Multiparametric magnetic resonance imaging to characterize cabotegravir long-acting formulation depot kinetics in healthy adult volunteers

Beat M Jucker; Edward J Fuchs; Sarah Lee; Valeriu Damian; Paul Galette; Robert Janiczek; Katarzyna J Macura; Michael A Jacobs; Ethel D Weld; Meiyappan Solaiyappan; Ronald D'Amico; Jafar Sadik Shaik; Kalpana Bakshi; Kelong Han; Susan Ford; David Margolis; William Spreen; Manish K Gupta; Craig W Hendrix; Parul Patel

doi:10.1111/bcp.14977

Multiparametric magnetic resonance imaging to characterize cabotegravir long-acting formulation depot kinetics in healthy adult volunteers

Br J Clin Pharmacol. 2022 Feb;88(4):1655-1666. doi: 10.1111/bcp.14977. Epub 2021 Jul 31.

Authors

Beat M Jucker¹, Edward J Fuchs², Sarah Lee³, Valeriu Damian¹, Paul Galette¹, Robert Janiczek¹, Katarzyna J Macura², Michael A Jacobs², Ethel D Weld², Meiyappan Solaiyappan², Ronald D'Amico⁴, Jafar Sadik Shaik¹, Kalpana Bakshi¹, Kelong Han¹, Susan Ford⁵, David Margolis⁴, William Spreen⁴, Manish K Gupta¹, Craig W Hendrix², Parul Patel⁴

Affiliations

¹ GlaxoSmithKline, Collegeville, PA, USA.
² Departments of Internal Medicine and Radiology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
³ Amallis Consulting Ltd, London, UK.
⁴ ViiV Healthcare, Research Triangle Park, NC, USA.
⁵ GlaxoSmithKline, Research Triangle Park, NC, USA.

Abstract

Aim: Cabotegravir long-acting (LA) intramuscular (IM) injection is being investigated for HIV preexposure prophylaxis due to its potent antiretroviral activity and infrequent dosing requirement. A subset of healthy adult volunteers participating in a Phase I study assessing cabotegravir tissue pharmacokinetics underwent serial magnetic resonance imaging (MRI) to assess drug depot localization and kinetics following a single cabotegravir LA IM targeted injection.

Methods: Eight participants (four men, four women) were administered cabotegravir LA 600 mg under ultrasonographic-guided injection targeting the gluteal muscles. MRI was performed to determine injection-site location in gluteal muscle (IM), subcutaneous (SC) adipose tissue and combined IM/SC compartments, and to quantify drug depot characteristics, including volume and surface area, on Days 1 (≤2 hours postinjection), 3 and 8. Linear regression analysis examined correlations between MRI-derived parameters and plasma cabotegravir exposure metrics, including maximum observed concentration (C_max ) and partial area under the concentration-time curve (AUC) through Weeks 4 and 8.

Results: Cabotegravir LA depot locations varied by participant and were identified in the IM compartment (n = 2), combined IM/SC compartments (n = 4), SC compartment (n = 1) and retroperitoneal cavity (n = 1). Although several MRI parameter and exposure metric correlations were determined, total depot surface area on Day 1 strongly correlated with plasma cabotegravir concentration at Days 3 and 8, C_max and partial AUC through Weeks 4 and 8.

Conclusion: MRI clearly delineated cabotegravir LA injection-site location and depot kinetics in healthy adults. Although injection-site variability was observed, drug depot surface area correlated with both plasma C_max and partial AUC independently of anatomical distribution.

Keywords: HIV/AIDS; MRI; antiretrovirals; cabotegravir; pharmacokinetics-pharmacodynamic.

Publication types

Clinical Trial, Phase I
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Anti-HIV Agents*
Diketopiperazines
Female
HIV Infections* / drug therapy
Humans
Injections, Intramuscular
Kinetics
Male
Multiparametric Magnetic Resonance Imaging*
Pyridones
Volunteers

Substances

Anti-HIV Agents
Diketopiperazines
Pyridones
cabotegravir