red the obligation to submit the results of studies with glecaprevir/pibrentasvir in one or more subsets of the paediatric population from 3 years to less than 18 years in the treatment of chronic hepatitis C (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The pharmacokinetic properties of the components of Maviret are provided in Table 11.
Table 11: Pharmacokinetic properties of the components of Maviret in healthy subjects
a. Median Tmax 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 Maviret 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 AUC24, 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 Maviret is required based on race or ethnicity.
Gender/weight
No dose adjustment of Maviret is required based on gender or body weight.
Elderly
No dose adjustment of Maviret is required in elderly patients. Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 88 years) analysed, age did not have a clinically relevant effect on the exposure to glecaprevir or pibrentasvir.
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 pharmacokin |
