Page 904 - Basic _ Clinical Pharmacology ( PDFDrive )

890 SECTION VIII Chemotherapeutic Drugs

5’ NTR Structural proteins Nonstructural proteins 3’ NTR

Metalloprotease
Envelope Serine protease RNA
Capsid glycoproteins RNA helicase Cofactors polymerase

C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B

NS3/4A protease NS5A inhibitors NS5B polymerase
inhibitors “ ... previr ” “ ... asvir ” inhibitors “ ... buvir ”
Telaprevir Daclatasvir Nucleosides Non-
Boceprevir Ledipasvir Sofosbuvir nucleosides
Simeprevir Velpatasvir Dasabuvir
Paritaprevir Ombitasvir
Grazoprevir Elbasvir

FIGURE 49–4 HCV genome and potential targets of drug action. C, E1, E2, etc, protein products of specific genes; Nucs, nucleoside
inhibitors; Non-Nucs, nonnucleoside inhibitors. (Adapted, with permission, from Asselah T, Marcellin P: Direct-acting antivirals for the treatment of chronic hepatitis
C: One pill a day for tomorrow. Liver Int 2012;32 Suppl 1:88.)

Grazoprevir The absolute bioavailability of paritaprevir is 53%. Peak
plasma concentrations are reached 4–5 hours post-ingestion of
Grazoprevir is a potent, pan-genotypic protease inhibitor, the combination. It is ~98% protein-bound. The primary route
reversibly binding to HCV NS3/4A protease. It is distinct from of metabolism is via CYP3A4, as well as CYP3A5. Ombitasvir/
earlier-generation protease inhibitors due to its pan-genotypic paritaprevir/ritonavir is contraindicated in patients with moderate
activity, as well activity against some of the major resistance- or severe hepatic impairment.
associated variants (R155K and D168Y) resulting in failure with The metabolism of paritaprevir, ritonavir, and dasabuvir by
first-generation protease inhibitors. It is only available in combi- the CYP3A system incurs multiple potential drug-drug interac-
nation with elbasvir for treatment of HCV genotypes 1 and 4. tions. Co-administration of the combination with drugs highly
Grazoprevir can be taken without regard to food. Oral expo- dependent on CYP3A for clearance, moderate or strong inducers
sures are ~2-fold greater in HCV-infected subjects than in healthy of CYP3A, strong inducers of CYP2C8, or strong inhibitors of
subjects. Peak plasma concentrations are reached at a median of 2 CYP2C8 is contraindicated.
hours after ingestion. Grazoprevir is extensively bound to plasma The most commonly reported adverse reactions in patients
proteins (98.8%), and distributes predominantly to the liver, receiving paritaprevir were nausea, pruritus and insomnia.
likely facilitated by active transport through the OATP1B1/3 liver Increased serum aminotransferases have also been reported, partic-
uptake transporter. It is partially eliminated by oxidative metabo- ularly in women using concomitant ethinyl estradiol–containing
lism, primarily by CYP3A and is mostly eliminated in the feces. contraceptive medications.
Its geometric mean terminal half-life is 31 hours.
Elbasvir/grazoprevir should not be administered to patients with
moderate or severe hepatic impairment, or in conjunction with Simeprevir
organic anion transporting polypeptides 1B1/3 (OATP1B1/3)
inhibitors, strong inducers or inhibitors of CYP3A, or efavirenz. Simeprevir was one of the earliest protease inhibitors available;
The most commonly reported side effects during therapy with however, it is considered a second-generation HCV protease
elbasvir/grazoprevir were fatigue, headache, and nausea. Eleva- inhibitor because of the enhanced binding affinity and specificity
tions in serum aminotransferases may occur. for NS3/4A. It is used in combination with sofosbuvir, with or
without ribavirin, for treatment of HCV genotype 1, or it may be
Paritaprevir administered in combination with peg interferon-alfa and ribavi-
rin. Simeprevir must be taken with food to maximize absorption.
Paritaprevir is only available as a fixed-dose combination with Mean absolute bioavailability is 62%. Peak plasma concentrations
ombitasvir and ritonavir for treatment of HCV genotype 4, and is are reached 4–6 hours post-ingestion. It is extensively bound to
administered in combination with dasabuvir for genotype 1 infec- plasma proteins (>99%), metabolized in the liver by CYP3A path-
tion. Ritonavir functions as a pharmacologic booster of paritapre- ways, and undergoes biliary excretion. Simeprevir is not recom-
vir concentrations via its effect on CYP metabolism, although it mended in patients with moderate or severe hepatic impairment
does not have activity against HCV. because of 2- to 5-fold increases in exposure. In addition, mean