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

Abstract

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.

A population pharmacokinetic model based on HPTN 077 of long‐acting injectable cabotegravir for HIV PrEP

“…The estimated variability from occasion to occasion on the absorption rate (k a ) was 38.5%. This variability is relatively large, but reasonable, for a long‐acting injectable formulation, since the absorption of the injectable formulation of cabotegravir is influenced by the depth, vascularity, lymphatics and fat content of the injection site, as is true of many other long‐acting depot formulations, including paloperidone 14,27–29 . For comparison, in one population PK study of paliperidone, the BOV on clearance, volume of distribution and dose fraction in the central compartment were 26% CV, 14% CV and 0.07 SD, respectively 29 .…”

“…This variability is relatively large, but reasonable, for a long-acting injectable formulation, since the absorption of the injectable formulation of cabotegravir is influenced by the depth, vascularity, lymphatics and fat content of the injection site, as is true of many other long-acting depot formulations, including paloperidone. 14,[27][28][29] For comparison, in one population PK study of paliperidone, the BOV on clearance, volume of distribution and dose fraction in the central compartment were 26% CV, 14% CV and 0.07 SD, respectively. 29 In our examination of whether BOV varied according to characteristics such as sex, race and BMI, we found no significant associations between any of these characteristics and BOV.…”

“…There may be a difference in CAB-LA PK for any given dose depending on whether depot location is subcutaneous or intramuscular; in a companion tissue PK study to HPTN 077, when location of injection depot was visualized with magnetic resonance imaging (MRI), recipients with subcutaneous depot locations had lower peak concentrations, longer terminal half-life, and higher area under the concentration curve (AUC) than individuals whose depot location was intramuscular. 14 Large double-blind, double-dummy randomized controlled phase 3 efficacy trials followed, which compared the HIV preventive efficacy of CAB-LA to that of oral tenofovir disoproxil fumarateemtricitabine (F-TDF), and found superiority in HIV preventive efficacy of CAB-LA in both cisgender women (HPTN 084) and cisgender men and transgender women who have sex with men (HPTN 083). 15,16 17 The timing of these concentration dips occurred between the first and second injection in three out of the four cases.…”

“…These two factors, however, only explained 10% of the elimination‐phase PK variability of CAB‐LA; other significant contributors to its PK variability are as yet undefined. There may be a difference in CAB‐LA PK for any given dose depending on whether depot location is subcutaneous or intramuscular; in a companion tissue PK study to HPTN 077, when location of injection depot was visualized with magnetic resonance imaging (MRI), recipients with subcutaneous depot locations had lower peak concentrations, longer terminal half‐life, and higher area under the concentration curve (AUC) than individuals whose depot location was intramuscular 14 …”

MRI/PET multimodal imaging of the innate immune response in skeletal muscle and draining lymph node post vaccination in rats

“…18 FDG PET provided excellent signal differentiation from background in muscle and draining lymph node following vaccination and importantly, the quantitative readouts were less variable than the standard clinical scoring of reactogenicity ( 9 ). Additionally, T2 weighted magnetic resonance imaging (MRI) is a sensitive biomarker for assessing musculoskeletal tissue inflammation and edema ( 13 ) and has been used in rodents and humans to characterize the acute temporal drug disposition and inflammatory response of a long acting injectable in muscle ( 14 , 15 ).…”