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Population pharmacokinetics of cabotegravir following administration of oral tablet and long-acting intramuscular injection in adult HIV-1-infected and uninfected subjects. | LitMetric

AI Article Synopsis

  • The study aimed to analyze the pharmacokinetics of cabotegravir, focusing on how different factors (both intrinsic and extrinsic) affect the drug's variability in the body using data from various clinical trials.
  • Researchers utilized advanced statistical tools like NONMEM and R to evaluate a large dataset of plasma concentrations from HIV-1-infected and uninfected subjects, testing different dosing methods and identifying trends related to demographics and health metrics.
  • The findings suggest a population pharmacokinetic model that can guide dosing strategies without necessitating adjustments based on individual factors like race or age, highlighting certain influences from smoking and body metrics on drug absorption and clearance.

Article Abstract

Aim: To characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability.

Methods: Analyses were implemented in NONMEM and R. Concentrations below the quantitation limit were modelled with likelihood-based approaches. Covariate relationships were evaluated using forward addition (P < .01) and backward elimination (P < .001) approaches. The impact of each covariate on trough and peak concentrations was evaluated through simulations. External validation was performed using prediction-corrected visual predictive checks.

Results: The model-building dataset included 23 926 plasma concentrations from 1647 adult HIV-1-infected (72%) and uninfected (28%) subjects in 16 studies at seven dose levels (oral 10-60 mg, long-acting [LA] intramuscular injection 200-800 mg). A two-compartment model with first-order oral and LA absorption and elimination adequately described the data. Clearances and volumes were scaled to body weight. Estimated relative bioavailability of oral to LA was 75.6%. Race and age were not significant covariates. LA absorption rate constant (KA ) was 50.9% lower in females and 47.8% higher if the LA dose was given as two split injections. KA decreased with increasing BMI and decreasing needle length. Clearance was 17.4% higher in current smokers. The impact of any covariate was ≤32% on trough and peak concentrations following LA administration. The final model adequately predicted 5097 plasma concentrations from 647 subjects who were not included in the model-building dataset.

Conclusions: A cabotegravir population pharmacokinetic model was developed that can be used to inform dosing strategies and future study design. No dose adjustment based on subject covariates is recommended.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9543358PMC
http://dx.doi.org/10.1111/bcp.15439DOI Listing

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