glecaprevir and pibrentasvir
Regulatory sources consulted
Approved indications
- Treatment of chronic HCV infection in adults and adolescents aged at least 12 years or weighing at least 45 kg; smaller patients require non-interchangeable granules.
Contraindications
Absolute
- Hypersensitivity to glecaprevir, pibrentasvir, or excipients.
- Child-Pugh C hepatic impairment.
- Concomitant atazanavir, atorvastatin, simvastatin, dabigatran, or ethinyl-estradiol-containing medicines.
- Concomitant strong P-gp or CYP3A inducers such as rifampicin, carbamazepine, St John’s wort, phenobarbital, phenytoin, or primidone.
Clinical warnings
- Assess HBV before starting because of reactivation risk. — CIMA/AEMPS, ficha técnica 1171213001
- Hepatic decompensation and failure have been reported in advanced disease; monitor liver function. — CIMA/AEMPS, ficha técnica 1171213001
Drug interactions
- ModerateAtazanavir or rifampicin
Mechanism: They increase liver toxicity or markedly reduce efficacy.
Recommendation: Do not combine.
CIMA/AEMPS, ficha técnica 1171213001
- HighVitamin K antagonist anticoagulants
Mechanism: Improved liver function may change INR.
Recommendation: Monitor INR closely.
CIMA/AEMPS, ficha técnica 1171213001
- HighDigoxin, statins, and cyclosporine
Mechanism: Transporter inhibition may increase exposure; ethinyl-estradiol products above the label limit increase ALT risk.
Recommendation: Apply the specific limits and adjustments for digoxin, each statin, and cyclosporine. Ethinyl-estradiol-containing medicines are contraindicated.
CIMA/AEMPS, ficha técnica 1171213001
Adverse events
Common (≥1%)
Headache and fatigue
Rare but serious
HBV reactivation and hepatic decompensation
Pregnancy and lactation
Use during pregnancy is preferably avoided. Decide on breastfeeding after assessing maternal benefit and infant risk.
Recent literature (PubMed)
This was an open-label, randomized, single-dose, 2-period, crossover clinical trial with an adaptive design to evaluate the bioequivalence and comparative pharmacokinetics of generic glecaprevir/pibrentasvir versus the brand name product in healthy White male and female volunteers under fed conditions. Safety profiles were also assessed. A total of 56 healthy adult volunteers were enrolled and randomly assigned in a 1:1 ratio to receive a single dose of either the generic or reference formulation. After a 7-day washout period, subjects received the alternate product. Blood samples were collected at pre-specified time points up to 48 hours post-dosing. Plasma concentrations of glecaprevir and pibrentasvir were determined using a validated high-performance liquid chromatography-tandem mass spectrometry method. The geometric mean ratios of the test to the reference formulation for maximum plasma concentration (Cmax) and area under the concentration-time curve from drug administration to the last measurable concentration (AUC0-t) fell within the predefined bioequivalence range of 80%-125%. Both formulations demonstrated comparable pharmacokinetic profiles for glecaprevir and pibrentasvir, and can be considered bioequivalent. No adverse events were reported, and both formulations were well tolerated by all participants.
Mavyret, a combination medication of glecaprevir (GLE) and pibrentasvir (PIB), is approved to treat chronic and acute hepatitis C virus (HCV) (genotypes 1-6) infection in adults and pediatric patients ≥ 3 years old. To support approval, a two-part clinical trial was conducted in adolescents (≥ 12 to < 18 years) and children (≥ 3 to < 12 years) to identify the appropriate dosage and determine the efficacy and safety in pediatric patients. Population pharmacokinetic (popPK) analyses reported herein aimed to (1) characterize the pharmacokinetic (PK) parameters of orally administered GLE and PIB and the sources of PK variability in pediatric patients and (2) support the use of a body weight-based pediatric GLE/PIB dose ratio of 50/20 mg in HCV-infected children. PopPK models were built for GLE and PIB independently using nonlinear mixed-effects modeling and utilized data collected from 126 pediatric patients. Demographic, pathophysiological, and treatment factors were investigated for their impact on GLE and PIB PK. PopPK analyses of pediatric exposures confirmed comparable exposures to those of adults who achieved over 95% sustained virologic response (SVR12). The pediatric popPK model incorporated allometric body weight-based scaling and subsequently identified no covariate that significantly impacted GLE exposures. Similarly, no covariate beyond the specified allometric body weight scaling was identified to impact PIB exposures. The developed pediatric popPK models were able to describe the central tendency and variability of the data. These results supported the approval of body weight-based dosing regimens of GLE and PIB in children (< 45 kg) infected with any HCV genotype. NCT03067129.