Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Ghosal, Anima; Yuan, Yuan; Tong, Wei; Su, Ai-Duen; Gu, Chunyan; Chowdhury, Swapan K.; Kishnani, Narendra S.; Alton, Kevin B.

doi:10.1124/dmd.110.036996

Cited by 64 publications

(50 citation statements)

References 18 publications

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“…As BOC has low passive permeability and is eliminated primarily via hepatic metabolism by CYP3A4/5 and aldoketoreductases (Ghosal et al, 2011), uptake transporters may play an important role in the hepatic elimination of BOC. Our studies indicated that uptake of BOC in human hepatocytes was saturable.…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

et al. 2013

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The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldoketoreductases, was a reversible time-dependent inhibitor (k inact = 0.12 minute 21, K I = 6.1 mM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC 50 of 18 and 4.9 mM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions.

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Section: Discussionmentioning

confidence: 99%

“…Biotransformation is a major elimination pathway for BOC across preclinical species and humans. BOC undergoes extensive metabolism involving both cytochrome P450 (P450) CYP3A4/ 5-mediated oxidation and ketoreduction by cytosolic aldo-keto reductases (AKR)1C2 and AKR1C3 (Ghosal et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

et al. 2013

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“…Boceprevir is a potent, orally administered ketoamide inhibitor targeting the active site of the hepatitis C virus nonstructural protein 3 (NS3) protease, approved for the treatment of genotype 1 chronic hepatitis C virus infection in adult patients with compensated liver disease (3)(4)(5)(6). Addition of boceprevir to a pegylated interferon (peginterferon)-ribavirin backbone is associated with significantly increased rates of sustained virologic response (SVR) (7,8).…”

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“…Addition of boceprevir to a pegylated interferon (peginterferon)-ribavirin backbone is associated with significantly increased rates of sustained virologic response (SVR) (7,8). It is metabolized by aldoketoreductase and CYP3A4 and is a direct competitive and time-dependent inhibitor of CYP3A4/5, with inhibition constants in the low micromolar range (6), thus having the potential for drug-drug interactions with agents that are metabolized via these common pathways (3,5). In vitro, boceprevir has been shown to inhibit the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1 (50% inhibitory concentration [IC 50 ] of 18 M), but the clinical significance of this in vitro inhibition is unknown (6).…”

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Pharmacokinetic Evaluation of the Interaction between Hepatitis C Virus Protease Inhibitor Boceprevir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Pravastatin

Hulskotte

Feng

Xuan

et al. 2013

Antimicrob Agents Chemother

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bBoceprevir is a potent orally administered inhibitor of hepatitis C virus and a strong, reversible inhibitor of CYP3A4, the primary metabolic pathway for many 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Thus, the aim of the present study was to investigate drug-drug interactions between atorvastatin or pravastatin and boceprevir. We conducted a single-center, open-label, fixed-sequence, one-way-crossover study with 20 healthy adult volunteers. Subjects received single-dose atorvastatin (40 mg) or pravastatin (40 mg) on day 1, followed by boceprevir (800 mg three times daily) for 7 to 10 days. Repeat single doses of atorvastatin or pravastatin were administered in the presence of steady-state boceprevir. Atorvastatin exposure increased in the presence of boceprevir, with atorvastatin area under the concentrationtime curve from time zero to infinity after single dosing (AUC inf ) increasing 2.3-fold (90% confidence interval [CI], 1.85, 2.90) and maximum observed concentration in plasma (C max ) 2.7-fold (90% CI, 1.81, 3.90). Pravastatin exposure was slightly increased in the presence of boceprevir, with pravastatin AUC inf increasing 1.63-fold (90% CI, 1.03, 2.58) and C max 1.49-fold (90% CI, 1.03, 2.14). Boceprevir exposure was generally unchanged when the drug was coadministered with atorvastatin or pravastatin. All adverse events were mild and consistent with the known safety profile of boceprevir. The observed 130% increase in AUC of atorvastatin supports the use of the lowest possible effective dose of atorvastatin when coadministered with boceprevir, without exceeding a maximum daily dose of 40 mg. The observed 60% increase in pravastatin AUC with boceprevir coadministration supports the initiation of pravastatin treatment at the recommended dose when coadministered with boceprevir, with close clinical monitoring. W orldwide, there are an estimated 130 to 170 million individuals infected with hepatitis C virus (1). Comorbidities, such as diabetes and obesity, are more common among patients with hepatitis C virus infection than in the general U.S. population, with as many as 25% of patients with hepatitis C virus infection at risk of comorbid disorders of lipid metabolism (2). Thus, patients with hepatitis C virus infection frequently receive concomitant treatments for hyperlipidemia, including the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors atorvastatin and pravastatin. Understanding potential drug interactions between hepatitis C therapies and HMG-CoA reductase inhibitors is important for optimal treatment of this patient population.Boceprevir is a potent, orally administered ketoamide inhibitor targeting the active site of the hepatitis C virus nonstructural protein 3 (NS3) protease, approved for the treatment of genotype 1 chronic hepatitis C virus infection in adult patients with compensated liver disease (3-6). Addition of boceprevir to a pegylated interferon (peginterferon)-ribavirin backbone is associated with significantly increased rates of sustain...

