Pharmacokinetics of Long-Acting Injectable Drugs

Abstract

Long-acting injectable (LAI) formulations represent a transformative strategy in clinical pharmacology, enabling sustained therapeutic plasma concentrations from a single depot administration and substantially improving patient adherence in chronic disease management. This study conducted a systematic pharmacokinetic (PK) comparison of six clinically approved LAI drugs spanning four therapeutic categories: antipsychotics (paliperidone palmitate 1-month, aripiprazole monohydrate), antiretrovirals (cabotegravir, rilpivirine), a contraceptive (medroxyprogesterone acetate), and an anti-osteoporotic agent (denosumab). Using non-compartmental analysis (NCA) and population PK modelling (PopPK) with NONMEM v7.5 in a prospective cohort of 240 adult patients across six clinical centres, we characterised the absorption, distribution, and elimination profiles of each agent under real-world dosing conditions. Paliperidone palmitate demonstrated the most prolonged absorption phase (mean Tmax = 13.2 +- 1.8 days) with a terminal half-life of 25.5 + 3.1 days and steady-state Cmin fluctuation index of 0.31 +- 0.04, the lowest across all agents. Cabotegravir-rilpivirine achieved virological suppression (HIV RNA < 50 copies/mL) in 93.2% of patients at week 48, with trough concentrations consistently exceeding the protein-adjusted IC90 by a median 4.7-fold. PopPK analysis identified body weight (OFV reduction 22.4), sex (OFV 14.7), and injection site (OFV 11.3) as statistically significant covariates influencing apparent clearance and volume of distribution. These findings establish a quantitative PK framework supporting individualised LAI dosing and provide covariate-informed dose adjustment guidance for special populations.