. 4.1k Downloads.AbstractHepatitis C virus (HCV)-infected patients often suffer from liver cirrhosis, which can be complicated by renal impairment.
Therefore, in this review we describe the treatment possibilities in HCV patients with hepatic and renal impairment. Cirrhosis alters the structure of the liver, which affects drug-metabolizing enzymes and drug transporters. These modifications influence the plasma concentration of substrates of drugs metabolized/transported by these enzymes. The direct-acting antivirals (DAAs) are substrates of, for example, cytochrome P450 enzymes in the liver. Most DAAs are not studied in HCV-infected individuals with decompensated cirrhosis, and therefore awareness is needed when these patients are treated. Most DAAs are contraindicated in cirrhotic patients; however, patients with a Child-Pugh score of B or C can be treated safely with a normal dose sofosbuvir plus ledipasvir or daclatasvir, in combination with ribavirin.
Patients with renal impairment (glomerular filtration rate GFR. Chronic hepatitis C virus (HCV)-related liver cirrhosis is the leading cause of liver transplantation in many countries ,. Eventually, 15–30% of chronically infected HCV patients develop liver cirrhosis ,. Symptoms of decompensated cirrhosis are portal hypertension (with increased risk for variceal bleedings), ascites, hepatic encephalopathy, and hepato-renal syndrome. In addition, cirrhotic patients have an enhanced risk of hepatocellular carcinoma, which is an important cause of mortality ,.HCV is associated with both renal and hepatic impairment, and care must be taken when prescribing direct-acting antivirals (DAAs) in these patients. The drugs described in this review are ribavirin and the novel DAAs.Impaired kidney or liver function may result in altered drug concentrations, causing either toxicity or subtherapeutic levels, because these organs are mainly responsible for metabolizing and excreting drugs. For instance, patients with reduced renal function have a decreased ability to eliminate water-soluble agents and patients with impaired liver function have reduced expression of drug-metabolizing enzymes and thus reduced metabolizing capacity.There is only limited information on the pharmacokinetics, safety, efficacy, and dosage in these special populations.
Moreover, this information is often difficult to find and not presented in a comprehensive manner. Therefore, the aim of this review is to give an overview of the pharmacokinetics, efficacy, and safety of drugs used for HCV treatment in patients with renal or hepatic impairment and to provide dose recommendations for prescribing these drugs in these special populations. An extensive search was performed using PubMed (1946 to October 2015) and EMBASE (1947 to October 2015) to identify peer-reviewed studies containing information on pharmacokinetics, efficacy, and safety in patients with impaired renal or hepatic function and HCV medication. Search terms used included generic and brand names. Various general search terms were also used describing impaired renal and hepatic function, e.g., ‘end stage renal disease’ (ESRD), ‘dialysis’, ‘cirrhosis’, and ‘hepatic impairment’.
Google, Google Scholar, and ClinicalTrials.gov were used to identify conference papers and abstracts. All searches were performed in the English language. Additional articles and primary sources were identified with citation snowballing. Lastly, the summary of product characteristics (SmPC) approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) prescribing information were main sources of information for this review.This review focuses on the novel DAAs, e.g., simeprevir, paritaprevir, asunaprevir, grazoprevir, daclatasvir, ombitasvir, ledipasvir, elbasvir, velpatasvir, sofosbuvir, and dasabuvir. To date, velpatasvir is not yet licensed.
The included DAAs are used in international guidelines or were submitted for registration up to November 2015 by the EMA and/or FDA. Ribavirin is also discussed because it is still a component of the therapy for cirrhotic patients. We omitted telaprevir and boceprevir from the review as their current use is limited. Additionally, we do not describe peginterferon-α as we believe it should not be used in patients with cirrhosis or renal impairment. 3 Pharmacokinetics. Bid twice dialy, EMA European Medicines Agency, FDA Food and Drug Administration, HCV hepatitis C virus, od once daily, SmPC summary of product characteristicsaThe US FDA prescribing information for Olysio TM comments that: the potential risks and benefits of OLYSIO TM (Janssen Therapeutics, Titusville, NJ, USA) should be carefully considered prior to use in patients with moderate or severe hepatic impairment.
The EMA SmPC comments that: the safety and efficacy of OLYSIO TM have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh score B or C); therefore, particular caution is recommended when prescribing OLYSIO TM to HCV-infected patients with moderate or severe hepatic impairmentbNo SmPC or prescribing information was available at time of publicationcThe SmPC Viekierax® (AbbVie, North Chicago, IL, USA) and Exviera ® (AbbVie, North Chicago, IL, USA) state that efficacy and safety are not studied in Child-Pugh score B patients. The US Prescribing information has been updated and both Child -Pugh score B and C are contraindicated. HCV drugNormal renal functionDegree of renal impairmentRemoved by dialysis?GFR 90 mL/minMild (GFR 50-89 mL/min))Moderate (GFR 30-49 mL/min)Severe (GFR 15-29 mL/min)ESRD (GFR. 1Overview of the hepatic or non-enzymatic metabolism of drugs used for the treatment of hepatitis C: cytochrome P450 enzymes involved and biliary and/or renal excretion of drug (metabolites). Asterisk The site of metabolism is unknown but two metabolizing pathways are involved: (1) a reversible phosphorylation pathway; and (2) a degradative pathway involving deribosylation and amide hydrolysis.
