Development of an Analytical Method for Determination of Related Substances and Degradation Products of Cabotegravir Using Analytical Quality by Design Principles.

Cabotegravir is one of the newly approved human immunodeficiency virus (HIV) integrase enzyme inhibitors used for the prevention and treatment of HIV infection. It is the first approved long-acting injectable antiretroviral therapy for HIV and is also very effective in combination with rilpivirine, a non-nucleoside reverse transcriptase inhibitor. Therefore, future drug development involving cabotegravir can be expected. We developed an ultrahigh performance liquid chromatography (UHPLC) method compatible with mass spectrometry for the determination of eight cabotegravir impurities. The described method is able to differentiate cabotegravir and its related substances as well as its degradation products. Analytical quality by design principles were used for method development. The method is robust within the defined method operable design region: flow rate = 0.32-0.40 mL/min; column temperature = 30-40 °C; pH of mobile phase A = 3.25-3.75, and the final percent of acetonitrile in gradient = 50.0-60.0%. Inside the method operable design region, a working optimal point was selected: pump flow rate = 0.36 mL/min; column temperature = 35 °C; pH of mobile phase A = 3.5, and final percent of acetonitrile in gradient = 55%. Method validation was performed, and the following parameters were verified: accuracy, repeatability, linearity, response factors, detection limit, and quantification limit. All method validation results were within selected criteria. The presented method could be used for the development of new pharmaceutical products based on cabotegravir.

Understanding of cabotegravir degradation through isolation and characterization of key degradation products and kinetic studies.

Cabotegravir is a novel human immunodeficiency virus integrase enzyme inhibitor used for prevention and treatment of HIV infection. The combinational final dosage form, as extended release injection suspension in combination with rilpivirine and as cabotegravir tablets (for lead-in therapy), was recently approved in Canada, EU and in USA and is currently seeking approval also in other countries. The subject of this investigation was to study the degradation of cabotegravir under different stress conditions as per the International Council for Harmonization (ICH) guidelines. The drug substance was found to be stable in thermal, photolytic and basic stress conditions, but degraded under acidic and oxidative stress conditions. It was determined that four main degradation products of cabotegravir are formed in forced degradation studies. All four main degradation products were isolated using preparative chromatography and subjected to NMR and HRMS analysis in order to determine their structure. We proposed degradation pathways of cabotegravir under acidic stress conditions in solution based on the structure of isolated degradation products, cabotegravir degradation kinetic studies and degradation studies on two isolated key degradation products. Moreover, degradation pathway to predominant oxidation degradation product is proposed based on the adduct of cabotegravir and peroxide species, which was identified by LC-HRMS analysis. This is the first report to the best of our knowledge that describes characterized cabotegravir forced degradation impurities and provides insights into its degradation pathways.

A literature review of the patent application publications on cabotegravir - an HIV integrase strand transfer inhibitor.

Introduction: Studies presented in the patent applications demonstrate that a new integrase strand transfer inhibitor cabotegravir might be used as long-acting antiretroviral formulation or delivery system that reduces dosing frequency and may therefore increase adherence and thus pre-exposure prophylaxis (PrEP) and treatment efficacy against HIV. As announced in 2019, the developer ViiV Healthcare seeks US and EU approval of long-acting, injectable HIV treatment.Area covered: This review covers all the patent applications published until October 2019 with cabotegravir in the examples or claim section of the patent application document. The patent applications cover drug substance synthesis, solid-state forms, therapeutic applications, in vitro and in vivo efficacy as well as the potential formulations of cabotegravir alone or in combination with other anti-HIV agents.Expert opinion: The results from multiple clinical studies suggest that cabotegravir can be used as PrEP agent and treatment agent against HIV. Multiple studies use cabotegravir in combination with other anti-HIV agents such as rilpivirine. Cabotegravir in combination with rilpivirine is an interesting therapeutic, due to the possibility of formulating long-acting formulation with dosing interval of every 4 weeks or less, thus reducing daily pill burden and improving patient's compliance.