Glecaprevir and Pibrentasvir

Glecaprevir/pibrentasvir is a fixed-dose combination of two pan-genotypic, direct-acting antiviral agents, glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor), targeting multiple steps in the HCV viral lifecycle.

Glecaprevir

Glecaprevir is a pan-genotypic inhibitor of the HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication.

Pibrentasvir

Pibrentasvir is a pan-genotypic inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of pibrentasvir has been characterised based on cell culture antiviral activity and drug resistance mapping studies.

Antiviral activity

The EC₅₀ values of glecaprevir and pibrentasvir against full-length or chimeric replicons encoding NS3 or NS5A from laboratory strains are presented in Table 1.

Table 1. Activity of glecaprevir and pibrentasvir against HCV genotypes 1-6 replicon cell lines:

NA = not available

The in vitro activity of glecaprevir was also studied in a biochemical assay, with similarly low IC₅₀ values across genotypes.

EC₅₀ values of glecaprevir and pibrentasvir against chimeric replicons encoding NS3 or NS5A from clinical isolates are presented in Table 2.

Table 2. Activity of glecaprevir and pibrentasvir against transient replicons containing NS3 or NS5A from HCV genotypes 1-6 clinical isolates:

NA = not available

Resistance

In cell culture

Amino acid substitutions in NS3 or NS5A selected in cell culture or important for the inhibitor class were phenotypically characterized in replicons.

Substitutions important for the HCV protease inhibitor class at positions 36, 43, 54, 55, 56, 155, 166, or 170 in NS3 had no impact on glecaprevir activity. Substitutions at amino acid position 168 in NS3 had no impact in genotype 2, while some substitutions at position 168 reduced glecaprevir susceptibility by up to 55-fold (genotypes 1, 3, 4), or reduced susceptibility by >100-fold (genotype 6). Some substitutions at position 156 reduced susceptibility to glecaprevir (genotypes 1 to 4) by >100-fold. Substitutions at amino acid position 80 did not reduce susceptibility to glecaprevir except for Q80R in genotype 3a, which reduced susceptibility to glecaprevir by 21-fold.

Single substitutions important for the NS5A inhibitor class at positions 24, 28, 30, 31, 58, 92, or 93 in NS5A in genotypes 1 to 6 had no impact on the activity of pibrentasvir. Specifically in genotype 3a, A30K or Y93H had no impact on pibrentasvir activity. Some combinations of substitutions in genotypes 1a and 3a (including A30K+Y93H in genotype 3a) showed reductions in susceptibility to pibrentasvir. In genotype 3b replicon, the presence of naturally occurring polymorphisms K30 and M31 in NS5A reduced susceptibility to pibrentasvir by 24-fold relative to the activity of pibrentasvir in genotype 3a replicon.

The pharmacokinetic properties of the components of glecaprevir/pibrentasvir combination are provided in the following table.

Pharmacokinetic properties of the components of glecaprevir/pibrentasvir in healthy subjects:

^a Median T_max following single doses of glecaprevir and pibrentasvir in healthy subjects.
^b Mean systemic exposure with moderate to high fat meals.
^c Single dose administration of [¹⁴C]glecaprevir or [¹⁴C]pibrentasvir in mass balance studies.
^d Oxidative metabolites or their byproducts accounted for 26% of radioactive dose. No glecaprevir metabolites were observed in plasma.

In patients with chronic hepatitis C infection without cirrhosis, following 3 days of monotherapy with either glecaprevir 300 mg per day (N=6) or pibrentasvir 120 mg per day (N=8) alone, geometric mean AUC₂₄ values were 13600 ng∙h/mL for glecaprevir and 459 ng∙h/mL for pibrentasvir. Estimation of the pharmacokinetic parameters using population pharmacokinetic models has inherent uncertainty due to dose non-linearity and cross interaction between glecaprevir and pibrentasvir. Based on population pharmacokinetic models for glecaprevir/pibrentasvir in chronic hepatitis C patients, steady-state AUC₂₄ values for glecaprevir and pibrentasvir were 4800 and 1430 ng∙h/mL in subjects without cirrhosis (N=1804), and 10500 and 1530 ng∙h/mL in subjects with cirrhosis (N=280), respectively. Relative to healthy subjects (N=230), population estimates of AUC_24,ss were similar (10% difference) for glecaprevir and 34% lower for pibrentasvir in HCV-infected patients without cirrhosis.

Linearity / non-linearity

Glecaprevir AUC increased in a greater than dose-proportional manner (1200 mg QD had 516-fold higher exposure than 200 mg QD) which may be related to saturation of uptake and efflux transporters.

