SKELAXIN

SKELAXIN- metaxalone tablet
Blenheim Pharmacal, Inc.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber.

Pharmacokinetics

The pharmacokinetics of metaxalone have been evaluated in healthy adult volunteers after single dose administration of SKELAXIN under fasted and fed conditions at doses ranging from 400 mg to 800 mg.

Absorption

Peak plasma concentrations of metaxalone occur approximately 3 hours after a 400 mg oral dose under fasted conditions. Thereafter, metaxalone concentrations decline log-linearly with a terminal half-life of 9.0 ± 4.8 hours. Doubling the dose of SKELAXIN from 400 mg to 800 mg results in a roughly proportional increase in metaxalone exposure as indicated by peak plasma concentrations (C max ) and area under the curve (AUC). Dose proportionality at doses above 800 mg has not been studied. The absolute bioavailability of metaxalone is not known.

The single-dose pharmacokinetic parameters of metaxalone in two groups of healthy volunteers are shown in Table 1.

Table 1: Mean (%CV) Metaxalone Pharmacokinetic Parameters
Dose (mg) C max (ng/mL) T max (h) AUC (ng•h/mL) t ½ (h) CL/F (L/h)
400 1 983 (53) 3.3 (35) 7479 (51) 9.0 (53) 68 (50)
800 2 1816 (43) 3.0 (39) 15044 (46) 8.0 (58) 66 (51)
1 Subjects received 1×400 mg tablet under fasted conditions (N=42)

2 Subjects received 2×400 mg tablets under fasted conditions (N=59)

Distribution, Metabolism, and Excretion

Although plasma protein binding and absolute bioavailability of metaxalone are not known, the apparent volume of distribution (V/F ~ 800 L) and lipophilicity (log P = 2.42) of metaxalone suggest that the drug is extensively distributed in the tissues. Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites. Hepatic Cytochrome P450 enzymes play a role in the metabolism of metaxalone. Specifically, CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19 appear to metabolize metaxalone.

Metaxalone does not significantly inhibit major CYP enzymes such as CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Metaxalone does not significantly induce major CYP enzymes such as CYP1A2, CYP2B6, and CYP3A4 in vitro.

Pharmacokinetics in Special Populations

Age:

The effects of age on the pharmacokinetics of metaxalone were determined following single administration of two 400 mg tablets (800 mg) under fasted and fed conditions. The results were analyzed separately, as well as in combination with the results from three other studies. Using the combined data, the results indicate that the pharmacokinetics of metaxalone are significantly more affected by age under fasted conditions than under fed conditions, with bioavailability under fasted conditions increasing with age.

The bioavailability of metaxalone under fasted and fed conditions in three groups of healthy volunteers of varying age is shown in Table 2.

Table 2: Mean (%CV) Pharmacokinetic Parameters Following Single Administration of Two 400 mg SKELAXIN Tablets (800 mg) under Fasted and Fed Conditions
Younger Volunteers Older Volunteers
Age (years) 25.6 ± 8.7 39.3 ± 10.8 71.5 ± 5.0
N 59 21 23
Food Fasted Fed Fasted Fed Fasted Fed
C max (ng/mL) 1816 (43) 3510 (41) 2719 (46) 2915 (55) 3168 (43) 3680 (59)
T max (h) 3.0 (39) 4.9 (48) 3.0 (40) 8.7 (91) 2.6 (30) 6.5 (67)
AUC 0-t (ng∙h/mL) 14531 (47) 20683 (41) 19836 (40) 20482 (37) 23797 (45) 24340 (48)
AUC (ng∙h/mL) 15045 (46) 20833 (41) 20490 (39) 20815 (37) 24194 (44) 24704 (47)
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