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Atazanavir renal dose ciprofloxacin

atazanavir renal dose ciprofloxacin

CLINICAL PHARMACOLOGY

Mechanism Of Action

Daclatasvir is a direct-acting antiviral agent (DAA) against the hepatitis C virus [see Microbiology].

Pharmacodynamics

Cardiac Electrophysiology

At a dose 3 times the maximum recommended dose, daclatasvir did not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in subjects with chronic HCV. Administration of daclatasvir tablets in HCV-infected subjects resulted in approximately dose-proportional increases in Cmax, AUC, and Cmin up to 60 mg once daily. Steady state is anticipated after approximately 4 days of once-daily daclatasvir administration. Exposure of daclatasvir was similar between healthy and HCV-infected subjects. Population pharmacokinetic estimates for daclatasvir 60 mg once daily in chronic HCV-infected subjects are shown in Table 8.

Table 8: Population Pharmacokinetic Estimates for Daclatasvir in Chronic HCV-Infected Subjects Receiving Daclatasvir 60 mg Once Daily and Sofosbuvir 400 mg Once Daily

Parameters Daclatasvir 60 mg once daily (n=152)
AUC0-24h (ng•h/mL)
  Mean ± standard deviation 10973 ± 5288
  Median (range) 9680 (3807-41243)
C24h (ng/mL)
  Mean ± standard deviation 182 ± 137
  Median (range) 148 (21-1050)
Absorption And Bioavailability

In HCV-infected subjects following multiple oral doses of daclatasvir tablet ranging from 1 mg to 100 mg once daily, peak plasma concentrations occurred within 2 hours post dose.

In vitro studies with human Caco-2 cells indicated that daclatasvir is a substrate of P-gp. The absolute bioavailability of the tablet formulation is 67%.

Effect Of Food On Oral Absorption

In healthy subjects, administration of a daclatasvir 60 mg tablet after a high-fat, high-caloric meal (approximately 951 total kcal, 492 kcal from fat, 312 kcal from carbohydrates, 144 kcal from protein) decreased daclatasvir Cmax and AUC(0-inf) by 28% and 23%, respectively, compared with fasted conditions. A food effect was not observed with administration of a daclatasvir 60 mg tablet after a low-fat, low-caloric meal (approximately 277 total kcal, 41 kcal from fat, 190 kcal from carbohydrates, 44 kcal from protein) compared with fasted conditions [see DOSAGE AND ADMINISTRATION].

Distribution

With multiple dosing, protein binding of daclatasvir in HCV-infected subjects was approximately 99% and independent of dose at the dose range studied (1-100 mg). In subjects who received daclatasvir 60 mg tablet orally followed by 100 μg [13C,15N]-daclatasvir intravenous dose, estimated volume of distribution at steady state was 47 L.

Metabolism

Daclatasvir is a substrate of CYP3A, with CYP3A4 being the primary CYP isoform responsible for metabolism. Following single-dose oral administration of 25 mg 14C-daclatasvir in healthy subjects, the majority of radioactivity in plasma was predominately attributed to parent drug (97% or greater).

Elimination

Following single-dose oral administration of 25 mg 14C-daclatasvir in healthy subjects, 88% of total radioactivity was recovered in feces (53% of the dose as unchanged daclatasvir) and 6.6% of the dose was excreted in the urine (primarily as unchanged daclatasvir). Following multiple-dose administration of daclatasvir in HCV-infected subjects, with doses ranging from 1 mg to 100 mg once daily, the terminal elimination half-life of daclatasvir ranged from approximately 12 to 15 hours. In subjects who received daclatasvir 60 mg tablet orally followed by 100 μg [13C,15N]-daclatasvir intravenous dose, the total clearance was 4.2 L/h.

Specific Populations

Renal Impairment

The pharmacokinetics of daclatasvir following a single 60 mg oral dose was studied in non– HCV-infected subjects with renal impairment. Using a regression analysis, the predicted AUC(0-inf) of daclatasvir was estimated to be 26%, 60%, and 80% higher in subjects with creatinine clearance (CLcr) values of 60, 30, and 15 mL/min, respectively, relative to subjects with normal renal function (CLcr of 90 mL/min, defined using the Cockcroft-Gault CLcr formula), and daclatasvir unbound AUC(0-inf) was predicted to be 18%, 39%, and 51% higher for subjects with CLcr values of 60, 30, and 15 mL/min, respectively, relative to subjects with normal renal function. Using observed data, subjects with end-stage renal disease requiring hemodialysis had a 27% increase in daclatasvir AUC(0-inf) and a 20% increase in unbound AUC(0-inf) compared to subjects with normal renal function as defined using the Cockcroft-Gault CLcr formula [see Use In Specific Populations].

