Population pharmacokinetics of the active metabolite of nabumetone in renal dysfunction

We determined the pharmacokinetics of 6-methoxy-2-naphythylacetic acid (6-MNA), the active metabolite of nabumetone, in normal subjects and in subjects with impaired renal function, including subjects requiring hemodialysis. Subjects received a 1000 mg oral dose of nabumetone either as a single dose or daily for 15 days. We used a noncompartmental pharmacokinetic analysis and compared those results to a population pharmacokinetic analysis performed with nonlinear mixed-effects modeling (NONMEM). The results of the two different analyses were similar. The elimination half-life increased with decreased renal function and ranged from 22 to 44 hours. The area under the curve decreased significantly at steady state, regardless of renal function. The apparent clearance determined by NONMEM analysis increased from 0.68 L/hr after a single dose to 1.13 L/hr at steady state. The apparent volume of distribution was directly proportional to the nonalbumin protein concentration and ranged from 23 to 60 L. We conclude that the pharmacokinetics of 6-MNA in this population are complicated by possible protein binding changes. However, the increased half-life in patients with renal failure is offset by changes in the apparent volume of distribution that prevent the accumulation of 6-MNA in the serum of patients with impaired renal function. Therefore dosage adjustments may not be necessary in patients with decreased renal function.