d 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).
Graph1
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
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& |