Daclatasvir is highly protein bound to plasma proteins and is unlikely to be removed by dialysis.

Hepatic Impairment

The pharmacokinetics of daclatasvir following a single 30 mg oral dose was studied in non– HCV-infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment compared to a corresponding matched control group. The Cmax and AUC(0-inf) of total daclatasvir (free and protein-bound drug) were lower by 46% and 43%, respectively, in Child-Pugh A subjects; by 45% and 38%, respectively, in Child-Pugh B subjects; and by 55% and 36%, respectively, in Child-Pugh C subjects. The Cmax and AUC(0-inf) of unbound daclatasvir were lower by 43% and 40%, respectively, in Child-Pugh A subjects; by 14% and 2%, respectively, in Child-Pugh B subjects; and by 33% and 5%, respectively, in Child-Pugh C subjects [see Use In Specific Populations].

Pediatric Patients

The pharmacokinetics of daclatasvir in pediatric patients has not been evaluated.

Geriatric Patients

Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18-79 years) analyzed, age did not have a clinically relevant effect on the pharmacokinetics of daclatasvir [see Use in Specific Populations].

Gender

Population pharmacokinetic analyses in HCV-infected subjects estimated that female subjects have a 30% higher daclatasvir AUC compared to male subjects. This difference in daclatasvir AUC is not considered clinically relevant.

Race

Population pharmacokinetic analyses in HCV-infected subjects indicated that race had no clinically relevant effect on daclatasvir exposure.

Drug Interactions

Cytochrome P450 (CYP) Enzymes

Daclatasvir is a substrate of CYP3A. In vitro, daclatasvir did not inhibit (IC50 greater than 40 microM) CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6. Daclatasvir did not have a clinically relevant effect on the exposure of midazolam, a sensitive CYP3A substrate.

Transporters

Daclatasvir is a substrate of P-gp. However, cyclosporine, which inhibits multiple transporters including P-gp, did not have a clinically relevant effect on the pharmacokinetics of daclatasvir. Daclatasvir, in vitro, did not inhibit OCT2 and did not have a clinically relevant effect on the pharmacokinetics of tenofovir, an OAT substrate. Daclatasvir demonstrated inhibitory effects on digoxin (a P-gp substrate) and rosuvastatin (an OATP 1B1, OATP 1B3, and BCRP substrate) in drug-drug interaction trials.

Drug interaction studies were conducted with daclatasvir and other drugs likely to be coadministered or drugs used as probes to evaluate potential drug-drug interactions. The effects of daclatasvir on the Cmax, AUC, and Cmin of the coadministered drug are summarized in

Table 9, and the effects of the coadministered drug on the Cmax, AUC, and Cmin of daclatasvir are summarized in Table 10. For information regarding clinical recommendations, see CONTRAINDICATIONS and DRUG INTERACTIONS. Drug interaction studies were conducted in healthy adults unless otherwise noted.

