Page 11 - EASL Recommendations on Treatment of Hepatitis C 2015 - Full version
P. 11
Clinical Practice Guidelines eliminated in the faeces. Dasabuvir is metabolised in the liver,
and its predominant metabolite is mainly cleared via biliary
The pharmacokinetics of daclatasvir following a single 60 mg excretion and faecal elimination with minimal renal clearance.
oral dose have been studied in non-HCV-infected subjects with
renal impairment. Daclatasvir unbound AUC was estimated to Pharmacokinetic results from hepatic impairment studies
be 18%, 39%, and 51% higher for subjects with creatinine clear- have shown that, in patients with severe hepatic impairment
ance values of 60, 30, and 15 ml/min, respectively, relative to (Child-Pugh C), the AUC of paritaprevir was increased 9.5-fold,
subjects with normal renal function. Subjects requiring whereas ombitasvir was reduced 54% and dasabuvir was
haemodialysis had a 27% increase in daclatasvir AUC and a 20% increased 3.3-fold. As a result, no dose adjustment is required
increase in unbound AUC compared to subjects with normal renal for patients with mild hepatic impairment (Child-Pugh A) and
function. Thus, no dose adjustment of daclatasvir is required for no dose adjustment is expected to be required for patients with
patients with any degree of renal impairment. moderate hepatic impairment (Child-Pugh B). In contrast, this
combination is contra-indicated in patients with severe hepatic
The most frequently reported side effects with daclatasvir impairment (Child-Pugh C).
were fatigue, headache and nausea.
The AUC of paritaprevir was increased 45% in patients with
Daclatasvir is a substrate of CYP34A, and a substrate and inhibi- severe renal impairment (creatinine clearance 15–29 ml/min),
tor of P-gp. In addition, it is an inhibitor of OATP1B1 and BCRP. Co- that of ritonavir 114%, and dasabuvir 50%. Currently, no dose
administration of daclatasvir with drugs that strongly induce adjustment is required for patients with mild, moderate or severe
CYP3A4 and P-gp and thus reduce daclatasvir exposure is contra- renal impairment. Whether paritaprevir, ombitasvir and/or
indicated. This includes anticonvulsants (carbamazepine, pheny- dasabuvir are partly removed by dialysis is unknown.
toin, oxcarbazepine, phenobarbital), antimycobacterials (rifampi-
cin, rifabutin, rifapentine), systemic dexamethasone and St John’s The most common side effects reported with the combination
wort. Strong inhibitors of CYP3A4 increase the plasma levels of of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir were
daclatasvir; therefore, dose adjustments of daclatasvir are recom- fatigue and nausea.
mended. The dose of daclatasvir should be reduced to 30 mg once
daily with atazanavir/ritonavir and cobicistat containing antiretro- Paritaprevir is primarily metabolised by CYP3A4, whereas
viral regimens. In contrast, recent data suggest that no dose adjust- dasabuvir is primarily metabolised by CYP2C8 and ombitasvir
ment is necessary with either darunavir/ritonavir or lopinavir/ undergoes hydrolysis. However, both ombitasvir and dasabuvir
ritonavir. In the ALLY-2 study in HIV-coinfected patients receiving can be metabolised by CYP3A4. Transporters seem to play an
sofosbuvir and daclatasvir, patients on a darunavir-based regimen important role in the disposition of these drugs, with paritaprevir
who had daclatasvir dose reduced to 30 mg (based on the original inhibiting OATP1B1/B3, P-gp and BCRP. Dasabuvir and ritonavir
atazanavir/ritonavir study data) had a reduced rate of SVR12, par- may also inhibit P-gp and BCRP. Given the metabolic profile of
ticularly in the 8-week treatment arm, pointing to the need for the the drugs and the presence of ritonavir, there is a potential for
standard dose of daclatasvir in patients on this boosted protease many drug-drug interactions. A comprehensive drug-drug inter-
inhibitor. With efavirenz (an enzyme inducer), the dose of dacla- action programme has been undertaken based on regulatory
tasvir is recommended to be increased to 90 mg. Due to a lack of guidance from both the European Medicines Agency and the US
data, the same is not recommended with etravirine and nevirapine, Food and Drug Administration. It is important to consider the
both enzyme inducers. There are no drug interactions with teno- drug interaction profile of the compounds as a combination
fovir, emtricitabine, abacavir, lamivudine, zidovudine, stavudine, (either with or without dasabuvir), because the drugs have
rilpivirine, raltegravir, dolutegravir or maraviroc. mutual effects on each other.
