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.
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.
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 (Cmax) 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
|1Subjects received 1x400 mg tablet under
fasted conditions (N=42)
2Subjects received 2x400 mg tablets under fasted conditions (N=59)
A randomized, two-way, crossover study was conducted in
42 healthy volunteers (31 males, 11 females) administered one 400 mg SKELAXIN
tablet under fasted conditions and following a standard high-fat breakfast.
Subjects ranged in age from 18 to 48 years (mean age = 23.5 ± 5.7 years).
Compared to fasted conditions, the presence of a high fat meal at the time of
drug administration increased C by 177.5% and increased AUC (AUC0-t, AUC∞)
by 123.5% and 115.4%, respectively. Time-to-peak concentration (Tmax) was also
delayed (4.3 h versus 3.3 h) and terminal half-life was decreased (2.4 h versus
9.0 h) under fed conditions compared to fasted.
In a second food effect study of similar design, two 400
mg SKELAXIN tablets (800 mg) were administered to healthy volunteers (N=59, 37
males, 22 females), ranging in age from 18-50 years (mean age = 25.6± 8.7
years). Compared to fasted conditions, the presence of a high fat meal at the
time of drug administration increased C by 193.6% and increased AUC (AUC0-t ,
AUC∞) by 146.4% and 142.2%, respectively. Time-to-peak concentration (Tmax)
was also delayed (4.9 h versus 3.0 h) and terminal half-life was decreased (4.2
h versus 8.0 h) under fed conditions compared to fasted conditions. Similar food
effect results were observed in the above study when one SKELAXIN 800 mg tablet
was administered in place of two SKELAXIN 400 mg tablets. The increase in
metaxalone exposure coinciding with a reduction in half-life may be attributed
to more complete absorption of metaxalone in the presence of a high fat meal
Figure 1: Mean (SD) Concentrations of Metaxalone
following an 800mg Dose under Fasted and Fed Conditions
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
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: Mean (%CV) Pharmacokinetic Parameters
Following Single Administration of Two 400 mg SKELAXIN Tablets (800 mg) under
Fasted and Fed Conditions
|25.6 ± 8.7
||39.3 ± 10.8
||71.5 ± 5.0
The effect of gender on the pharmacokinetics of
metaxalone was assessed in an open label study, in which 48 healthy adult
volunteers (24 males, 24 females) were administered two SKELAXIN 400 mg tablets
(800 mg) under fasted conditions. The bioavailability of metaxalone was
significantly higher in females compared to males as evidenced by Cmax (2115
ng/mL versus 1335 ng/mL) and AUC∞ (17884 ng·h/mL versus 10328 ng·h/mL).
The mean half-life was 11.1 hours in females and 7.6 hours in males. The apparent
volume of distribution of metaxalone was approximately 22% higher in males than
in females, but not significantly different when adjusted for body weight.
Similar findings were also seen when the previously described combined dataset
was used in the analysis.
The impact of hepatic and renal disease on the
pharmacokinetics of metaxalone has not been determined. In the absence of such information,
SKELAXIN should be used with caution in patients with hepatic and/or renal