Evaluation of the potential inhibition effect of Paritaprevir on UGT 1A1 enzyme activity using human liver microsomes
The treatment landscape of chronic hepatitis C (HCV) has changed substantially over the
last decade with the introduction of direct-acting antiviral drugs, creating more
options to treat the disease. However, the importance of clinically relevant drug-drug
interaction remains a challenge. Paritaprevir has been a successful candidate when used
in a multidrug regimen for the ... read moretreatment of HCV. However, its metabolic pathway overlaps
with that of many other drugs, resulting in increased exposure of the substrate to the
enzymes. A previous clinical study has shown that oral contraceptives containing 0.035mg
of ethinyl estradiol (EE) when given with Viekirex (Ombitasvir/paritaprevir/ritonavir)
increased the ethinyl estradiol Cmax by 16%, AUC 6% and Cmin 12%, which is a small
change. Paritaprevir Cmax, AUC, and Cmin decreased by 30%, 34%, and 13% respectively.
This can result in treatment failure or in some cases a health risk issue.
Co-administration of EE with Viekirex is contraindicated due to increase ALT level in
blood. The objective of this study was to evaluate the inhibitory effect of paritaprevir
on UGT 1A1 isoforms to identify the mechanism of inhibition of ethinyl estradiol
metabolism. We also wanted to relate the findings to different pharmacokinetic models to
evaluate whether the interaction was clinically significant. An in vitro study was done
in human liver microsomes to evaluate biotransformation of EE into its glucuronide
metabolites (EE-3-O-G, EE-17-O-G). The inhibition of metabolite formation rates by
paritaprevir was evaluated using different kinetic models. EE-3-O-G, the major
metabolite, demonstrated substrate inhibition characteristics. Paritaprevir inhibited EE
with an IC50 of 14.5±1.02 µM. Probenecid was used as a positive control
inhibitor with, an IC50 1.4±1.6 mM. The time-dependent inhibition study, in which
the inhibitor was pre-and not pre-exposed to the enzyme prior to substrate addition,
showed a very similar inhibitory concentration. The inhibition constant (ki) value for
paritaprevir on average was 20.6µM (≥ IC50). The pattern of inhibition
indicated that the inhibition was reversible with competitive characteristics. The ratio
of in vivo maximum concentration of paritaprevir to in vitro ([I]/ki) was 0.01658,
indicating that a clinically significant drug-drug interaction is
Thesis (M.S.)--Tufts University, 2017.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisors: David Greenblatt, and Margery Beinfeld.
Keyword: Pharmacology.read less