Meloxicam for juvenile rheumatoid arthritis patients: Is dosing on a mg/kg body weight basis justified?

Objectives & Background: Meloxicam is a nonsteroidal anti-inflammatory drug approved for the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis in adults. These indications are planned to be expanded including the indication, signs and symptoms of juvenile rheumatoid arthritis (JRA). JRA patients were dosed on a mg/kg body weight basis in the safety and efficacy studies performed. The objective of the population pharmacokinetic analysis was to develop a common model describing all available pharmacokinetic data of juvenile rheumatoid arthritis patients and investigate whether dosing by kg body weight in JRA patients results in similar exposure as in adults.

Methods: The dataset for the population pharmacokinetic analysis included 47 JRA patients with 486 plasma concentration measurements. From 18 JRA patients plasma profiles after a single dose of 0.25 mg/kg were obtained and from 29 JRA patients steady state profiles following once daily dosing with 0.375 mg/kg were available. The demographic characteristics sex, race, age, weight, height, body surface area (BSA) and body mass index (BMI) as well as creatinine clearance were to be tested as covariates on the pharmacokinetic parameters. Based on the final model typical plasma concentration-time profiles for different doses (0.125 to 0.375 mg/kg once daily) and weight groups (10 to 90 kg) were simulated and overlaid with a typical plasma concentration-time profile obtained in adults. NONMEM, version V, level 1.1, with the FOCE interaction method was used for data analysis and simulation.

Results: The plasma concentration time profiles were best described by an one‑compartment body model with sequential zero and first order absorption processes and first order elimination. Only weight was identified as a significant covariate on clearance and volume of distribution. The typical clearance (CL/F) and volume of distribution (V/F) estimates for a 34 kg JRA patient were 0.29 L/h and 6.2 L, respectively. These typical CL/F and V/F values increase/decrease by 2% and 2.5% per kg increase/decrease in body weight. 15.2% of the dose was absorbed by a zero order process over 0.7 h. The remaining 84.8% of the dose (F1) were absorbed by a first order absorption process with a rate constant of 2.13 h^-1 starting 0.834 h after administration. Estimates for interindividual variability were 44% in CL/F, 40% in V/F and 15% in F1. Residual variability was 27%.
The simulations showed that doses of 0.125 mg/kg, 0.250 mg/kg and 0.375 mg/kg once daily in JRA patients result in similar steady-state exposures as achieved with a 7.5 mg, 15 mg and 22.5 mg/kg in adults.

Conclusion: The pharmacokinetics in JRA patients were successfully described by an one compartment body model with sequential zero and first order absorption processes and first order elimination. As the steady-state exposures in JRA patients following once daily dosing of 0.125 mg/kg to 0.375 mg/kg meloxicam are comparable to the exposures seen in adults dosed with 7.5 mg to 22.5 mg the proposed dose individualisation on a mg/kg body weight basis is appropriate for JRA patients.