Table 9: Effect of DAKLINZA on the Pharmacokinetics of Concomitant Drugs

Concomitant Drug Coadministered Drug Dose DAKLINZA Dose Ratio of Pharmacokinetic Parameters of Coadministered Drug Combination/No Combination (90% CI)
C max AUC Cmina
Buprenorphine /Naloxone Stable maintenance 8/2 mg to 24/6 mg QD 60 mg QD Buprenorphineb 1.30 (1.03, 1.64) Norbuprenorphineb 1.65 (1.38, 1.99) Buprenorphineb 1.37 (1.24, 1.52) Norbuprenorphineb 1.62 (1.30, 2.02) Buprenorphineb 1.17 (1.03, 1.32) Norbuprenorphineb 1.46 (1.12, 1.89)
Darunavirc 600 mg BID with ritonavir 100 mg BID 30 mg QD 0.97 (0.80, 1.17) 0.90 (0.73, 1.11) 0.98 (0.67, 1.44)
Digoxin 0.125 mg QD 60 mg QD 1.65 (1.52, 1.80) 1.27 (1.20, 1.34) 1.18 (1.09, 1.28)
Dolutegravir 50 mg QD 60 mg QD 1.29 (1.07, 1.57) 1.33 (1.11, 1.59) 1.45 (1.25, 1.68)
Lopinavirc 400 mg BID with ritonavir 100 mg BID 30 mg QD 1.22 (1.06, 1.41) 1.15 (0.77, 1.72) 1.54 (0.46, 5.07)
Methadone Stable maintenance 40-120 mg QD 60 mg QD Total methadoned: 1.09 (0.99, 1.21) R-methadoned: 1.07 (0.97, 1.18) Total methadoned: 1.11 (0.97, 1.26) R-methadoned: 1.08 (0.94, 1.24) Total methadoned: 1.12 (0.96, 1.29) R-methadoned: 1.08 (0.93, 1.26)
Rosuvastatin 10 mg single dose 60 mg QD 2.04 (1.83, 2.26) 1.58 (1.44, 1.74) NA
Simeprevir 150 mg QD 60 mg QD 1.39 (1.27, 1.52) 1.44 (1.32, 1.56) 1.49 (1.33, 1.67)
Note: In Table 9, for the concomitant medication, drug-drug interaction data were not included if 90% CIs for Cmax, AUC, and Cmin (if applicable for Cmin) were within 80% to 125%. These concomitant medications include cyclosporine, escitalopram, ethinyl estradiol/norgestimate, midazolam, tacrolimus, and tenofovir disoproxil fumarate.
a Cmin was defined as either the Ctau or the Ctrough concentration value.
b The buprenorphine and norbuprenorphine pharmacokinetic parameters were dose normalized to 8 mg.
c Samples up to 6 hours collected; C0h substituted for C12h concentration value.
d The methadone pharmacokinetic parameters were dose normalized to 40 mg. NA = Not available.

Table 10: Effect of Coadministered Drugs on DAKLINZA Pharmacokinetics

Concomitant Drug Coadministered Drug Dose DAKLINZA Dose Ratio of Pharmacokinetic Parameters of Daclatasvir Combination/No Combination (90% CI)
Cmax AUC Cmina
Atazanavir/ ritonavir 300 mg/100 mg QD 20 mg QD
(test arm)
0.45
(0.41, 0.49)b
0.70
(0.65, 0.75)b
1.22
(1.08, 1.37)b
Cyclosporine 400 mg single dose 60 mg QD 1.04
(0.94, 1.15)
1.40
(1.29, 1.53)
1.56
(1.41, 1.71)
Darunavir/ ritonavir 800 mg/100 mg QD 30 mg QD
(test arm)
0.38
(0.35, 0.42)b
0.70
(0.66, 0.75)b
NA
Dolutegravir 50 mg QD 60 mg QD 1.03
(0.84, 1.25)
0.98
(0.83, 1.15)
1.06
(0.88, 1.29)
Efavirenz 600 mg QD 120 mg QD
(test arm)
1.67
(1.51, 1.84)b
1.37
(1.21, 1.55)b
0.83
(0.69, 1.00)b
Escitalopram 10 mg QD 60 mg QD 1.14
(0.98, 1.32)
1.12
(1.01, 1.26)
1.23
(1.09, 1.38)
Famotidine 40 mg single dose 60 mg single dose
(2 hours after famotidine administration)
0.56
(0.46, 0.67)
0.82
(0.70, 0.96)
0.89
(0.75, 1.06)
Ketoconazole 400 mg QD 10 mg single dose 1.57
(1.31, 1.88)
3.00
(2.62, 3.44)
NA
Lopinavir/ ritonavir 400 mg/100 mg BID 30 mg QD
(test arm)
0.34
(0.31, 0.37)b
0.58
(0.54, 0.62)b
NA
Omeprazole 40 mg single dose 60 mg single dose 0.64
(0.54, 0.77)
0.84
(0.73, 0.96)
0.92
(0.80, 1.05)
Rifampin 600 mg QD 60 mg single dose 0.44
(0.40, 0.48)
0.21
(0.19, 0.23)
NA
Simeprevir 150 mg QD 60 mg QD 1.50
(1.39, 1.62)
1.96
(1.84, 2.10)
2.68
(2.42, 2.98)
Tenofovir disoproxil fumarate 300 mg QD 60 mg QD 1.06
(0.98, 1.15)
1.10
(1.01, 1.21)
1.15
(1.02, 1.30)
Note: In Table 10, drug-drug interaction data for daclatasvir were not included for a study with tacrolimus because the 90% CIs for Cmax, AUC, and Cmin were within 80% to 125%.
a Cmin was defined as either the Ctau or the Ctrough daclatasvir concentration value.
b Observed, non-dose normalized data. For the reference arm, a 60 mg QD dose of daclatasvir was administered without the HIV comedications (boosted protease inhibitors, efavirenz) in order to compare the effect on daclatasvir exposures.
NA = Not available.