Pibrentasvir AUC increased in a greater than dose-proportional manner at doses up to 120 mg, (over 10-fold exposure increase at 120 mg QD compared to 30 mg QD), but exhibited linear pharmacokinetics at doses ≥120 mg. The non-linear exposure increase <120 mg may be related to saturation of efflux transporters.

Pibrentasvir bioavailability when coadministered with glecaprevir is 3-fold of pibrentasvir alone. Glecaprevir is affected to a lower extent by coadministration with pibrentasvir.

Pharmacokinetics in special populations

Race / ethnicity

No dose adjustment of glecaprevir/pibrentasvir is required based on race or ethnicity.

Gender / weight

Tablets 100 mg/40 mg: No dose adjustment of glecaprevir/pibrentasvir is required based on gender or body weight ≥45 kg.

Granules 50 mg/20 mg: No dose adjustment of glecaprevir/pibrentasvir is required based on gender.

Elderly

No dose adjustment of glecaprevir/pibrentasvir is required in elderly patients. Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (12 to 88 years) analysed, age did not have a clinically relevant effect on the exposure to glecaprevir or pibrentasvir.

Paediatric population

At the recommended doses according to the patient’s body weight, exposures of glecaprevir and pibrentasvir in children aged 3 to <12 years fell within the efficacious exposure range in adults from Phase ⅔ studies. Glecaprevir/pibrentasvir is available as a tablet for children 12 years to less than 18 years or weighing more than 45 kg. The granules were not studied in children greater than 12 years old. Tablets and the granules are not interchangeable. The pharmacokinetics of glecaprevir and pibrentasvir have not been established in children <3 years of age or under 12 kg in weight.

Renal impairment

Glecaprevir and pibrentasvir AUC were increased ≤56% in non-HCV infected subjects with mild, moderate, severe, or end stage renal impairment not on dialysis compared to subjects with normal renal function. Glecaprevir and pibrentasvir AUC were similar with and without dialysis (≤18% difference) in dialysis-dependent non-HCV infected subjects. In population pharmacokinetic analysis of HCV-infected subjects, 86% higher glecaprevir and 54% higher pibrentasvir AUC were observed for subjects with end stage renal disease, with or without dialysis, compared to subjects with normal renal function. Larger increases may be expected when unbound concentration is considered.

Overall, the changes in exposures of glecaprevir/pibrentasvir in HCV-infected subjects with renal impairment with or without dialysis were not clinically significant.

Hepatic impairment

At the clinical dose, compared to non-HCV infected subjects with normal hepatic function, glecaprevir AUC was 33% higher in Child-Pugh A subjects, 100% higher in Child-Pugh B subjects, and increased to 11-fold in Child-Pugh C subjects. Pibrentasvir AUC was similar in Child-Pugh A subjects, 26% higher in Child-Pugh B subjects, and 114% higher in Child-Pugh C subjects. Larger increases may be expected when unbound concentration is considered.

Population pharmacokinetic analysis demonstrated that following administration of glecaprevir/pibrentasvir in HCV-infected subjects with compensated cirrhosis, exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic HCV-infected subjects. The mechanism for the differences between glecaprevir exposure in chronic Hepatitis C patients with or without cirrhosis is unknown.

Glecaprevir and pibrentasvir were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rodent micronucleus assays. Carcinogenicity studies with glecaprevir and pibrentasvir have not been conducted.

No effects on mating, female or male fertility, or early embryonic development were observed in rodents at up to the highest dose tested. Systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 63 and 102 times higher, respectively, than the exposure in humans at the recommended dose.

In animal reproduction studies, no adverse developmental effects were observed when the components of glecaprevir/pibrentasvir were administered separately during organogenesis at exposures up to 53 times (rats; glecaprevir) or 51 and 1.5 times (mice and rabbits, respectively; pibrentasvir) the human exposures at the recommended dose of glecaprevir/pibrentasvir. Maternal toxicity (anorexia, lower body weight, and lower body weight gain) with some embryofoetal toxicity (increase in post-implantation loss and number of resorptions and a decrease in mean foetal body weight), precluded the ability to evaluate glecaprevir in the rabbit at clinical exposures. There were no developmental effects with either compound in rodent peri/postnatal developmental studies in which maternal systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 47 and 74 times, respectively, the exposure in humans at the recommended dose. Unchanged glecaprevir was the main component observed in the milk of lactating rats without effect on nursing pups. Pibrentasvir was the only component observed in the milk of lactating rats without effect on nursing pups.