glecaprevir and pibrentasvir
Sources réglementaires consultées
Indications approuvées
- Traitement de l’infection chronique par le VHC chez l’adulte et l’adolescent âgé d’au moins 12 ans ou pesant au moins 45 kg ; les patients plus petits nécessitent des granulés non interchangeables.
Contre-indications
Absolues
- Hypersensibilité au glécaprévir, au pibrentasvir ou aux excipients.
- Insuffisance hépatique Child-Pugh C.
- Association à l’atazanavir, l’atorvastatine, la simvastatine, au dabigatran ou à des médicaments contenant de l’éthinylestradiol.
- Association à des inducteurs puissants de la P-gp ou du CYP3A tels que rifampicine, carbamazépine, millepertuis, phénobarbital, phénytoïne ou primidone.
Mises en garde cliniques
- Rechercher le VHB avant l’instauration en raison du risque de réactivation. — CIMA/AEMPS, ficha técnica 1171213001
- Décompensation et insuffisance hépatiques ont été rapportées en maladie avancée ; surveiller la fonction hépatique. — CIMA/AEMPS, ficha técnica 1171213001
Interactions médicamenteuses
- ModéréeAtazanavir ou rifampicine
Mécanisme: Ils augmentent la toxicité hépatique ou réduisent fortement l’efficacité.
Recommandation: Ne pas associer.
CIMA/AEMPS, ficha técnica 1171213001
- SévèreAnticoagulants antagonistes de la vitamine K
Mécanisme: L’amélioration hépatique peut modifier l’INR.
Recommandation: Surveiller étroitement l’INR.
CIMA/AEMPS, ficha técnica 1171213001
- SévèreDigoxine, statines et ciclosporine
Mécanisme: L’inhibition des transporteurs peut augmenter l’exposition ; les produits contenant de l’éthinylestradiol au-delà de la limite de l’étiquette augmentent le risque d’élévation des ALAT.
Recommandation: Appliquer les limites et ajustements propres à la digoxine, à chaque statine et à la ciclosporine. Les médicaments contenant de l’éthinylestradiol sont contre-indiqués.
CIMA/AEMPS, ficha técnica 1171213001
Effets indésirables
Communs (≥1%)
Céphalées et fatigue
Rares mais graves
Réactivation du VHB et décompensation hépatique
Grossesse et allaitement
Il est préférable d’éviter l’utilisation pendant la grossesse. Décider de l’allaitement après évaluation du bénéfice maternel et du risque pour le nourrisson.
Bibliographie récente (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.