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“…The administration of such drugs in the context of HCV recurrence on the liver graft is one of the most important clinical challenges in the field of LT. One limitation is the potential for interaction with calcineurin inhibitors such as cyclosporine and tacrolimus (5). Two distinct pathways extensively metabolize boceprevir, the cytochrome P450 (CYP) (mainly CYP3A) and aldo-ketoreductase pathways (11). Boceprevir is a potent inhibitor of CYP3A4 based on the results of in vitro assessments and of drug-drug interaction studies performed with oral midazolam, with coadministration increasing more than 5-fold the midazolam exposure (17).…”

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Practical Management of Boceprevir and Immunosuppressive Therapy in Liver Transplant Recipients with Hepatitis C Virus Recurrence

Coilly

Furlan

Roche

et al. 2012

Antimicrob Agents Chemother

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f Hepatitis C virus (HCV) recurrence is the most important complication in HCV liver transplant patients. Boceprevir with pegylated interferon and ribavirin (PegIFN/RBV) enabled improvement in sustained virological response rates of patients with genotype 1 HCV. Boceprevir interacts with immunosuppressive therapy (IT) by inhibiting the cytochrome P450 3A enzyme. Our aim was to study interactions and assess the safety of boceprevir in the context of HCV recurrence. Boceprevir (800 mg three times a day) initiated after a 4-week lead-in phase was associated with cyclosporine (three patients), tacrolimus (two patients), and everolimus (one patient) in five liver transplant patients with genotype 1 HCV infection who experienced HCV recurrence. The mean follow-up period after HCV therapy was 14.8 ؎ 3.1 weeks. Estimated oral clearances of IT decreased on average by 50%, requiring reduced dosing regimens. Anemia occurred in all patients, with a mean fall in hemoglobin levels between baseline and week 12 of 3.12 ؎ 2.27 g/dl. All patients required administration of ␤-erythropoietin (n ‫؍‬ 5), three needed ribavirin dose reduction, and one needed a blood transfusion. A virological response was observed in all patients (mean HCV viral load [HVL] decrease at week 12, 6.64 ؎ 0.35 log 10 IU/ml). These preliminary results in liver transplant patients with HCV recurrence demonstrate the feasibility and safety of coadministration of boceprevir and IT. E nd-stage liver disease due to hepatitis C virus (HCV) is still a common indication for liver transplantation (LT) (6). However, a recurrence of HCV infection is the most frequent cause of death and graft loss, accounting for two-thirds of graft failures. The natural history of HCV is accelerated after LT, leading to cirrhosis in 20 to 30% of patients 5 years post-LT (4). The decompensation rate is higher than 70% at 3 years in liver transplant recipients with established cirrhosis, versus less than 10% in immunocompetent patients (4). Progression from decompensation to death is also accelerated after LT, with a 3-year survival rate of Ͻ10% following the onset of HCV-related allograft failure (4). Few patients (Ͻ5%) experience cholestatic hepatitis, but their prognosis is the poorest (7). To prevent or to treat these occurrences, standard anti-HCV therapy, represented by pegylated interferon and ribavirin, can achieve a sustained virological response (SVR) in 30% of patients, who have a less severe outcome and lower mortality than nonresponders (21). Boceprevir is a novel peptidometic NS3 protease inhibitor that forms a covalent and reversible complex with the NS3 protease in vitro in the HCV replicon system. Recently, two phase III trials showed that combining boceprevir with pegylated interferon and ribavirin increased SVR rates in naive and previously treated nontransplant patients with genotype 1 HCV from 38% to 66% (SPRINT-2) and 21% to 66% (RESPOND-2), respectively (2, 20). The administration of such drugs in the context of HCV recurrence on the liver graft is one of the most...

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Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Cited by 64 publications

References 18 publications

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

Pharmacokinetic Evaluation of the Interaction between Hepatitis C Virus Protease Inhibitor Boceprevir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Pravastatin

Practical Management of Boceprevir and Immunosuppressive Therapy in Liver Transplant Recipients with Hepatitis C Virus Recurrence

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