Plus or minus Sofosbuvir is extensively metabolized in the liver in the active metabolite GS-461203, followed by dephosphorylation which results in the inactive compound GS-331007. ASV asunaprevir, CYP cytochrome P450, DCV daclatasvir, DSV dasabuvir, EBV elbasvir, GRZ grazoprevir, LDV ledipasvir, OBV ombitasvir, PTV paritaprevir, RBV ribavirin, SIM simeprevir, SOF sofosbuvir, VPV velpatasvir 3.1 Protease Inhibitors 3.1.1 SimeprevirSimeprevir is a second-wave, first-generation PI and is prescribed at a dose of 150 mg/day. Simeprevir is highly bound to plasma proteins (99.9%), and is a substrate of various drug transporters such as P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP) 1B1, OATP1B2, OATP2B1, and multidrug resistance protein (MRP2), and different cytochrome P450 (CYP) enzymes (intestinal CYP3A4, CYP2C19, and CYP2C8). The plasma concentration of simeprevir was two- to three-fold higher in HCV-infected patients than in healthy subjects.Compared with healthy individuals, simeprevir steady-state area under the plasma concentration–time curve (AUC) was 2.4- and 5.2-fold higher in Child-Pugh score B (CP-B) and score C (CP-C) patients, respectively. Therefore, the manufacturer recommends that simeprevir should not be used in CP-C patients and that caution should be taken in CP-B patients. Another trial reported similar results: non-HCV CP-B patients had twofold increased exposure compared with healthy individuals and CP-C patients had twofold higher exposure to simeprevir than CP-B patients. After a dose of 150 mg, Sekar et al.
observed equal exposure and protein binding between non-HCV Child-Pugh score A (CP-A) and CP-B subjects.The steady-state AUC of simeprevir increased (62%) in patients with severe renal impairment (Glomerular Filtration Rate GFR: 15–29 mL/min). This may indicate that exposure may increase in patients with severe renal impairment and ESRD (GFR ≤15 mL/min). Thus caution is needed in these patients. However, the label states that simeprevir can be used by patients with all grades of renal impairment. At last, simeprevir is not removed by dialysis. 3.1.2 AsunaprevirAsunaprevir is a PI that has activity against multiple genotypes. It is used at a dose of 100 mg twice daily which is metabolized by the liver (CYP3A4) and mainly excreted through the biliary system.
Asunaprevir is 98.8% bound to serum proteins ,.The pharmacokinetics of asunaprevir were studied in non-HCV infected subjects with CP-A/B/C and compared with healthy volunteers; they were comparable in CP-A subjects and controls. Maximum concentration ( C max) and AUC increased 10- and 5-fold in CP-B subjects and 23- and 32-fold in CP-C subjects, respectively. Therefore, it is not recommended that CP-B/C patients be treated with asunaprevir. Protein binding in all groups was 99.5% and the unbound fraction was ± 0.004.Asunaprevir was studied in non-HCV subjects dependent on dialysis compared with healthy controls. Protein binding, C max, AUC, and trough concentration ( C trough) were not affected by dialysis. Comparable results were presented in an open-label study in HCV-uninfected subjects with normal (GFR 90 mL/min), mild (GFR 50–89 mL/min), moderate (GFR 30–49 mL/min), or severe renal disease (GFR 99.8% bound to plasma proteins.No relevant differences were seen in between the pharmacokinetics of control patients with normal hepatic function and CP-C patients after a dose of ledipasvir 60 mg. Single and multiple doses of ledipasvir 30 mg (in combination with 200 mg of the investigational PI vedroprevir) resulted in a reduction of the C max (36%) and an extended elimination half-life ( t ½) in CP-C patients (84.4 vs.
45.7 h in healthy subjects). The free fraction of ledipasvir increased in patients with severe hepatic impairment (0.21 vs. 0.11% in healthy subjects). No significant changes were seen between CP-B patients and control subjects.No pharmacokinetic differences were observed between healthy subjects and patients with severe renal impairment, although no safety data are available for patients with GFR 80 mL/min). Elbasvir pharmacokinetics showed similar results: AUC was 86% higher and C trough was 107% higher. The unbound fraction of grazoprevir was comparable between the three treatment groups.
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The unbound fraction of elbasvir was below the limit of detection ,. 3.4.4 Paritaprevir/Ritonavir, Ombitasvir, and DasabuvirThe fixed-dose combination of paritaprevir (75 mg), ritonavir (50 mg), and ombitasvir (12.5 mg) is administered as two tablets once daily with or without dasabuvir 250 mg twice daily.Paritaprevir is a second-generation PI, which is a substrate of CYP3A4/5, P-gp, OATP1B1, and OATP1B3. Ritonavir is added to improve the pharmacokinetics of paritaprevir by inhibiting CYP3A4 (‘boosting’). Paritaprevir itself also inhibits various drug transporters and is 97–98.6% bound to plasma proteins. After hepatic metabolism, paritaprevir is excreted through the biliary system. CP-C patients had 3.2- and 9.5-fold higher C max and AUC values than control subjects ,. Paritaprevir is contraindicated in CP-B/C patients.