The dose of daclatasvir should also be reduced to 30 mg with Ritonavir is a strong inhibitor of CYP3A4; thus, co-ad-
the antibacterials clarithromycin, telithromycin, erythromycin ministration with drugs metabolised by this enzyme may result
and the antifungals ketoconazole, itraconazole, posaconazole in markedly increased plasma concentrations. A number of
and voriconazole. Studies have been performed with acid-reduc- drugs are contra-indicated because elevated plasma exposure
ing agents (famotidine, omeprazole), escitalopram and an oral would lead to serious adverse events, including: alfuzosin,
contraceptive with no dose adjustment of daclatasvir or the co- amiodarone, astemizole, terfenadine, cisapride, ergot deriva-
medication. However, due to daclatasvir inhibiting some trans- tives, lovastatin, simvastatin, atorvastatin, oral midazolam, tri-
port proteins, monitoring is required with dabigatran and digoxin azolam, quetiapine, quinidine, salmeterol, sildenafil when used
and other P-gp substrates. for pulmonary arterial hypertension. Also contra-indicated are
enzyme inducers that might compromise virological efficacy,
Ritonavir-boosted paritaprevir, ombitasvir and dasabuvir. e.g. carbamazepine, phenytoin, phenobarbital, rifampicin, St
Paritaprevir is an NS3-4A protease inhibitor which is metabolised John’s wort, enzalutamide, and enzyme inhibitors that might
primarily by CYP3A4 and is given with a low dose of the CYP3A increase paritaprevir exposure, e.g. azole antifungals, some
inhibitor ritonavir as a pharmacokinetic enhancer. This enables macrolide antibiotics.
once daily administration and a lower dose than would be
required without ritonavir. Ombitasvir is an NS5A inhibitor given In addition to the contra-indications, there are other drugs
in a fixed-dose combination with paritaprevir/ritonavir. The where caution needs to be exercised and there may be require-
recommended dose of this combination is two tablets of riton- ment for a dosage adjustment, altered timing of administration
avir/paritaprevir/ombitasvir (50 mg/75 mg/12.5 mg per tablet) or additional monitoring. Drug interactions need to be carefully
taken orally once daily with food. Dasabuvir is a non-nucleoside considered in the setting of coinfection with HIV. Atazanavir
inhibitor of HCV RNA-dependent RNA polymerase in 250 mg and darunavir should be taken without ritonavir and other pro-
tablets administered twice daily in combination with riton- tease inhibitors are contra-indicated. Efavirenz, etravirine and
avir/paritaprevir/ombitasvir in genotype 1 patients. nevirapine are contra-indicated, and rilpivirine should be used
cautiously with repeat ECG monitoring. The exposure of raltegra-
Paritaprevir is excreted predominantly into the faeces. vir and dolutegravir may be increased, but this is not linked to
Ombitasvir shows linear kinetics, and is predominantly
10
and its predominant metabolite is mainly cleared via biliary
The pharmacokinetics of daclatasvir following a single 60 mg excretion and faecal elimination with minimal renal clearance.
oral dose have been studied in non-HCV-infected subjects with
renal impairment. Daclatasvir unbound AUC was estimated to Pharmacokinetic results from hepatic impairment studies
be 18%, 39%, and 51% higher for subjects with creatinine clear- have shown that, in patients with severe hepatic impairment
ance values of 60, 30, and 15 ml/min, respectively, relative to (Child-Pugh C), the AUC of paritaprevir was increased 9.5-fold,
subjects with normal renal function. Subjects requiring whereas ombitasvir was reduced 54% and dasabuvir was
haemodialysis had a 27% increase in daclatasvir AUC and a 20% increased 3.3-fold. As a result, no dose adjustment is required
increase in unbound AUC compared to subjects with normal renal for patients with mild hepatic impairment (Child-Pugh A) and
function. Thus, no dose adjustment of daclatasvir is required for no dose adjustment is expected to be required for patients with
patients with any degree of renal impairment. moderate hepatic impairment (Child-Pugh B). In contrast, this
combination is contra-indicated in patients with severe hepatic
The most frequently reported side effects with daclatasvir impairment (Child-Pugh C).
were fatigue, headache and nausea.
The AUC of paritaprevir was increased 45% in patients with
Daclatasvir is a substrate of CYP34A, and a substrate and inhibi- severe renal impairment (creatinine clearance 15–29 ml/min),
tor of P-gp. In addition, it is an inhibitor of OATP1B1 and BCRP. Co- that of ritonavir 114%, and dasabuvir 50%. Currently, no dose
administration of daclatasvir with drugs that strongly induce adjustment is required for patients with mild, moderate or severe
CYP3A4 and P-gp and thus reduce daclatasvir exposure is contra- renal impairment. Whether paritaprevir, ombitasvir and/or
indicated. This includes anticonvulsants (carbamazepine, pheny- dasabuvir are partly removed by dialysis is unknown.
toin, oxcarbazepine, phenobarbital), antimycobacterials (rifampi-
cin, rifabutin, rifapentine), systemic dexamethasone and St John’s The most common side effects reported with the combination
wort. Strong inhibitors of CYP3A4 increase the plasma levels of of ritonavir-boosted paritaprevir, ombitasvir and dasabuvir were
daclatasvir; therefore, dose adjustments of daclatasvir are recom- fatigue and nausea.