No clinically relevant interaction is anticipated for daclatasvir or the following concomitant medications: peginterferon alfa, ribavirin, or antacids. No clinically relevant interaction is anticipated for daclatasvir with concomitant use of rilpivirine.

Microbiology

Mechanism Of Action

Daclatasvir is an inhibitor of NS5A, a nonstructural protein encoded by HCV. Daclatasvir binds to the N-terminus of NS5A and inhibits both viral RNA replication and virion assembly. Characterization of daclatasvir-resistant viruses, biochemical studies, and computer modeling data indicate that daclatasvir interacts with the N-terminus within Domain 1 of the protein, which may cause structural distortions that interfere with NS5A functions.

Antiviral Activity

Daclatasvir had median EC50 values of 0.008 nM (range, 0.002-0.03 nM; n=35), 0.002 nM (range, 0.0007-0.006 nM; n=30), and 0.2 nM (range, 0.006-3.2 nM; n=17) against hybrid replicons containing genotypes 1a, 1b, and 3a subject-derived NS5A sequences, respectively, without detectable daclatasvir resistance-associated polymorphisms at NS5A amino acid positions 28, 30, 31, or 93. Daclatasvir activity was reduced against genotypes 1a, 1b, and 3a subject-derived replicons with resistance-associated polymorphisms at positions 28, 30, 31, or 93, with median EC50 values of 76 nM (range, 4.6-2409 nM; n=5), 0.05 nM (range, 0.002-10 nM; n=12), and 13.5 nM (range, 1.3-50 nM; n=4), respectively. Similarly, the EC50 values of daclatasvir against 3 genotype 3b and 1 genotype 3i subject-derived NS5A sequences with polymorphisms (relative to a genotype 3a reference) at positions 30+31 (genotype 3b) or 30+62 (genotype 3i) were ≥ 3620 nM.

Daclatasvir was not antagonistic with interferon alfa, HCV NS3/4A protease inhibitors, HCV NS5B nucleoside analog inhibitors, and HCV NS5B non-nucleoside inhibitors in cell culture combination antiviral activity studies using the cell-based HCV replicon system.

Resistance

In Cell Culture

HCV genotype 1a, 1b, and 3a replicon variants with reduced susceptibility to daclatasvir were selected in cell culture, and the genotype and phenotype of daclatasvir-resistant NS5A amino acid variants were characterized. Phenotypic analysis of genotype 1a replicons expressing single NS5A M28T, Q30E, Q30H, Q30R, L31V, Y93C, Y93H, and Y93N substitutions exhibited 500-, 18500-, 1083-, 900-, 2500-, 1367-, 8500-, and 34833-fold reduced susceptibility to daclatasvir, respectively. For genotype 1b, L31V and Y93H single substitutions and L31M/Y93H and L31V/Y93H combinations exhibited 33-, 30-, 16000-, and 33667-fold reduced susceptibility to daclatasvir, respectively. A P32-deletion (P32X) in genotype 1b reduced daclatasvir susceptibility by > 1,000,000-fold. For genotype 3a, single A30K, L31F, L31I, and Y93H substitutions exhibited 117-, 320-, 240-, and 3733-fold reduced susceptibility to daclatasvir, respectively.

In Clinical Studies

Among subjects with HCV genotype 1 or genotype 3 infection and treated in the ALLY-1, -2, and -3 trials with DAKLINZA and sofosbuvir with or without ribavirin for 12 weeks, 31 subjects (11 with genotype 1a, 1 with genotype 1b, and 19 with genotype 3) qualified for resistance analysis due to virologic failure. Post-baseline NS5A and NS5B population-based nucleotide sequence analysis results were available for 31 and 28 subjects, respectively.

