Research ArticlePharmacokinetics, Pharmacodynamics and Drug Transport and MetabolismA Phase 1 Study to Evaluate the Effect of Crushing, Cutting Into Half, or Grinding of Glecaprevir/Pibrentasvir Tablets on Exposures in Healthy Subjects
Introduction
Hepatitis C virus (HCV) infection is a chronic liver disease that affects more than 70 million people worldwide.1 There are 6 major HCV genotypes (GTs) with GT1 being the most prevalent worldwide.2 GT2 and GT3 infections are more common in Latin America (5% to 30%), Europe (20% to 40%), and Asia (30% to 45%), GT4 is more commonly found in Africa and the Middle-East, particularly Egypt, GT5 in South Africa, and GT6 in Southeast Asia.3, 4
Therapy for HCV has improved considerably over the past few years with the approval of several interferon-free direct-acting antiviral (DAA) regimens with or without ribavirin (RBV). Although these regimens have demonstrated sustained virologic response rates >90%,5, 6, 7, 8 limitations of these regimens include inconsistent efficacy across all HCV GTs and subpopulations, requirement for RBV, inability of certain populations to take RBV, significant drug-drug interactions, and limited options for patients who have failed previous DAA treatments, subjects with renal insufficiency and end-stage renal disease. As such, there is an unmet need for a potent pangenotypic regimen that can address specific treatment challenges.
The combination of DAAs glecaprevir (GLE, a nonstructural 3/4A protease inhibitor discovered by AbbVie and Enanta) and pibrentasvir hydrate (PIB, a nonstructural 5A inhibitor), (Mavyret™), is approved for use as a pangenotypic (GT1-6), once-daily, RBV-free treatment for chronic HCV infection.9 The combination has demonstrated high efficacy in HCV GT1-6 infected subjects, including subjects with compensated cirrhosis (Child-Pugh A) and chronic kidney disease.10, 11 GLE/PIB is a fixed-dose combination of GLE and PIB, as 3 oral tablets of 100/40 mg dose strength for a total dose of 300/120 mg, administered once daily with food. Coformulated GLE/PIB is an immediate-release film-coated bilayer tablet manufactured using hot melt extrusion technology platform with a nonfunctional film coating.
Certain populations such as adolescents, the elderly, and some hospitalized patients may have difficulty swallowing whole tablets. Dysphagia is a common complication in elderly individuals.12 This could lead to noncompliance and nonadherence wherein such patients either skip or delay taking medications or employ alternate methods of administration such as crushing or splitting the tablets and taking them with liquids or jellies.13, 14 Such tablet manipulation methods may affect the pharmacokinetic properties of the drug and in some cases may also affect the relative bioavailability, which can result in decreased efficacy. Tablet manipulations may also lead to altered palatability (e.g., sugar coated tablets), drug instability (e.g., enteric-coated tablets), or increased toxicity.15, 16 For example, altering an enteric-coated tablet may lead to decreased absorption of the active drug from the stomach if the absorption of the drug is pH-dependent. Thus, it is important to understand how tablet manipulations can affect the bioavailability and absorption kinetics of the drug.
The objective of this study was to evaluate the pharmacokinetics and assess the impact of 4 different methods of tablet manipulation including cutting the tablet into half or grinding into powder or administering the ground powder mixed with 1 oz Jell-O or as a crushed tablet on the bioavailability of GLE/PIB relative to the “intact” film-coated bilayer tablets in healthy subjects.
Section snippets
Methods
The Vista Medical Center East Institutional Review Board (Waukegan, IL) reviewed and approved the study protocol and informed consent form. Informed consent was obtained from the subjects prior to performing any study-related procedures. This study was conducted in accordance with applicable regulations governing clinical study conduct and ethical principles originating in the Declaration of Helsinki.
Demographic and Baseline Characteristics
A total of 25 adult subjects (male and female) were enrolled, and all subjects completed the study. Subjects were randomized to receive GLE/PIB 300/120 mg tablets intact or after different tablet manipulations of the GLE/PIB tablet. All subjects were included in the pharmacokinetic and statistical analyses. A summary of baseline demographics of all subjects is shown in Table 2.
Pharmacokinetic and Statistical Analysis
The median plasma concentration-time profiles for the 5 regimens are shown in Figure 1. Pharmacokinetic parameters for
Discussion
This study was designed to evaluate the effects of different methods of tablet manipulations on bioavailability of GLE and PIB relative to the “whole” or “intact” film-coated bilayer tablets. GLE and PIB were administered as coformulated immediate-release tablets with food for the treatment of chronic HCV infection in phase 3 studies. At the target therapeutic dose of GLE/PIB 300/120 mg once daily, the regimen consists of administration of 3 × 100/40 mg coformulated tablets.
Both GLE and PIB
Acknowledgments
AbbVie contributed to the study design, research, and interpretation of data, and the writing, reviewing, and approving of the publication. The authors thank the clinical sites and investigators and AbbVie study team members for assistance with the conduct of the study and Xia Wan and the AbbVie Drug Analysis department for supporting drug assay development. The authors would also like to thank Nancy Sever and Cristina Fisher for their guidance on formulation-related discussions.
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2019, Drug Discovery TodayCitation Excerpt :In addition, the effect of different tablet manipulations (namely splitting, crushing or grinding) on the BA of the two compounds was assessed in a Phase I clinical trial. Splitting tablets demonstrated no relevant impact on BA, but crushing or grinding is not recommended [211]. This study is also part of QbD, because it enhances the knowledge on the product behavior, apart from providing guidance on adequate administration to patients.
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Conflict of interest: All authors are employees of AbbVie and may hold AbbVie stock or stock options. Medical writing support was provided by Amy Rohrlack, an AbbVie employee.