Naproxen Dose and Concentration: Response Relationship in Rheumatoid Arthritis

Abstract

Information on the relationship between the plasma concentration of nonsteroidal anti-inflammatory drugs (NSAIDs) and clinical response in rheumatoid arthritis is sparse. As a result treatment is often relatively empirical. Standard doses are prescribed and an apparent lack of response leads either to the prescription of another drug, or an increase in the dose beyond that recommended. This study investigated 18 patients given three doses (500, 1000 and 1500 mg/day) of naproxen in a randomized double-blind design for 12 days at a time. Using a linear modelling approach we found that three out of four clinical response measurements improved linearly with increasing naproxen trough concentrations, suggesting that most patients will achieve an improvement in symptoms if the dose of naproxen is increased up to 1500 mg/day. However, since trough naproxen concentrations show a less than proportional increase with increasing dose (due to saturation of binding sites on plasma albumin), the improvement in response will be less dramatic as the dose is increased.

An LC–MS/MS procedure for the quantification of naproxen in human plasma: Development, validation, comparison with other methods, and application to a pharmacokinetic study

“…The mean half-life was 18.5 h. Table 4 shows the pharmacokinetic parameters of naproxen after administration of a tablet of 220 mg naproxen sodium in comparison to pharmacokinetic parameters reported in previously published studies. Dose-dependent studies of naproxen in healthy volunteers after single and multiple doses observed a non- linear relationship between naproxen and plasma concentrations at higher doses [69,70]. Segre [71] reported a linear relationship between naproxen dose and plasma concentrations within 100-300 mg single dose, and a non-linear relationship at multiple doses of 375-750 mg naproxen.…”

“…The plasma protein binding sites are assumed to be saturated at high naproxen doses, which results in a higher concentration of unbound naproxen and leads to a higher excretion rate and clearance [60]. This unbound naproxen concentration was shown to be proportional to naproxen concentrations at 500, 1000, and 1500 mg doses [69]. For this reason the PK parameters in Table 4 are not shown dose-corrected.…”

Modeling Sex Differences in Pharmacokinetics, Pharmacodynamics, and Disease Progression Effects of Naproxen in Rats with Collagen-Induced Arthritis

“…However, dosing regimens for NPX in treating RA have been empirical due to the lack of convincing information on the relationship between drug exposure and clinical response. The NPX concentration-response relationship in RA was explored (Dunagan et al, 1988;Day et al, 1995), but only a trend was obtained and the pharmacokinetics (PK) and pharmacodynamics (PD) of NPX were not quantitatively analyzed. Recent studies (Huntjens et al, 2006(Huntjens et al, , 2010 assessed the correlation between in vitro and in vivo exposure-effect relationships of NPX as well as the impact of chronic inflammation on the PK/PD of NPX.…”

Clinical Pharmacokinetics of Drugs Used in Juvenile Arthritis

“…However, such a relationship exists in adult rheumatoid arthritis (Day et al 1982): 75% of 22 patients with serum naproxen concentrations of 55 to 92 mg/L responded to the therapy. Interestingly, clinical effects appear to parallel total concentration more closely than unbound concentration (Dunagan et al 1988), which may be attributable to the observed nonlinearity in the protein binding of naproxen (Runkel et al 1974).…”