Virus from all 31 subjects at the time of virologic failure harbored one or more of the following NS5A resistance-associated substitutions (including pre-existing amino acid polymorphisms or treatment-emergent substitutions): M28T, Q30H/K/R, L31M/V, H54R, H58D/P, or Y93C/N for genotype 1a subjects, P32-deletion (P32X) for the genotype 1b subject, and A30K/S, L31I, S62A/L/P/R/T, or Y93H for genotype 3 subjects. Among HCV genotype 1a virologic failure subjects, the most common NS5A amino acid substitutions occurred at position Q30 (Q30H/K/R; 73% [8/11], all treatment-emergent). Among HCV genotype 3 virologic failure subjects, the most common NS5A amino acid polymorphism or treatment-emergent substitution was Y93H (89% [17/19], treatment-emergent in 11 of 17 subjects).

For NS5B, 6 of 28 subjects at the time of virologic failure had virus with NS5B substitutions possibly associated with sofosbuvir resistance or exposure: A112T, L159F, E237G, or Q355H (genotype 1a subjects), or S282T+Q355H (genotype 3 subject).

Persistence Of Resistance-Associated Substitutions

Limited data for DAKLINZA and sofosbuvir regimens on the persistence of daclatasvir resistance-associated substitutions are available. In a separate long-term follow-up study of predominately HCV genotype 1-infected subjects treated with daclatasvir-containing regimens in phase 2/3 clinical trials, viral populations with treatment-emergent NS5A resistance-associated substitutions persisted at detectable levels for more than 1 year in most subjects.

Effect Of Baseline HCV Amino Acid Polymorphisms On Treatment Response

Genotype 1a NS5A polymorphisms: In HCV genotype 1a-infected subjects with cirrhosis, the presence of an NS5A amino acid polymorphism at position M28, Q30, L31, or Y93 (defined as any change from reference identified by population-based nucleotide sequencing) was associated with reduced efficacy of DAKLINZA and sofosbuvir with or without ribavirin for 12 weeks in the ALLY-1 and ALLY-2 trials (see Table 11). Due to the limited sample size, insufficient data are available to determine the impact of specific NS5A polymorphisms at these positions on SVR12 rates in subjects with cirrhosis. Six of 54 subjects (11%) with cirrhosis had one of the following specific NS5A polymorphisms at baseline: M28V/T (n=2), Q30R (n=1), L31M (n=2), or Y93N (n=1); 2 subjects with M28V or Q30R achieved SVR12 while 4 subjects with M28T, L31M, or Y93N did not achieve SVR. Eleven of 112 subjects (10%) without cirrhosis had one or more of the following specific NS5A polymorphisms at baseline: M28T/V (n=3), Q30H/L/R (n=5), L31M (n=1), and Y93C/H/S (n=4); all noncirrhotic subjects with these baseline NS5A polymorphisms achieved SVR12. Based on an analysis of 1026 HCV genotype 1a NS5A amino acid sequences from pooled clinical trials, the prevalence of polymorphisms at these positions was 11% overall, and 11% in the U.S.

Genotype 1b NS5A polymorphisms: In a pooled analysis of 43 subjects infected with HCV genotype 1b with available baseline nucleotide sequence data in ALLY-1 and -2, virus from 21% (n=9) of subjects receiving DAKLINZA and sofosbuvir with or without ribavirin had one of the following baseline NS5A amino acid polymorphisms: R30K/M/Q (n=4), L31M (n=2), or Y93H (n=3). All 9 subjects with NS5A polymorphisms achieved SVR12, including 5 who were noncirrhotic and 4 who were in the post-transplant period.

Genotype 3 NS5A polymorphisms: In the ALLY-3 trial in which HCV genotype 3-infected subjects received DAKLINZA and sofosbuvir for 12 weeks, the presence of an NS5A Y93H polymorphism was associated with a reduced SVR12 rate (see Table 11). In a pooled analysis of 175 subjects infected with HCV genotype 3 with available baseline nucleotide sequence data in the ALLY-1, -2, and -3 trials, virus from 7% (13/175) of subjects had the NS5A Y93H polymorphism, and all 13 of these subjects were in the ALLY-3 trial. Phylogenetic analysis of NS5A sequences indicated that all genotype 3 subjects with available data in the ALLY-1, -2, and -3 trials (n=175) were infected with HCV subtype 3a.

