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

Abstract

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.

Reversible, Time-Dependent Inhibition of CYP3A-Mediated Metabolism of Midazolam and Tacrolimus by Telaprevir in Human Liver Microsomes

“…We do not believe the formation of VRT-127394 can easily explain the remarkable IC50 shift following preincubation since the competitive K i of VRT-127394 is about equal to that of telaprevir (6). Similar in vitro findings of reversible TDI have been reported with another first-generation HCV protease inhibitor, boceprevir (23). Furthermore, observations of reversible TDI involving cytochrome P450s is not limited to the HCV protease inhibitors.…”

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

“…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).…”

“…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).…”

“…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). In a recent drug-drug interaction trial with digoxin, boceprevir showed only limited Pglycoprotein (P-gp) inhibitory potential at clinically relevant concentrations (9).…”

Raltegravir Has a Low Propensity To Cause Clinical Drug Interactions through Inhibition of Major Drug Transporters: an In Vitro Evaluation

“…Inhibition studies in transporter-transfected cells. Inhibition of OATP1B1-, OATP1B3-, OAT1-, and OAT3-mediated uptake was determined in MDCKII-OATP1B1, MDCKII-OATP1B3, MDCKII-OAT1, and MDCKII-OAT3 cells as described previously (30)(31)(32). OCT1, OCT2, MATE1, and MATE2-K-mediated uptake were measured in CHO-K1-OCT1, CHO-K1-OCT2, CHO-K1-MATE1, and MDCKII-MATE2-K cells, respectively.…”