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

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.

FIGURE 1

Study protocol illustrating cabotegravir oral dose lead‐in (30 mg day⁻¹), washout, cabotegravir LA (600 mg) gluteal muscle‐targeted injection and PK assessment visits and follow‐up. MRI was performed on Days 1 (≤2 h postinjection), 3 and 8. IM, intramuscular; LA, long acting; MRI, magnetic resonance imaging; PK, pharmacokinetics; QD, once daily

FIGURE 2

Temporal MRI of cabotegravir LA depots in representative sites. (A) SC adipose tissue thickness (red line) along the needle track varied greatly in participants. Ultrasonographic‐guided cabotegravir LA injections were administered in (B) RP, (C) IM, (D) SC and (E) IM and SC locations. Each panel contains a representative image of the serial, transverse, T2‐weighted slice section obtained through the same depot location on Days 1, 3 and 8. Each depot was segmented to show RP depot in blue, gluteal muscle depot in red, and SC adipose depot in green. MRI T2 reference phantoms were placed next to the participant. IM, intramuscular; LA, long acting; MRI, magnetic resonance imaging; RP, retroperitoneal; SC, subcutaneous; T2, transverse relaxation time constant

FIGURE 3

MRI‐assessed cabotegravir LA depot volume and surface area. (A) Total drug depot volume and (B) surface area were measured for each participant on Days 1, 3 and 8. (C) Total drug depot volume and (D) surface area were measured in RP, IM, SC, and IM and SC tissue compartments for each participant. In those participants who received the drug administered in the IM and SC tissue compartment, both IM and SC contributions to the average (E) total depot volume and (F) surface area in these individuals were assessed. Data in panels (C) and (D) are presented as mean ± SEM. Data in panels (E) and (F) are presented as mean values for both IM and SC depots. IM, intramuscular; LA, long acting; MRI, magnetic resonance imaging; RP, retroperitoneal; SC, subcutaneous; SEM, standard error of mean

FIGURE 4

MRI‐assessed cabotegravir LA depot mean T2 and mean ADC parameters. (A) Total drug depot mean T2 and (B) mean ADC were measured for each participant on Days 1, 3 and 8. (C) Total drug depot mean T2 and (D) mean ADC were measured in RP, IM, SC, and IM and SC tissue compartments for each participant. Data in panels (C) and (D) are presented as mean ± SEM. On Day 1 in participant 1, RP ADC was not measured. ADC, apparent diffusion coefficient; IM, intramuscular; LA, long acting; MRI, magnetic resonance imaging; RP, retroperitoneal; SC, subcutaneous; SEM, standard error of mean; T2, transverse relaxation time constant

FIGURE 5

Plasma cabotegravir pharmacokinetics profile. (A) Plasma cabotegravir concentration is shown for each imaging participant out to 84 days after cabotegravir LA administration. (B) Mean plasma cabotegravir concentration is shown for depot location. IM, intramuscular; LA, long acting; RP, retroperitoneal; SC, subcutaneous. Data in panel (B) are presented as mean ± standard error of mean

FIGURE 6

Linear regression analysis performed on cabotegravir exposure metrics and MRI‐derived parameters. The strongest positive correlations between plasma cabotegravir concentrations (Days 1, 3 and 8) and exposure metrics (C _max, AUC_0‐4wk, AUC_0‐8wk) and MRI‐measured cabotegravir LA depot volume, surface area, T2 and ADC parameters were with (A) total depot surface area observed on Day 1. Conversely, the strongest negative correlations between plasma cabotegravir concentrations and exposure metrics and MRI‐measured cabotegravir LA depot volume, surface area, T2, and ADC parameters were with (B) T2 observed on Day 1. ADC, apparent diffusion coefficient; AUC, area under the concentration–time curve; C _max, maximum concentration; LA, long acting; MRI, magnetic resonance imaging; T2, transverse relaxation time constant