Page 902 - Basic _ Clinical Pharmacology ( PDFDrive )

888 SECTION VIII Chemotherapeutic Drugs

There are four current classes of DAAs, which are defined by grazoprevir should not be administered to patients with moder-
their mechanism of action and therapeutic target: nonstructural ate or severe hepatic impairment or in conjunction with organic
protein (NS) 3/4A protease inhibitors, NS5B nucleoside poly- anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors,
merase inhibitors, NS5B non-nucleoside polymerase inhibitors, strong inducers or inhibitors of CYP3A, or efavirenz.
and NS5A inhibitors. The main targets of the DAAs are the The most commonly reported side effects during therapy with
HCV-encoded proteins that are vital to the replication of the virus elbasvir/grazoprevir were fatigue, headache, and nausea. Eleva-
(Figure 49–1). tions in serum aminotransferases may occur.
The safety profiles of all the combination regimens (see
Table 49–7) are generally excellent, with adverse events of mild Ledipasvir
severity and very low rates of discontinuation due to adverse Ledipasvir was the first NS5A inhibitor to be available in the
events in clinical trials in the absence of concurrent ribavirin use.
United States. It is available in a fixed-dose combination with
sofosbuvir. Ledipasvir is not recommended for treatment of HCV
NS5A INHIBITORS genotype 2 infection (since potency is lost in the presence of the
highly prevalent L31M polymorphism) or genotype 3 (due to the
The NS5A protein plays a role in both viral replication and the availability of more efficacious therapies (see Table 49–7).
assembly of HCV; however the exact mechanism of action of the Ledipasvir is not affected by food intake. Median peak plasma
HCV NS5A inhibitors remains unclear. concentrations occur 4–4.5 hours after oral administration of ledi-
pasvir/sofosbuvir. It is highly bound (>99.8%) to plasma proteins;
Daclatasvir unchanged ledipasvir is the major species present in feces. The
median terminal half-life of ledipasvir following administration of
Daclatasvir is used in combination with sofosbuvir for treatment ledipasvir/sofosbuvir is 47 hours. No dose adjustment is required
of HCV genotypes 1, 2, and 3. It may be taken with or without in the setting of mild or moderate renal insufficiency or mild,
food and does not require adjustment for renal or hepatic impair- moderate or severe hepatic insufficiency. The dose in patients with
ment. Exposure of daclatasvir was similar between healthy and severe renal insufficiency has not yet been determined.
HCV-infected subjects. Protein binding is ~99%. It is metabo- Ledipasvir is an inhibitor of the drug transporters P-gp and
lized via CYP3A and excreted primarily in the feces. Terminal BCRP and may increase intestinal absorption of co-administered
elimination half-life is 12–15 hours. substrates for these transporters. Additionally, co-administration
Daclatasvir is generally well tolerated. The most common of P-gp inducers (e.g., rifampin or St. John’s wort) with ledipasvir/
adverse effects in patients receiving daclatasvir/sofosbuvir were sofosbuvir may decrease plasma concentrations of both of these
headache and fatigue, usually mild or moderate in severity. Serious agents.
symptomatic bradycardia has been reported in patients receiving The most common adverse reactions in patients receiving
daclatasvir with sofosbuvir and amiodarone. ledipasvir/sofosbuvir were fatigue, headache and asthenia. Serious
Daclatasvir is primarily metabolized through CYP3A metabo- symptomatic bradycardia has been reported in patients receiving
lism and should not be given with strong inducers of this enzyme. ledipasvir with sofosbuvir and amiodarone.
In addition, dose adjustment is required when co-administered
with strong CYP3A inhibitors or moderate CYP3A inducers. Ombitasvir
Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp),
organic anion transporting polypeptide (OATP) 1B1 and 1B3, Ombitasvir is available only as a fixed-dose combination with
and breast cancer resistance protein (BCRP). paritaprevir and ritonavir for the treatment of HCV genotype 4,
and is given in combination with dasabuvir, paritaprevir, and rito-
Elbasvir navir to treat genotype 1 (see Table 49–7). As in HIV infection,
ritonavir is administered as a pharmacologic “booster” to increase
Elbasvir has in vitro activity against most major HCV genotypes, plasma concentrations of paritaprevir via its effect on CYP3A,
as well as some viral variants resistant to earlier NS5A inhibitors. although it does not have activity against HCV.
It is only available as a fixed-dose combination with grazoprevir, The absolute bioavailability of ombitasvir is 48%. Peak plasma
recommended for treatment of HCV genotypes 1 and 4 (see concentrations are reached 5 hours post-ingestion of the combi-
Table 49–7). nation. It is 99.9% protein-bound; the route of metabolism is via
The presence of baseline NS5A resistance-associated variants biliary excretion. Ombitasvir/paritaprevir/ritonavir is contrain-
(RAVs) significantly reduced rates of SVR at 12 weeks using dicated in patients with moderate or severe hepatic impairment.
elbasvir/grazoprevir regimen in patients with genotype 1a. Since Ombitasvir is an inhibitor of UGT1A1. Although ombitasvir
10–15% of patients without prior exposure will have NS5A RAVs, is not metabolized by the CYP3A system, paritaprevir, ritonavir,
baseline testing should be considered prior initiation of therapy. and dasabuvir are, with the resulting potential for multiple drug-
Absorption is not food-dependent. Peak concentrations after drug interactions. Co-administration of the combination with
ingestion occur at a median of 3 hours. Elbasvir is extensively drugs that highly dependent on CYP3A for clearance, moderate or
bound to plasma proteins (>99.9%), partially eliminated by oxi- strong inducers of CYP3A, strong inducers of CYP2C8, or strong
dative metabolism, and primarily excreted in the feces. Elbasvir/ inhibitors of CYP2C8 is contraindicated.