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 (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 ParametersDose (mg)
| Cmax (ng/mL)
| Tmax (h)
| AUC∞ (ng•h/mL) | t½(h) | CL/F(L/h) |
4001
| 983 (53)
| 3.3 (35)
| 7479 (51)
| 9.0 (53)
| 68 (50)
|
8002
| 1816 (43)
| 3.0 (39)
| 15044 (46)
| 8.0 (58)
| 66 (51)
|
1Subjects received 1x400 mg tablet under fasted conditions (N=42)
2Subjects received 2x400 mg tablet under fasted conditions (N=59)
Food Effects
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 Cmax 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 Cmax 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).
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.
Pharmacokinetics in Special PopulationsAge:
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 |
| Cmax (ng/mL) | 1816
(43) | 3510
(41) | 2719
(46) | 2915
(55) | 3168
(43) | 3680
(59) |
| Tmax (h) | 3.0
(39) | 4.9
(48) | 3.0
(40) | 8.7
(91) | 2.6
(30) | 6.5
(67) |
| AUC0-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) |
Gender:
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.
Hepatic/Renal Insufficiency:
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
impairment.
