Affiliation:
1. Sydney Pharmacy School, Sydney Local Health District, Faculty of Medicine and Health, School of Medical Sciences, University of
Sydney, NSW2000, Australia
Abstract
Abstract:
Asunaprevir, daclatasvir, and beclabuvir are direct-acting antiviral agents used in the treatment of
patients infected with hepatitis C genotype 1b. This article reviews the biotransformation and disposition of these
drugs in relation to the safety and efficacy of therapy. CYP3A4 and 3A5 catalyze the oxidative biotransformation
of the drugs, while P-glycoprotein mediates their efflux from tissues. Asunaprevir is also a substrate
for the influx transporters OATP1B1 and OATP2B1 and the efflux transporter MRP2, while beclabuvir is also
a substrate for the efflux transporter BCRP. Liver disease decreases the expression of CYPs and transporters
that mediate drug metabolism and disposition. Serum asunaprevir concentrations, but not those of daclatasvir
or beclabuvir, are increased in patients with severe liver disease, which may produce toxicity. Pharmacogenomic
variation in CYPs and transporters also has the potential to disrupt therapy with asunaprevir, daclatasvir and
beclabuvir; some variants are more prevalent in certain racial groups. Pharmacokinetic drug-drug interactions,
especially where asunaprevir, daclatasvir, and beclabuvir are victim drugs, are mediated by coadministered rifampicin,
ketoconazole and ritonavir, and are attributable to inhibition and/or induction of CYPs and transporters.
Conversely, there is also evidence that asunaprevir, daclatasvir and beclabuvir are perpetrators of drug
interactions with coadministered rosuvastatin and dextromethorphan. Together, liver disease, pharmacogenomic
variation and drug-drug interactions may disrupt therapy with asunaprevir, daclatasvir and beclabuvir due to
the impaired function of important CYPs and transporters.
Publisher
Bentham Science Publishers Ltd.