Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor

Mosure, Kathleen W.; Knipe, Jay O.; Browning, Marc; Arora, Vinod; Shu, Yue‐Zhong; Phillip, Thomas; McPhee, Fiona; Scola, Paul M.; Balakrishnan, Anand; Soars, Matthew G.; Santone, Kenneth S.; Sinz, Michael

doi:10.1002/jps.24356

Cited by 30 publications

(25 citation statements)

References 35 publications

(77 reference statements)

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“…Reduced efflux ratios (assay performed at 5 lM asunaprevir) in the presence of the P-glycoprotein and breast cancer resistance protein (BCRP) inhibitor GF120918 (efflux ratio 1.9), the P-glycoprotein and multidrug resistance-associated protein 2 (MRP2) inhibitor MK-571 (efflux ratio 1.4) and the BCRP inhibitor fumitremorgin C (efflux ratio 20) suggested that asunaprevir is a substrate for P-glycoprotein and possibly for MRP2 (unpublished results). The involvement of P-glycoprotein as an efflux mechanism for asunaprevir was confirmed in a comparison of asunaprevir bioavailability in wild-type (28 %) and P-glycoprotein-knockout mice (mdr 1a/ 1b; [100 %) [15].…”

Section: Absorptionmentioning

confidence: 93%

“…In animal species, the apparent volume of distribution at steady state (V ss ) was similar to total body water (in dogs and monkeys) or greater than total body water (in mice and rats), and indicated extravascular distribution [15]. Although the addition of protein from 4 % fetal bovine serum (asunaprevir 10 lM 68.1 % bound) or 40 % human serum (asunaprevir 10 lM 97.6 % bound) to the replicon assay medium resulted in a modest attenuation of asunaprevir potency, the results obtained were comparable to data for other NS3 inhibitors [10].…”

Section: Distributionmentioning

confidence: 97%

“…Oral bioavailability in non-clinical species (rats, dogs, monkeys and wild-type mice) was variable (ranging from 10 to [100 %), was dose dependent (in rats: 3-to 7-fold increase between 10 and 30 mg/kg; in dogs: 5-fold increase between 4 and 10 mg/kg) [15] and demonstrated a significant (p = 0.036) food effect (3.6-fold increase in the area under the plasma concentration-time curve [AUC] in fed dogs) (unpublished results).…”

Section: Absorptionmentioning

confidence: 99%

“…In animals, 18-54 % of the dose was recovered as metabolites. The recovery of asunaprevir and metabolites in the faeces of bile duct-cannulated animals after intravenous administration of [ 14 C]-asunaprevir indicates direct intestinal excretion of asunaprevir and metabolites [15].…”

Section: Eliminationmentioning

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: Absorptionmentioning

confidence: 93%

Section: Distributionmentioning

confidence: 97%

Section: Absorptionmentioning

confidence: 99%

Section: Eliminationmentioning

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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“…where BDC dogs were administered IV doses of [ 14 C]ASV (3 mg/kg), $10% of radioactivity was recovered as unchanged ASV in the feces, suggesting that direct intestinal excretion played a role in the clearance of ASV (Mosure et al, 2015). The potential role of transporters in the biliary and intestinal secretion has been investigated and will be published in a separate manuscript.…”

Section: Discussionmentioning

confidence: 97%

Characterization of ADME properties of [¹⁴C]asunaprevir (BMS-650032) in humans

Gong¹,

Eley

et al. 2015

Xenobiotica

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1. Asunaprevir (ASV, BMS-650032), a highly selective and potent NS3 protease inhibitor, is currently under development for the treatment of chronic hepatic C virus infection. This study describes in vivo biotransformation in humans and the identification of metabolic enzymes of ASV. 2. Following a single oral dose of [(14)C]ASV to humans, the majority of radioactivity (>73% of the dose) was excreted in feces with <1% of the dose recovered in urine. Drug-related radioactivity readily appeared in circulation and the plasma radioactivity was mainly attributed to ASV. A few minor metabolites were observed in human plasma and are not expected to contribute to the pharmacological activity because of low levels. The area under the curve (AUC) values of each circulating metabolite in humans were well below their levels in animals used in the long-term toxicological studies. In bile and feces, intact ASV was a prominent radioactive peak suggesting that both metabolism and direct excretion played important roles in ASV clearance. 3. The primary metabolic pathways of ASV were hydroxylation, sulfonamide hydrolysis and the loss of isoquinoline. In vitro studies with human cDNA expressed CYP enzymes and with human liver microsomes (HLM) in the presence of selective chemical inhibitors demonstrated that ASV was primarily catalyzed by CYP3A4 and CYP3A5.

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A Reversible Chemogenetic Switch for Chimeric Antigen Receptor T Cells**

et al. 2022

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As ar evolutionary cancer treatment, the chimeric antigen receptor (CAR) Tcell therapysuffers from complications such as cytokine release syndromes and Tcell exhaustion. Their mitigation desires controllable activation of CAR-T cells that is achievable through regulatory displayo fC ARs.B y embedding the hepatitis Cv irus NS3 protease (HCV-NS3) between the single-chain variable fragment (scFv) and the hinge domain, we showed that the displayo fa nti-CD19 scFv on CAR-T cells was positively correlated to the presence of ac linical HCV-NS3 inhibitor asunaprevir (ASV). This novel CARd esign that allows the displayo fa nti-CD19 scFv in the presence of ASV and its removal in the absence of ASV creates apractically reversible chemical switch. We demonstrated that the intact CARonTcells can be repeatedly turned on and off by controlling the presence of ASV in adose dependent manner both in vitro and in vivo,whichenables delicate modulation of CAR-T activation during cancer treatment.

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Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor

Cited by 30 publications

References 35 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

Characterization of ADME properties of [¹⁴C]asunaprevir (BMS-650032) in humans

A Reversible Chemogenetic Switch for Chimeric Antigen Receptor T Cells**

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Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor

Cited by 30 publications

References 35 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

Characterization of ADME properties of [14C]asunaprevir (BMS-650032) in humans

A Reversible Chemogenetic Switch for Chimeric Antigen Receptor T Cells**

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Characterization of ADME properties of [¹⁴C]asunaprevir (BMS-650032) in humans