Table 11: Impact of NS5A Amino Acid Polymorphisms on SVR12 Rates in Subjects with HCV Genotype 1a or Genotype 3 Infection in Phase 3 Trials of DAKLINZA + Sofosbuvir ± Ribavirin

NS5A Polymorphisms SVR12 Rates after 12 Weeks of Treatment with DAKLINZA + Sofosbuvir ± Ribavirina
With NS5A Polymorphism(s) %
(n/N)
Without NS5A Polymorphism(s) %
(n/N)b
HCV genotype 1a-infected subjects: M28,c Q30,cL31,c or Y93c 76% (13/17) 95% (142/149)
  Without cirrhosisd 100% (11/11) 99% (100/101)
  With cirrhosis (Child-Pugh A, B, or C) 33% (2/6) 88% (42/48)
HCV genotype 3-infected subjects: Y93H 54% (7/13) 92% (149/162)
  Without cirrhosisd 67% (6/9) 98% (125/128)
  With cirrhosis (Child-Pugh A, B, or C) 25% (1/4) 71% (24/34)
a HCV genotype 1a-infected subjects received DAKLINZA + sofosbuvir ± ribavirin for 12 weeks in the ALLY-1 and ALLY-2 trials. HCV genotype 3-infected subjects received DAKLINZA + sofosbuvir for 12 weeks in the ALLY-3 trial; no data on the impact of Y93H are available for HCV genotype 3-infected subjects treated with DAKLINZA + sofosbuvir ± ribavirin in ALLY-1 and ALLY-2 trials.
b None of the 11 subjects with Child-Pugh C cirrhosis had an indicated NS5A polymorphism; 5 achieved SVR (genotype 1a: 4/9; genotype 3a: ½).
c Any change from genotype 1a reference.
d Includes subjects who were post-transplant with undefined cirrhosis status.
Cross-Resistance

Based on resistance patterns observed in cell culture replicon studies and HCV-infected subjects, cross-resistance between daclatasvir and other NS5A inhibitors is expected. Cross-resistance between daclatasvir and other classes of direct-acting antivirals is not expected. The impact of prior daclatasvir treatment experience on the efficacy of other NS5A inhibitors has not been studied. Conversely, the efficacy of DAKLINZA in combination with sofosbuvir has not been studied in subjects who have previously failed treatment with regimens that include an NS5A inhibitor.

Clinical Studies

Description Of Clinical Trials

The efficacy of DAKLINZA in combination with sofosbuvir and with or without ribavirin was evaluated in three phase 3 clinical trials, as summarized in Table 12 [see Clinical Studies]. HCV RNA levels were measured during these clinical trials using the COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL. Sustained virologic response was the primary endpoint and was defined as HCV RNA below the LLOQ at post-treatment week 12 (SVR12).

Table 12: Genotype 1 and 3 Patient Populations from DAKLINZA Trials:

Trial Population Study Arms and Duration (Number of Subjects Treated)
ALLY-3 (AI444218) Genotype 3, treatment-naive and treatment-experienced, with or without cirrhosis DAKLINZA and sofosbuvir for 12 weeks (N=152)
ALLY-2 (AI444216) Genotype 1 and 3, treatment-naive and treatment-experienced, with or without cirrhosis, HCV/HIV-1 coinfection DAKLINZA and sofosbuvir for 12 weeks (N=137)
ALLY-1 (AI444215) Genotype 1 and 3, treatment-naive or treatment-experienced, with or without cirrhosis, including decompensated cirrhosis and post-transplant DAKLINZA and sofosbuvir and ribavirin for 12 weeks (N=103)
Clinical Trials In HCV Genotype 3 (ALLY-3)

ALLY-3 was an open-label trial that included 152 subjects with chronic HCV genotype 3 infection and compensated liver disease who were treatment naive (n=101) or treatment experienced (n=51). Most treatment-experienced subjects had failed prior treatment with peginterferon/ribavirin, but 7 subjects had been treated previously with a sofosbuvir regimen and 2 subjects with a regimen containing an investigational agent. Previous exposure to NS5A inhibitors was prohibited. Subjects received DAKLINZA 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment.

