Pharmacokinetics of 3 formulations of meloxicam in cynomolgus macaques (Macaca fascicularis)

Abstract

Meloxicam is a commonly used COX2-preferential NSAID in both human and veterinary patients. Minimal information has been published regarding appropriate dosing in nonhuman primates. Here we investigated the pharmacokinetic parameters of 3 formulations of meloxicam in cynomolgus macaques. A single dose of meloxicam SR, an extended-release formulation purported to provide therapeutic levels for as long as 72 h, was compared with the intramuscular and oral formulations dosed for 3 consecutive days and as a single dose. The oral formulation, both over 3 d and as a single dose, yielded lower plasma levels and a shorter duration than did intramuscular and sustained-release subcutaneous formulations. The intramuscular formulation, both over 3 d and as a single dose, provided lower plasma levels and a shorter duration than did a sustained-release subcutaneous formulation. The sustained-release formulations generated the highest plasma concentrations for the longest periods of time. None of the formulations caused significant effects on kidney or liver function. Our results indicate that the sustained-release formulation of meloxicam can achieve an adequate steady-state plasma concentration for 2 to 3 d in nonhuman primates. The standard intramuscular formulation provides adequate plasma concentrations for 12 to 24 h, with waxing and waning levels associated with daily dosing. The oral formulation has limited utility in nonhuman primates because of low circulating levels of drug.

Figure 1.

The macaque (female) with the worst injection site reaction during the first round of meloxicam SR administration (SR1). (A) 1 h, (B) 4 h, and (C) 72 h after injection.

Figure 2.

Plasma concentration of meloxicam after single injections of 2 meloxicam SR formulations (SR1 [red] and SR2 [blue]) and 3 consecutive daily intramuscular (black) and oral (gray) doses of meloxicam (0, 23, and 47 h). Plasma concentrations are reported for each sex (male, squares; female, triangles) individually and for all animals combined (lines with no symbols). All groups contained 3 male and 3 female macaques, except SR2 had 6 animals of each sex.

Figure 3.

Plasma concentration levels for intramuscular (top) and oral (bottom) meloxicam. Both formulations showed higher concentration levels in female (gray lines; n = 3) than male (black lines; n = 3) macaques. The oral formulation began to achieve a steady-state concentration over time, whereas the intramuscular formulation did not show this pattern. Both formulations rapidly declined following cessation of dosing.

Figure 4.

Plasma concentration of meloxicam SR1 (gray line; 3 female [triangles] and 3 male [squares] macaques) and SR2 (black line; 6 female and 6 male macaques) after a single subcutaneous dose. Initial concentrations were high but rapidly were metabolized to lower concentrations, leveling off to slow declines at approximately 48 to 72 h.

Figure 5.

Meloxicam plasma concentrations after a single dosage of meloxicam SR (SR1 [red] and SR2 [blue]), intramuscular [black], and oral [gray] formulations. The plasma concentrations are reported for each sex [female, triangles; male, squares) individually and for all animals combined. All groups contained 3 male and 3 female macaques, except SR2 had 6 animals of each sex.