A Phase 1 Study to Evaluate the Effect of Crushing, Cutting Into Half, or Grinding of Glecaprevir/Pibrentasvir Tablets on Exposures in Healthy Subjects

• Published in: Journal of pharmaceutical sciences Vol. 107; no. 6; pp. 1724 - 1730
• Main Authors: Oberoi, Rajneet K., Zhao, Weihan, Sidhu, Dilraj S., Viani, Rolando M., Trinh, Roger, Liu, Wei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2018
• Subjects: Adult; anti-infectives; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - blood; Area Under Curve; Benzimidazoles - administration & dosage; Benzimidazoles - adverse effects; Benzimidazoles - blood; bioavailability; Biological Availability; clinical pharmacokinetics; Cross-Over Studies; Female; formulation; Humans; Male; Middle Aged; oral absorption; Particle Size; pharmacokinetics; Quinoxalines - administration & dosage; Quinoxalines - adverse effects; Quinoxalines - blood; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - blood; Tablets; GLE; Cmax; DAA; RBV; PIB; anti-infectives; GT; AUC; bioavailability; t1/2; Tmax; clinical pharmacokinetics; formulation; pharmacokinetics; HCV; oral absorption
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2018.02.015

Glecaprevir (GLE) and pibrentasvir (PIB) are direct-acting antivirals coformulated as a combination tablet for once-daily treatment of chronic hepatitis C virus infection. The objective of this study was to evaluate the effect of different methods of tablet manipulations–cutting in half, grinding into powder, or crushing—on the bioavailability of GLE and PIB relative to whole film–coated bilayer tablets. This was a phase 1, single-dose, open-label, randomized, 5-period, nonfasting crossover study in 25 healthy adult male and female subjects. Intensive pharmacokinetic measurements were carried out up to 48 h after dosing on day 1 of each period. Safety and tolerability was assessed throughout the study. Compared with the reference whole tablets, cutting into half had minimal impact on GLE and PIB exposures (≤15% difference), whereas grinding or crushing the tablets resulted in lower exposures (27% to 61%) for GLE and higher exposures (21% to 83%) for PIB. These results provide guidance on appropriate administration of GLE/PIB in patients who have difficulty swallowing whole tablets.