The 152 treated subjects in ALLY-3 had a median age of 55 years (range, 24-73); 59% of the subjects were male; 90% were white, 5% were Asian, and 4% were black. Most subjects (76%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 21% of the subjects had compensated cirrhosis, and 40% had the IL28B rs12979860 CC genotype.

SVR12 and outcomes in subjects without SVR12 in ALLY-3 are shown by patient population in Table 13. SVR12 rates were comparable regardless of HCV treatment history, age, gender, IL28B allele status, or baseline HCV RNA level. For SVR outcomes related to baseline NS5A amino acid polymorphisms, see Microbiology.

Table 13: ALLY-3: SVR12 in Treatment-Naive and Treatment-Experienced Subjects with or without Cirrhosis with Genotype 3 HCV Treated with DAKLINZA in Combination with Sofosbuvir for 12 Weeks

Treatment Outcomes Total n=152
SVR12
All 89% (135/152)
No cirrhosisa 96% (115/120)
With cirrhosis 63% (20/32)
Outcomes for subjects without SVR12
On-treatment virologic failureb 0.7% (1/152)
Relapsec 11% (16/151)
a Includes 11 subjects with missing or inconclusive cirrhosis status.
b One subject had quantifiable HCV RNA at end of treatment.
c Relapse rates are calculated with a denominator of subjects with HCV RNA not detected at the end of treatment.
Clinical Trials In HCV/HIV Coinfected Subjects (ALLY-2)

ALLY-2 was an open-label trial that included 153 subjects with chronic hepatitis C and HIV coinfection who received DAKLINZA and sofosbuvir for 12 weeks. Subjects with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll. Subjects were HCV treatment-naive (n=101) or HCV treatment-experienced (n=52). Prior exposure to NS5A inhibitors was prohibited. The dose of DAKLINZA was 60 mg once daily (dose-adjusted for concomitant antiretroviral use) and the dose of sofosbuvir was 400 mg once daily [see DRUG INTERACTIONS].

The 153 treated subjects had a median age of 53 years (range, 24-71); 88% of subjects were male; 63% were white, 33% were black, and 1% were Asian. Sixty-eight percent of subjects had HCV genotype 1a, 15% had HCV genotype 1b, 8% had genotype 2, 7% had genotype 3, and 2% had genotype 4. Most subjects (80%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 16% of the subjects had compensated cirrhosis, and 73% had IL28B rs12979860 non-CC genotype. Concomitant HIV therapy included PI-based regimens (darunavir + ritonavir, atazanavir + ritonavir, or lopinavir/ritonavir) for 46% of subjects, NNRTI-based regimens (efavirenz, nevirapine, or rilpivirine) for 26%, integrase-based regimens (raltegravir or dolutegravir) for 26%, and nucleoside-only regimens (abacavir + emtricitabine + zidovudine) for 1%. Two patients were not receiving treatment for HIV.

SVR and outcomes in subjects with HCV genotype 1 without SVR12 in ALLY-2 are shown by patient population in Table 14. Available data on subjects with HCV genotype 2, 4, 5, or 6 infection are insufficient to provide recommendations for these genotypes; therefore, these results are not presented in Table 14. SVR12 rates were comparable regardless of antiretroviral therapy, HCV treatment history, age, race, gender, IL28B allele status, HCV genotype 1 subtype, or baseline HCV RNA level. For SVR outcomes related to baseline NS5A amino acid polymorphisms, see Microbiology.

No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. There was no change in absolute CD4+ T-cell counts at the end of 12 weeks of treatment.

Table 14: ALLY-2: SVR12 in Subjects with Genotype 1 and 3 HCV/HIV Coinfection Treated with DAKLINZA in Combination with Sofosbuvir for 12 Weeks

Treatment Outcomes Total n=137
SVR12
Genotype 1 97% (123/127)
  No cirrhosisa 98% (103/105)
  With cirrhosis 91% (20/22)
Genotype 3b 100% (10/10)
Outcomes for genotype 1 subjects without SVR12
  On-treatment virologic failurec 0.8% (1/127)
  Relapsed 1.6% (2/126)
  Missing post-treatment data 0.8% (1/126)
a Includes 5 subjects with inconclusive cirrhosis status.
b One subject with cirrhosis.
c One subject had detectable HCV RNA at end of treatment.
d Relapse rates are calculated with a denominator of subjects with HCV RNA not detected at the end of treatment.
Clinical Trials In Subjects With Child-Pugh A, B, Or C Cirrhosis Or With HCV Recurrence After Liver Transplantation (ALLY-1)

