Metaxalone

Absorption

Metaxalone pharmacokinetics were evaluated in two groups of healthy volunteers that received a single oral dose of 800 mg of metaxalone or 400 mg of metaxalone (0.5 times the approved recommended dose) [the 400 mg strength of metaxalone is not currently marketed by Lannett Company, Inc.]. Metaxalone pharmacokinetic parameters are presented below as mean (% CV) unless otherwise specified. Observed metaxalone peak plasma concentrations (Cmax) and area under the curve (AUC) are shown in Table 1. Doubling the dose of metaxalone from 400 mg (0.5 times the approved recommended dose) to 800 mg resulted in a proportional increase in metaxalone Cmax and AUC.
Table 1: Metaxalone Exposure after a Single-Dose of Metaxalone Under Fasting Conditions
Dose
Cmax
2
AUC∞
2
400 mg1
983 (53) ng/mL
7,479 (51) ng•h/mL
800 mg
1,816 (43) ng/mL
15,044 (46) ng•h/mL
1 0.5 times the approved recommended dose
2 Mean (% CV)
Absorption
The absolute bioavailability of metaxalone is not known. Peak plasma metaxalone concentrations occurred at a mean Tmax of 3.3 hours (1.5 – 5 hours) of metaxalone under fasted conditions.
The single-dose pharmacokinetic parameters of metaxalone in two groups of healthy volunteers who received 400 mg or 800 mg of metaxalone are shown in Table 1.
Effect of Food: Peak plasma metaxalone concentrations were noted at a mean Tmax of 4.3 hours (1.5 – 12 hours) under fed conditions. The mean Tmax under fasting and fed conditions was 3.3 and 4.3 hours, respectively. Metaxalone exposure was increased and the half-life (t1/2) was decreased following metaxalone administration with a high fat meal as shown in Table 2. 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.
Table 2: Relative Changes in Metaxalone Exposure, Tmax, and t1/2 Following Metaxalone Administration with a High Fat Meal Compared to Fasting
Dose
(mg)
Cmax
(ng/mL)
AUC0-t
(ng•h/mL)
AUC0-INF
(ng∙h/mL)
Tmax
(hrs)
t1/2
(hrs)
400 mg*
↑ 78%
↑ 24%
↑ 15%
↑ 30%
↓ 73%
800 mg
↑ 94%
↑ 46%
↑ 42%
↑ 63%
↓ 48%
* 0.5 times the approved recommended dose.
Distribution
Metaxalone apparent volume of distribution is approximately 800 Liters; however, plasma protein binding is unknown.
Elimination
Metaxalone mean ± SD terminal t1/2 is 9 ± 4.8 hours and apparent clearance is approximately 67 ± 34 L/h under fasted conditions.
Metabolism: Metaxalone is primarily metabolized by CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19.
Excretion: Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites.
Specific Populations
The effect of renal impairment and hepatic impairment on metaxalone pharmacokinetics is unknown [see Use in Specific Populations (8.6, 8.7)].
Geriatric Patients: The effects of age on the pharmacokinetics of metaxalone were determined following administration of 800 mg of metaxalone under fasted and fed conditions. Age had a significantly greater effect on metaxalone pharmacokinetics under fasted conditions than under fed conditions. Bioavailability under fasted conditions increased with age. Metaxalone bioavailability under fasted and fed conditions in the three groups of healthy volunteers of varying age is shown in Table 3.
Table 3: Metaxalone Pharmacokinetic Parameters under Fasted and Fed Conditions in Three Age Groups Following Oral Administration of 800 mg of Metaxalone
Mean Age in Years
(± SD)
26 ± 9 Years Old
39 ± 11 Years Old
72 ± 5 Years Old
Fasted vs. Fed State
Fasted
Fed
Fasted
Fed
Fasted
Fed
Cmax (ng/mL)1
1816 (43)
3510 (41)
2719 (46)
2915 (55)
3168 (43)
3680 (59)
Tmax (hours)1
3 (39)
4.9 (4.8)
3 (40)
8.7 (91)
2.6 (30)
6.5 (67)
AUC0-t (ng∙h/mL)1
14531 (47)
20683 (41)
19836 (40)
20482 (37)
23797 (45)
24340 (48)
AUC∞ (ng∙h/mL)1
15045 (46)
20833 (41)
20490 (39)
20815 (37)
24194 (44)
24704 (47)
1 Mean values (% CV)
Male and Female Patients: T …