Document resource
Background Few data on plasma exposure and no data on intracellular (IC, intra-PBMC) accumulation of long-acting cabotegravir and rilpivirine (CAB/RPV LA) administered intramuscularly are currently available. Therefore, our aim was to evaluate CAB and RPV plasma and IC pharmacokinetics (PK), including the intracellular inhibitory quotient (IQ), and to explore the potential role of PK parameters on virological efficacy during an almost 3-year follow-up (FU).Methods Participants receiving CAB/RPV every two months were enrolled after informed consent. Plasma and IC CAB and RPV trough concentrations (Ctrough) were quantified using a validated UHPLC-MS/MS method at the end of each dosing interval, every two months from month 1 to month 31 (M1–M31). The intracellular inhibitory quotient (IQ) was defined as the ratio between IC concentration and the protein-adjusted inhibitory concentration 90% (PA-IC90), established in literature as 12 ng/mL for RPV and 166 ng/mL for CAB. An IQ value above 1 is considered necessary to ensure optimal antiviral activity and adequate intracellular penetration in PBMCs. Virological assessment was performed at each timepoint. PK parameters were expressed as geometric mean (95%CI). Comparisons were performed using Mann-Whitney and Spearman tests.Results Overall, 703 IC determinations from 148 participants were included; 86.3% were male, median age was 51 years (49–52) and BMI 24.5 kg/m 2 (23.9–25.0); in 90.3% of IC, VL was <20 copies/mL. Study population characteristics are summarized in table 1. Across 703 IC determinations, the overall mean IQ was 26.2 (24.5–27.9) for RPV and 0.97 (0.91–1.03) for CAB. CAB and RPV IQ parameters during FU are reported in figure 1. No significant correlation was observed between IQ values and virosuppression for either drug. The IQ for both drugs remained stable over time, with no significant differences. Strong and significant correlations were observed between plasma and IC concentrations at all follow-up timepoints (p<0.001).Conclusions Our study provides the first longitudinal characterization of intracellular exposure and inhibitory quotient (IQ) of long-acting CAB and RPV. RPV achieved intracellular concentrations approximately 20-fold above the IQ efficacy threshold, despite greater variability in plasma exposure, indicating substantial intracellular accumulation. In contrast, CAB intracellular concentrations remained close to the target IQ value of approximately 1, even in the presence of higher and more stable plasma levels. No association between IQ and virological failure was observed. Furthermore, no intracellular determination showed IQ values below the predefined cut-off for both drugs simultaneously. These findings support the long-term pharmacological robustness of CAB/RPV LA and emphasize the importance of intracellular PK assessment to better characterize antiviral efficacy and interindividual variability.Abstract OC73 Table 1Demographical and clinical characteristics of study population (n=148)Abstract OC73 Figure 1Inhibitory quotient (IQ) over time during follow-up from month 1 to month 31. (a) Rilpivirine IQ, (b) CAB IQ; Linear red solid line represents the IQ cut-off of 1