Model based comparison of cabotegravir pharmacokinetics following thigh and gluteal injections

Abstract

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Model based comparison of cabotegravir pharmacokinetics following thigh and gluteal injections

Susan Ford¹, Kelong Han¹, Ronald D'Amico² and William Spreen²

¹GSK; ²ViiV Healthcare

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 [i]vastus lateralis[/i] (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.

Material and methods: Fourteen participants (pts) who were HIV negative and received a 600 mg single thigh injection in phase 1 study 208832 and 118 pts who were HIV-positive and received thigh injections [400 mg monthly (QM) × 4 or 600 mg every-2-months (Q2M) × 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 analysed. 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[sup] − 1[/sup]. 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.

Conclusions: PPK modelling 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.