Long-acting cabotegravir and rilpivirine plasma exposures in the clinical setting: The role of pharmacogenetics

Abstract

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Long-acting cabotegravir and rilpivirine plasma exposures in the clinical setting: The role of pharmacogenetics

Jessica Cusato¹, Micol Ferrara², Miriam Antonucci², Razvan Goldan¹, Sara Soloperto¹, Giovanni Di Perri³, Antonio D'avolio¹, Andrea Calcagno³ and Stefano Bonora³

¹Department of Medical Sciences, Laboratory of Clinical Pharmacology and Pharmacogenetics, University of Turin; ²ASL Città di Torino; ³Unit of Infectious Diseases, Department of Medical Sciences, University of Turin

Background: Wide inter-individual variability in the pharmacokinetics of rilpivirine (RPV) and cabotegravir (CABO) has been reported in the first weeks after starting long acting injectable drugs (LAI) treatment. Furthermore, reduced RPV and/or CABO plasma trough concentrations combined with other risk factors (i.e. resistance-associated mutations, BMI  ≥  30 kg/m²) have been related with increased risk of virologic failure. However, data on the potential role of pharmacogenetics in affecting LAI pharmacokinetics and, possibly, the clinical outcome are lacking. Consequently, we aimed at evaluating the impact of genetic polymorphisms in affecting LAI drug exposure in PWH.

Material and methods: RPV and CABO concentrations were quantified by chromatography, both in plasma and in peripheral blood mononuclear cells (PBMCs), before starting therapy (oral administration, baseline, only for RPV) and at 1, 3, 5, 7, 9 and 11 months (M) of therapy with LAI administration. The 4 × PA-IC90 were considered as the efficacy cut-off values, set at 50 and 664 ng/mL for RPV and CABO, respectively. Regression analysis was performed in order to evaluate which factors are able to predict the efficacy-related values of 50 ng/mL for RPV and 664 ng/mL for CABO respectively at 3 months of therapy.

Polymorphisms in genes encoding enzymes and transporters involved in drug metabolism and elimination (CYP2C19, CYP3A4, CYP3A5, UGT1A1, ABCB1, ABCG2) were analysed through real-time PCR.

Results: One hundred and seventy-seven PWH were enrolled: 85.3% males with median age of 50.7 years (IQR 43.3; 59.1). Median plasma and PBMC antiretroviral drug levels at different timings are reported in Table 1. Following associations were found: baseline plasma RPV and ABCB1 3435 CT/TT (p = .039) and UGT1A1 023 TT (p = .028), 1 M CABO intracellular levels and ABCB1 1236 CT/TT (p = .047), M3 ratio CABO and CYP2C19 AA (p = .025) and UGT1A1 023 CT/TT (p = .009), M3 RPV plasma and CYP3A4*22 (p = .035), M5 ratio CABO and ABCG2 421 CA/AA (p = .020), M5 plasma CABO and UGT1A1 023 TT (p = .010), M9 plasma RPV and CYP3A4*22 (p = .046), M11 plasma RPV and ABCB1 1236 CT/TT (p = .042), M11 intracellular RPV and ABCG2 421 CA/AA (p = .012) and finally, 11 M CABO plasma concentrations and CYP2C19 GA/AA (p = .006).

Regression analysis reported age and CYP3A4*22 as predictors of the RPV efficacy cut-off value of 50 ng/mL (34.5% of patients were below this level), whereas gender, CYP2C19*2 AA and ABCG2 421 AA predictors of the CABO cut-off value of 664 ng/mL (7.9% of patients were below this level) at 3 months of therapy.

Conclusions: This is the first study reporting a potential impact of genetic variants in affecting LAI concentrations and the risk of suboptimal drug exposure. Further research is needed to elucidate the complex interactions between genetics, drug metabolism and treatment outcomes, ultimately paving the way for personalized and precision medicine approaches in HIV care.