ALLY-1 was an open-label trial of DAKLINZA, sofosbuvir, and ribavirin that included 113 subjects with chronic HCV infection and Child-Pugh A, B, or C cirrhosis (n=60) or HCV recurrence after liver transplantation (n=53). Subjects with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll. Subjects could be HCV treatment-naive or treatment-experienced, although prior exposure to NS5A inhibitors was prohibited. Subjects received DAKLINZA 60 mg once daily, sofosbuvir 400 mg once daily, and ribavirin for 12 weeks and were monitored for 24 weeks post treatment. Subjects received an initial ribavirin dose of 600 mg or less daily with food; the initial and on-treatment dosing of ribavirin was modified based on hemoglobin and creatinine clearance measurements. If tolerated, the ribavirin dose was titrated up to 1000 mg per day. A high proportion of reductions in ribavirin dosing occurred in the trial. By week 6, approximately half of the subjects received 400 mg per day or less of ribavirin. In total, 16 subjects (15%) completed less than 12 weeks and 11 subjects (10%) completed less than 6 weeks of ribavirin therapy, respectively. For the cohort of patients with cirrhosis (Child-Pugh A, B, or C), the median time to discontinuation of ribavirin was 43 days (range, 8-82, n=9). For the post-transplant cohort, the median time to discontinuation of ribavirin was 20 days (range, 3-57, n=7).

The 113 treated subjects in ALLY-1 had a median age of 59 years (range, 19-82); 67% of the subjects were male; 96% were white, 4% were black, and 1% Asian. Most subjects (59%) were treatment-experienced, and most (71%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL. Fifty-eight percent of subjects had HCV genotype 1a, 19% had HCV genotype 1b, 4% had genotype 2, 15% had genotype 3, 4% had genotype 4, and 1% had genotype 6, 77% had IL28B rs12979860 non-CC genotype. Among the 60 subjects in the cirrhosis cohort, 20% were Child-Pugh A, 53% were Child-Pugh B, and 27% were Child-Pugh C, and 35% had a Baseline Model for End-Stage Liver Disease (MELD) score of 15 or greater. Most (55%) of the 53 subjects in the post-transplant cohort had F3 or F4 fibrosis (based on FibroSURE® results).

SVR12 and outcomes in subjects without SVR12 in ALLY-1 are shown for subjects with HCV genotype 1 by patient population in Table 15. Available data on subjects with HCV genotype 2, 4, 5, or 6 infection are insufficient to provide recommendations; therefore, these results are not presented in Table 15.

SVR12 rates were comparable regardless of age, gender, IL28B allele status, or baseline HCV RNA level. For SVR12 outcomes related to baseline NS5A amino acid polymorphisms, see Microbiology. No HCV genotype 1 or genotype 3 subjects with Child-Pugh C cirrhosis had baseline resistance-associated NS5A amino acid polymorphisms. SVR12 rates were comparable between genotype 3 (5/6 with Child-Pugh B or C cirrhosis and 10/11 post-liver transplant) and genotype 1 subjects with or without decompensated cirrhosis.

Table 15: ALLY-1: SVR12 in Genotype 1 Subjects with Child-Pugh A, B, or C Cirrhosis or with HCV Genotype 1 Recurrence after Liver Transplantation Treated with DAKLINZA in Combination with Sofosbuvir and Ribavirin for 12 Weeks

Treatment Outcomes Child-Pugh A, B, or C Cirrhosis
n=45
Post-Liver Transplant
n=41
SVR12
Genotype 1 82% (37/45) 95% (39/41)
  Child-Pugh A 91% (10/11) -
  Child-Pugh B 92% (22/24) -
  Child-Pugh C 50% (5/10) -
  Genotype 1a 76% (26/34) 97% (30/31)
  Genotype 1b 100% (11/11) 90% (9/10)
Outcomes for subjects without SVR12
  On-treatment virologic failure 2% (1/45)a 0
  Relapseb 16% (7/44) 5% (2/41)
a One subject had detectable HCV RNA at end of treatment.
b Relapse rates are calculated with a denominator of subjects with HCV RNA not detected at end of treatment.

Source: http://www.rxlist.com/daklinza-drug.htm


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