mended. The dose of daclatasvir should be reduced to 30 mg once
daily with atazanavir/ritonavir and cobicistat containing antiretro- Paritaprevir is primarily metabolised by CYP3A4, whereas
viral regimens. In contrast, recent data suggest that no dose adjust- dasabuvir is primarily metabolised by CYP2C8 and ombitasvir
ment is necessary with either darunavir/ritonavir or lopinavir/ undergoes hydrolysis. However, both ombitasvir and dasabuvir
ritonavir. In the ALLY-2 study in HIV-coinfected patients receiving can be metabolised by CYP3A4. Transporters seem to play an
sofosbuvir and daclatasvir, patients on a darunavir-based regimen important role in the disposition of these drugs, with paritaprevir
who had daclatasvir dose reduced to 30 mg (based on the original inhibiting OATP1B1/B3, P-gp and BCRP. Dasabuvir and ritonavir
atazanavir/ritonavir study data) had a reduced rate of SVR12, par- may also inhibit P-gp and BCRP. Given the metabolic profile of
ticularly in the 8-week treatment arm, pointing to the need for the the drugs and the presence of ritonavir, there is a potential for
standard dose of daclatasvir in patients on this boosted protease many drug-drug interactions. A comprehensive drug-drug inter-
inhibitor. With efavirenz (an enzyme inducer), the dose of dacla- action programme has been undertaken based on regulatory
tasvir is recommended to be increased to 90 mg. Due to a lack of guidance from both the European Medicines Agency and the US
data, the same is not recommended with etravirine and nevirapine, Food and Drug Administration. It is important to consider the
both enzyme inducers. There are no drug interactions with teno- drug interaction profile of the compounds as a combination
fovir, emtricitabine, abacavir, lamivudine, zidovudine, stavudine, (either with or without dasabuvir), because the drugs have
rilpivirine, raltegravir, dolutegravir or maraviroc. mutual effects on each other.
The dose of daclatasvir should also be reduced to 30 mg with Ritonavir is a strong inhibitor of CYP3A4; thus, co-ad-
the antibacterials clarithromycin, telithromycin, erythromycin ministration with drugs metabolised by this enzyme may result
and the antifungals ketoconazole, itraconazole, posaconazole in markedly increased plasma concentrations. A number of
and voriconazole. Studies have been performed with acid-reduc- drugs are contra-indicated because elevated plasma exposure
ing agents (famotidine, omeprazole), escitalopram and an oral would lead to serious adverse events, including: alfuzosin,
contraceptive with no dose adjustment of daclatasvir or the co- amiodarone, astemizole, terfenadine, cisapride, ergot deriva-
medication. However, due to daclatasvir inhibiting some trans- tives, lovastatin, simvastatin, atorvastatin, oral midazolam, tri-
port proteins, monitoring is required with dabigatran and digoxin azolam, quetiapine, quinidine, salmeterol, sildenafil when used
and other P-gp substrates. for pulmonary arterial hypertension. Also contra-indicated are
enzyme inducers that might compromise virological efficacy,
Ritonavir-boosted paritaprevir, ombitasvir and dasabuvir. e.g. carbamazepine, phenytoin, phenobarbital, rifampicin, St
Paritaprevir is an NS3-4A protease inhibitor which is metabolised John’s wort, enzalutamide, and enzyme inhibitors that might
primarily by CYP3A4 and is given with a low dose of the CYP3A increase paritaprevir exposure, e.g. azole antifungals, some
inhibitor ritonavir as a pharmacokinetic enhancer. This enables macrolide antibiotics.
once daily administration and a lower dose than would be
required without ritonavir. Ombitasvir is an NS5A inhibitor given In addition to the contra-indications, there are other drugs
in a fixed-dose combination with paritaprevir/ritonavir. The where caution needs to be exercised and there may be require-
recommended dose of this combination is two tablets of riton- ment for a dosage adjustment, altered timing of administration
avir/paritaprevir/ombitasvir (50 mg/75 mg/12.5 mg per tablet) or additional monitoring. Drug interactions need to be carefully
taken orally once daily with food. Dasabuvir is a non-nucleoside considered in the setting of coinfection with HIV. Atazanavir
inhibitor of HCV RNA-dependent RNA polymerase in 250 mg and darunavir should be taken without ritonavir and other pro-
tablets administered twice daily in combination with riton- tease inhibitors are contra-indicated. Efavirenz, etravirine and
avir/paritaprevir/ombitasvir in genotype 1 patients. nevirapine are contra-indicated, and rilpivirine should be used
cautiously with repeat ECG monitoring. The exposure of raltegra-
Paritaprevir is excreted predominantly into the faeces. vir and dolutegravir may be increased, but this is not linked to
Ombitasvir shows linear kinetics, and is predominantly
10
