CLINICAL PHARMACOLOGY
Cyclobenzaprine relieves skeletal muscle spasm of local origin without interfering with muscle function. Cyclobenzaprine has not been shown to be effective in muscle spasm due to central nervous system disease. In animal models, cyclobenzaprine reduced or abolished skeletal muscle hyperactivity. Animal studies indicate that cyclobenzaprine does not act at the neuromuscular junction or directly on skeletal muscle. Such studies show that cyclobenzaprine acts primarily within the central nervous system at the brain stem as opposed to the spinal cord level, although an overlapping action on the latter may contribute to its overall skeletal muscle relaxant activity. Evidence suggests that the net effect of cyclobenzaprine is a reduction of tonic somatic motor activity, influencing both gamma (γ) and alpha (alpha) motor systems. Pharmacological studies in animals demonstrated a similarity between the effects of cyclobenzaprine and the structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine caused slight to moderate increase in heart rate in animals.
Pharmacokinetics
Absorption
In a single-dose study comprised of healthy adult males (n=15), the dose adjusted ratios of the arithmetic means of AUC0-168 and AUC0-∞ indicated that exposure of the AMRIX 30 mg was about 16% and 10% higher than that of AMRIX 15 mg, respectively. The dose-adjusted ratios of the arithmetic means of Cmax indicated that the peak plasma concentration of AMRIX 30 mg was about 20% higher than that of AMRIX 15 mg. The half-lives and time to peak plasma cyclobenzaprine concentration were similar for both AMRIX 15 mg and 30 mg. These data are summarized below.
Table 1: Summary of Pharmacokinetic Parameters in Healthy Adult Subjects
| SD = standard deviation |
Parameter
Mean ± SD |
AMRIX 15 mg
(N=15) |
AMRIX 30 mg
(N=14) |
| AUC0-168 (ng•hr/mL) |
318.3 ± 114.7 |
736.6 ± 259.4 |
| AUC0-∞ (ng•hr/mL) |
354.1 ± 119.8 |
779.9 ± 277.6 |
| Cmax (ng/mL) |
8.3 ± 2.2 |
19.9 ± 5.9 |
| Tmax (hrs) |
8.1 ± 2.9 |
7.1 ± 1.6 |
| t1/2 (hrs) |
33.4 ± 10.3 |
32.0 ± 10.1 |
A food effect study conducted in healthy adult subjects (n=15) utilizing a single dose of AMRIX 30 mg demonstrated a statistically significant increase in bioavailability when AMRIX 30 mg was given with food relative to the fasted state. There was a 35% increase in peak plasma cyclobenzaprine concentration (Cmax) and a 20% increase in exposure (AUC0-168 and AUC0-∞) in the presence of food. No effect, however, was noted in Tlag, Tmax, or the shape of the mean plasma cyclobenzaprine concentration versus time profile. Cyclobenzaprine in plasma was first detectable in both the fed and fasted states at 1.5 hours.
In a multiple-dose study utilizing AMRIX 30 mg administered once daily for 7 days in a group of healthy adult volunteers (n=35) a 2.5-fold accumulation of plasma cyclobenzaprine levels was noted at steady-state.
Metabolism and Elimination
Cyclobenzaprine is extensively metabolized and is excreted primarily as glucuronides via the kidney. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine. Cyclobenzaprine has an elimination half-life of 32 hours (range 8-37 hours; n=18); plasma clearance is 0.7 L/min following single dose administration of AMRIX.
Special Populations
Elderly
Although there were no notable differences in Cmax or Tmax, cyclobenzaprine plasma AUC is increased by 40% and the plasma half-life of cyclobenzaprine is prolonged in elderly subjects greater than 65 years of age (50 hours) after dosing with AMRIX compared to younger subjects (32 hours). Pharmacokinetic characteristics of cyclobenzaprine following multiple-dose administration of AMRIX in the elderly were not evaluated.
Table 2: Summary of Pharmacokinetic Parameters of AMRIX 30 mg Extended-Release Capsules, By Age Group
| * Measured over the entire 24 hour period |
| SD = standard deviation |
| Parameter Mean ± SD |
AMRIX 30 mg QD |
18 to 45 years
(N=18) |
65 to 75 years
(N=17) |
| AUC0-168 (ng•hr/mL) |
715.1 ± 264.2 |
945.9 ± 255.2 |
| AUC0-∞ (ng•hr/mL) |
751.2 ± 271.5 |
1055.2 ± 301.9 |
| Cmax (ng/mL)* |
19.2 ± 5.6 |
19.2 ± 5.1 |
| Tmax (hrs)* |
6.8 ± 1.9 |
8.5 ± 2.3 |
| t1/2 (hrs) |
32.4 ± 8.1 |
49.0 ± 8.3 |
Hepatic Impairment
In a pharmacokinetic study of immediate-release cyclobenzaprine in 16 subjects with hepatic impairment (15 mild, 1 moderate per Child-Pugh score), both AUC and Cmax were approximately double the values seen in the healthy control group. The pharmacokinetics of cyclobenzaprine in subjects with severe hepatic impairment is not known.
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