Page 903 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 49 Antiviral Agents 889

The most commonly reported adverse reactions in patients combination. It is >99.5% protein-bound. The primary route of
receiving ombitasvir were nausea, pruritus and insomnia. Increased metabolism is via CYP2C8, as well as CYP3A. This combination
serum aminotransferases have also been reported, particularly in is contraindicated in patients with moderate or severe hepatic
women using concomitant ethinyl estradiol-containing contracep- impairment.
tive medications. The metabolism of paritaprevir, ritonavir, and dasabuvir by the
CYP3A system incurs multiple potential drug-drug interactions.
Velpatasvir Co-administration of the combination with drugs that highly
dependent on CYP3A for clearance, moderate or strong inducers
Velpatasvir is available only in a fixed-dose combination with the of CYP3A, strong inducers of CYP2C8, or strong inhibitors of
sofosbuvir. It is the first once-daily single-tablet regimen with CYP2C8 is contraindicated.
pangenotypic activity. No dose adjustment is required for patients The most commonly reported adverse reactions in patients
with mild or moderate renal insufficiency, or any degree of hepatic receiving dasabuvir were nausea, pruritus and insomnia. Increased
impairment. Sofosbuvir exposure is increased in patients with serum aminotransferases have also been reported, particularly in
severe renal impairment, including those on dialysis. women using concomitant ethinyl estradiol-containing contracep-
Velpatasvir is administered without regard to food; peak tive medications.
plasma concentrations are observed at 3 hours post-dose. It is
>99% bound to plasma proteins. Metabolism is by CYP2B6 Sofosbuvir
CYP2C8, and CYP3A4. Its median terminal half-lives is 15 hours.
Velpatasvir and sofosbuvir are substrates of P-gp and BCRP; The nucleotide analog sofosbuvir is administered in combination
velpatasvir is also transported by OATP1B1 and OATP1B3. with several other anti-HCV medications, including daclatasvir,
Inducers of P-gp and/or moderate or potent inducers of CYP2B6, simeprevir, peginterferon-alfa plus ribavirin, or ribavirin alone.
CYP2C8, or CYP3A4 (e.g., rifampin, St. John’s wort, carbamaze- It is also available in a fixed-dose combination with ledipasvir for
pine) may decrease plasma concentrations of velpatasvir and/or treatment of HCV genotypes 1, 4, 5, and 6 (see Table 49–7).
sofosbuvir; co-administration with drugs that inhibit P-gp and/ Sofosbuvir is a prodrug that is rapidly converted after ingestion
or BCRP may increase velpatasvir and/or sofosbuvir concentra- to GS-331007, which is efficiently taken up by hepatocytes and
tions and drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may converted by cellular kinase to its pharmacologically active uridine
increase plasma concentration of velpatasvir. analog 5’-triphosphate form GS-461203. The triphosphate is
The most common adverse events in patients receiving velpa- incorporated by the HCV RNA polymerase into the elongating
tasvir/sofosbuvir were headache and fatigue. RNA primer strand, resulting in chain termination.
Sofosbuvir is administered without regard to food; peak plasma
concentrations are observed at 0.5–1 hour post-dose. It is 61–65%
NS5B RNA POLYMERASE INHIBITORS bound to plasma proteins and is metabolized in the liver. Renal
clearance is the major elimination pathway for GS-331007. The
NS5B is an RNA-dependent RNA polymerase involved in post- median terminal half-lives of sofosbuvir and GS-331007 are
translational processing that is necessary for replication of HCV. 0.4 and 27 hours, respectively. No dose adjustment is required
The enzyme has a catalytic site for nucleoside binding and at least for patients with mild or moderate renal insufficiency, or any
four other sites at which a non-nucleoside compound can bind degree of hepatic impairment. Sofosbuvir exposure is increased in
and cause allosteric alteration. The enzyme’s structure is highly patients with severe renal impairment, including those on dialysis.
conserved across all HCV genotypes, giving agents that inhibit Sofosbuvir is a substrate of drug transporter P-gp; therefore,
NS5B efficacy against all six genotypes. potent P-gp inducers in the intestine may decrease sofosbuvir
There are two classes of polymerase inhibitors; these act at concentrations and should not be co-administered.
distinct stages of RNA synthesis. Nucleoside/nucleotide analogs Sofosbuvir is generally well tolerated. Drug-specific adverse
(eg, sofosbuvir) target the catalytic site of NS5B, and are activated effects are difficult to discern since it is always administered with
within the hepatocyte through phosphorylation to nucleoside other antiviral agents. In patients receiving sofosbuvir with ledi-
triphosphate, which competes with nucleotides, resulting in chain pasvir, the most commonly reported adverse effects were fatigue,
termination. Non-nucleoside analogues (e.g., dasabuvir) act as headache, and asthenia. Rare cases of symptomatic bradycardia
allosteric inhibitors of NS5B. have been reported patients taking sofosbuvir and amiodarone
in combination with another DAAs, particularly in patients
Dasabuvir also receiving beta blockers, or in those with underlying cardiac
comorbidities and/or advanced liver disease.
Dasabuvir is a non-nucleoside NS5B polymerase inhibitor, avail-
able only as a fixed-dose combination with ombitasvir, paritapre-
vir, and ritonavir for treatment of HCV genotype 1. Ritonavir NS3/4A PROTEASE INHIBITORS
functions as a pharmacologic booster to increase paritaprevir
plasma concentrations. NS3/4A protease inhibitors are inhibitors of the NS3/4A serine
The absolute bioavailability of dasabuvir is 70%. Peak protease, an enzyme involved in post-translational processing and
plasma concentrations are reached 4 hours post-ingestion of the replication of HCV (Figure 49–4).