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Cited by 102 publications

References 56 publications

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

Application of Static Models to Predict Midazolam Clinical Interactions in the Presence of Single or Multiple Hepatitis C Virus Drugs

Phosphocholine Conjugation: An Unexpected In Vivo Conjugation Pathway Associated with Hepatitis C NS5B Inhibitors Featuring A Bicyclo[1.1.1]Pentane

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