Population pharmacokinetic analysis of meloxicam in rheumatoid arthritis patients

Abstract

Aim To perform a nonlinear mixed effect modelling (NONMEM) population pharmacokinetic analysis of meloxicam plasma concentrations in rheumatoid arthritis (RA) patients participating in three clinical trials, and to evaluate the effects of age, weight, gender and concomitant medications on meloxicam pharmacokinetics. Methods Meloxicam was administered to RA patients once daily for 3 weeks or 6 months at doses between 7.5 and 60 mg. Plasma samples were obtained at least 7 days after the first dose and meloxicam plasma concentrations were quantified by h.p.l.c.. Results NONMEM analysis was conducted on plasma samples derived from 586 patients. A one-compartmental model was found to describe the data adequately. For a typical subject in the population, a clearance of 0.377 l h -1 (95% confidence interval (CI) 0.0304-0.449) in males and 0.347 l h -1 (95% CI 0.274-0.419) in females was obtained. The volume of distribution was estimated to be 14.9 l. The findings were corroborated by subsequent analysis using WinBUGS. Analysis of covariates showed that age and gender both significantly ( P < 0.005) affected clearance. The effect of age was relatively small and a dose adjustment of <10% was deemed unnecessary. Differences between males and females were attributed to differences in weight. No clinically relevant drug-drug interactions were found, although sulphasalazine and glucocorticoids both significantly ( P < 0.005) affected meloxicam clearance ( + 19% and -12%, respectively). The mechanisms by which these agents affect meloxicam clearance remain to be elucidated. Conclusions The population pharmacokinetic meloxicam data from patients with RA gave similar results to those obtained from phase I trials. However, uncommon drug interactions may not be detected in phase I trials because of the small number of observations made.

Assessing the efficiency of mixed effects modelling in quantifying metabolism based drug–drug interactions: using in vitro data as an aid to assess study power

“…To date no well accepted rule exists for minimum levels of COMED in a POPPK study. Empirically some investigators include only COMEDs occurring in 5% of the population [22]. The current study confirms that lower levels of COMED can be detected using POPPK even for borderline inhibitors.…”

Pharmacokinetics and Pharmacodynamics of Meloxicam in East Asian Populations: The Role of Ethnicity on Drug Response

“…These data can also be extrapolated to other drugs that are mainly metabolized by hepatic CYP2C9 and have low hepatic extraction ratios. In addition, Meineke & Türck reported that body weights and age influence the CL of meloxicam, and that body weights affected the volume of distribution of meloxicam in patients with rheumatoid arthritis. However, neither body weights nor ages were statistically significant covariates for CL in the present study, whereas CYP2C9 genotype was a strong predictor of the CL of meloxicam.…”

“…Meloxicam is a cyclooxygenase inhibitor commonly used to treat patients with pain due to rheumatoid arthritis and surgery . The dose proportionality between orally administered doses of 7.5–30 mg has been confirmed, and the total clearance, volume of distribution, and absolute bioavailability have been reported to be 7.2 mL/min, 10.7 L, and 89% in healthy subjects, respectively.…”

Comparative pharmacokinetic and pharmacodynamic evaluation of branded and generic formulations of meloxicam in healthy male volunteers

“…The exclusion of women from participating in the present study was due to sex-dependent differences in the PK of meloxicam, as previously reported by Meineke and Türck,14 who demonstrated that both age and sex significantly affected meloxicam clearance.…”