CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

617

Model-Based Comparison of Cabotegravir Pharmacokinetics Following Thigh and Gluteal Injections Kelong Han 1 , Ronald D'Amico 2 , William Spreen 2 , Susan Ford 3 1 GSK, Collegeville, PA, USA, 2 ViiV Healthcare, Check location, 3 GSK, Durham, NC, USA Background: Cabotegravir (CAB) long-acting (LA) intramuscular (IM) gluteal injections are approved for HIV-1 pre-exposure prophylaxis (PrEP) and combination treatment with rilpivirine. The vastus lateralis (lateral) thigh muscle is a potential alternative site of administration in cases of gluteal injection fatigue or physical obstruction. We aimed to characterize CAB pharmacokinetics (PK) and its association with demographics following thigh administration in comparison to gluteal administration using population PK (PPK) analysis. Methods: Fourteen participants (pts) who were HIV-negative and received a 600mg single thigh injection in Phase 1 Study 208832 and 118 pts who were HIV-positive and received thigh injections [400mg monthly (QM) x 4 or 600mg every-2-months (Q2M) x 2] after >3 years of gluteal injections in Phase 3b Study 207966 (ATLAS-2M) provided CAB concentrations for the analysis. An established gluteal PPK model was fit to PK data following both gluteal and thigh injections, enabling within-person comparison in ATLAS-2M pts. Gluteal parameters were fixed. Thigh parameters including absorption rate constant (KA-thigh) and bioavailability (F-thigh) were estimated. CAB PK profiles following chronic or intermittent thigh injections administered QM and Q2M were simulated and compared to gluteal injections. PK target was that 95% of pts maintain concentrations >0.45 µg/mL, the 5th percentile of observed CAB trough concentration following the gluteal initiation injection in Phase 3 Studies. Results: 1254 concentrations from 366 thigh injections and 2022 concentrations from 1631 gluteal injections were analyzed. Similar to gluteal administration, KA-thigh was associated with sex and BMI. KA-thigh was correlated with and was generally faster than KA-gluteal, described by the additive linear relationship: KA-thigh = KA-gluteal + 0.000253 h -1 . Terminal half-life of thigh administration was 26% (male) and 39% (female) shorter than for gluteal administration. F-thigh was 90% of gluteal injection. PK target was maintained following chronic QM thigh injections or alternating thigh-gluteal injections for either QM or Q2M regimens but not following chronic Q2M thigh injections. (Figure). Conclusion: PPK modeling and simulation support chronic thigh administration of CAB LA QM and intermittent thigh injections for both QM and Q2M regimens. However, simulated chronic Q2M thigh administration did not maintain PK target established in pivotal trials and therefore is not recommended.

Poster Abstracts

616

Pharmacokinetics of Long-Acting Cabotegravir and Rilpivirine in Elderly Using PBPK Modelling Sara Bettonte 1 , Mattia Berton 1 , Felix Stader 2 , Manuel Battegay 1 , Catia Marzolini 1 1 University Hospital Basel, Basel, Switzerland, 2 Certara, Sheffield, United Kingdom Background: The quality of life of people with HIV (PWH) has significantly increased thanks to potent single pill antiretroviral regimens characterized by a good tolerability. Another milestone has been reached with long-acting (LA) formulations which enable infrequent dosing. Clinical trials of LA agents were mostly conducted in standard populations, leading to a lack of knowledge on their pharmacokinetics in elderly PWH. Physiologically based pharmacokinetic (PBPK) model is a mathematical tool approved by the regulatory authorities used to simulate clinical unknown scenarios. The aim of this study was to determine the pharmacokinetics of LA cabotegravir and rilpivirine in virtual elderly individuals. Methods: Our in-house PBPK model built in Matlab®2020a and implemented with an intramuscular framework was verified against clinical observed data for cabotegravir and rilpivirine after oral and intramuscular administration. As for PBPK modelling guidelines, the model was considered verified when the predictions were within 2-fold of clinical observed data. The effect of ageing on the pharmacokinetics of LA cabotegravir and rilpivirine was evaluated by using two separate cohorts of virtual individuals aged 20-50 (50% female) and 65-85 (50% female), respectively. The design of the ATLAS/FLAIR and ATLAS-2M studies was reproduced in our PBPK model and the fold change in elderly relative to young was determined for area under the concentration-time curve (AUC) and trough concentration (C min ) at steady state. Results: The PBPK model was successfully verified as all the predictions were within 2-fold of clinically observed data. Age related physiological changes did not significantly impact the C min and AUC of LA cabotegravir administered every month (Q4W), and the AUC of LA rilpivirine Q4W since the ratios (elderly vs young) were predicted to be within the bioequivalence range (0.8-1.25 fold). On the other hand, the Cmin of LA rilpivirine administered Q4W was 28% higher in elderly relative to young. Additionally, the Cmin and AUC of LA cabotegravir administered every other month (Q8W) were predicted to be 29% and 26% higher in elderly relative to young, respectively. Similarly, the Cmin and AUC of rilpivirine Q8W were 46% and 41% higher in elderly (Fig. 1). Conclusion: Age related physiological changes are predicted to modestly increase the AUC and Cmin of LA cabotegravir and rilpivirine. Thus, elderly PWH could possibly be at lower risk for sub-optimal drug exposure at the end of the dosing interval.

CROI 2024 173