The unbound fraction was 1.1% in subjects with normal hepatic function and 0.78, 0.75, and 1.2% by patients with CP-A, CP-B, and CP-C, respectively.In patients with mild, moderate, and severe renal insufficiency, the AUC of paritaprevir increased by 19, 33, and 45%. C max was comparable with control subjects.Ombitasvir is an NS5A inhibitor and highly metabolized: only 8.9% of the unchanged drug is excreted, and a total of 13 metabolites were identified. Amide hydrolysis and oxidative metabolism are responsible for its biotransformation.
Ombitasvir is 99.9% bound to plasma proteins and biliary excretion is the major elimination pathway. In CP-C patients, ombitasvir reduced the AUC and C max values by 68 and 54%, respectively. The unbound fraction of ombitasvir increased from 0.020% in control subjects and CP-A/B patients to 0.047% in CP-C patients ,. Ombitasvir exposure was not affected by any degree of renal insufficiency.Dasabuvir is an NS5B polymerase inhibitor and a substrate of CYP2C8, CYP3A4, P-gp, BCRP, and organic cation transporter (OCT) 1. Dasabuvir is hepatically metabolized into seven metabolites, of which M1 accounts for 21% of the administered dose. However, unchanged dasabuvir accounts for 60% of the exposure.
Dasabuvir is 99.5% and M1 94.5% bound to plasma proteins. The AUC values of dasabuvir and M1 were equal in healthy controls and CP-A patients.
CP-B patients had reduced dasabuvir and M1 AUC values (16 and 57%, respectively). CP-C patients had elevated AUCs for dasabuvir and M1: 325 and 77%, respectively ,. Dasabuvir unbound fractions were lower in patients with CP-A, CP-B, and CP-C: 0.29, 0.28, and 0.42%, respectively (control subjects: 0.61%). The unbound fraction of M1 in control subjects was 5.8% and it was 5.1, 5.4, and 6.8% in CP-A, CP-B, and CP-C patients. Due to the elevated AUC of dasabuvir (and M1) in CP-C patients, dasabuvir is contraindicated in these patients.The AUC of dasabuvir decreased in patients with mild (21%), moderate (37%), and severe (50%) renal insufficiency.
As exposure slightly declines in patients with renal impairment, no dose adjustments are required in these patients.To conclude, paritaprevir/ritonavir plus ombitasvir with or without dasabuvir can be used safely in patients with any stage of renal impairment. Due to a recent FDA announcement, the label for this combination regimen has been updated, stating that paritaprevir/ritonavir and ombitasvir with or without dasabuvir is contraindicated for both CP-B and CP-C patients. These changes have been made based on results from post-marketing surveillance showing liver decompensation and liver failure in patients with advanced cirrhosis (CP-B/C) ( n = 26) after 1–4 weeks of treatment ,.
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3.5 Other Antivirals 3.5.1 RibavirinRibavirin is a guanine analog with activity against a range of RNA and DNA viruses. Ribavirin is always prescribed as part of a combination therapy. In general practice, ribavirin is administered in a weight-based dose (80 mL/min receiving the standard dose.Brennan et al. studied steady-state plasma concentrations in patients with renal impairment.
Data were hard to interpret because many dose adjustments were necessary due to toxicity in patients with moderate and severe renal insufficiency. At week 12 of treatment, these patients had 36 and 25% higher AUCs with adjusted daily doses of 600 and 400 mg, respectively, compared with control subjects. The apparent total clearance of ribavirin from plasma (CL/ F) was 20.0 L/h in patients with normal renal function but decreased in patients with renal insufficiency, ranging from 5 to 6 L/h. In a single-dose study, increased AUC and decreased clearance were linearly correlated with the severity of renal dysfunction (single dose of 400 mg).Taking into account the information from the literature and our clinical experience with ribavirin , , we recommend a weight-based loading dose of ribavirin followed by 200 mg/day in patients with severe renal dysfunction or ESRD.
We also recommend alternating 200 and 400 mg/day in patients with moderate renal function. Steady-state plasma concentrations of ribavirin are directly achieved using a loading dose, which is necessary due to its long t ½.
Ribavirin is not removed by dialysis and these patients often have lower hemoglobin levels. Caution is needed due to accumulation of ribavirin in the erythrocytes causing hemolysis.
If available, therapeutic drug monitoring can be helpful to individualize treatment with ribavirin in patients with impaired and/or variable renal function. 4 Efficacy and Safety. AE adverse event, bid twice daily, CP-A Child-Pugh Score A, CP-B Child-Pugh score B, CP-C Child-Pugh score C, EOT end of treatment, GT genotype, NR not reported, od once daily, SAE serious adverse event, SVR sustained virologic response, SVR4 sustained virologic response at week 4, SVR8 sustained virologic response at week 8, ULN upper limit of normalaWeight-based ribavirin = 500 mg bid for.