CLINICAL PHARMACOLOGY
Pharmacodynamics
Cevimeline is a cholinergic agonist which binds to muscarinic
receptors. Muscarinic agonists in sufficient dosage can increase secretion of
exocrine glands, such as salivary and sweat glands and increase tone of the
smooth muscle in the gastrointestinal and urinary tracts.
Pharmacokinetics
Absorption: After administration of a single 30 mg capsule,
cevimeline was rapidly absorbed with a mean time to peak concentration of 1.5 to
2 hours. No accumulation of active drug or its metabolites was observed
following multiple dose administration. When administered with food, there is a
decrease in the rate of absorption, with a fasting TMAX
of 1.53 hours and a TMAX of 2.86 hours after a meal; the
peak concentration is reduced by 17.3%. Single oral doses across the clinical
dose range are dose proportional.
Distribution: Cevimeline has a volume of distribution of approximately 6L/kg
and is less than 20% bound to human plasma proteins. This suggests that cevimeline is
extensively bound to tissues; however, the specific binding sites are
unknown.
Metabolism: Isozymes CYP2D6 and CYP3A3/4 are responsible for the metabolism
of cevimeline. After 24 hours, 86.7% of the dose was recovered (16.0% unchanged,
44.5% as cis and trans-sulfoxide, 22.3% of the dose as glucuronic acid conjugate
and 4% of the dose as N-oxide of cevimeline). Approximately 8% of the
trans-sulfoxide metabolite is then converted into the corresponding glucuronic
acid conjugate and eliminated. Cevimeline did not inhibit cytochrome P450
isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4.
Excretion: The mean half-life of cevimeline is 5+/-1 hours. After 24 hours,
84% of a 30 mg dose of cevimeline was excreted in urine. After seven days, 97%
of the dose was recovered in the urine and 0.5% was recovered in the feces.
Special Populations: The effects of renal impairment, hepatic impairment, or
ethnicity on the pharmacokinetics of cevimeline have not been
investigated.
Clinical Studies
Cevimeline has been shown to improve the symptoms of dry mouth in
patients with Sjögren’s Syndrome.
A 6-week, randomized, double blind, placebo-controlled study was conducted in
75 patients (10 men, 65 women) with a mean age of 53.6 years (range 33-75). The
racial distribution was Caucasian 92%, Black 1% and other 7%. The effects of
cevimeline at 30 mg tid (90 mg/day) and 60 mg tid (180 mg/day) were compared to
those of placebo. Patients were evaluated by a measure called global
improvement, which is defined as a response of “better” to the question, “Please
rate the overall condition of your dry mouth now compared with how you felt
before starting treatment in this study.” Patients also had the option of
selecting “worse” or “no change” as answers. Seventy-six percent of the patients
in the 30 mg tid group reported a global improvement in their dry mouth symptoms
compared to 35% of the patients in the placebo group. This difference was
statistically significant at p=0.0043. There was no evidence that patients in
the 60 mg tid group had better global evaluation scores than the patients in the
30 mg tid group.
A 12-week, randomized, double-blind, placebo-controlled study was conducted
in 197 patients (10 men, 187 women) with a mean age of 54.5 years (range 23-74).
The racial distribution was Caucasian 91.4%, Black 3% and other 5.6%. The
effects of cevimeline at 15 mg tid (45 mg/day) and 30 mg tid (90 mg/day) were
compared to those of placebo. Statistically significant global improvement in
the symptoms of dry mouth (p=0.0004) was seen for the 30 mg tid group compared
to placebo, but not for the 15 mg group compared to placebo. Salivary flow
showed statistically significant increases at both doses of cevimeline during
the study compared to placebo.
A second 12-week, randomized, double-blind, placebo-controlled study was
conducted in 212 patients (11 men, 201 women) with a mean age of 55.3 years
(range 24-75). The racial distribution was Caucasian 88.7%, Black 1.9% and other
9.4%. The effects of cevimeline at 15 mg tid (45 mg/day) and 30 mg tid (90
mg/day) were compared to those of placebo. No statistically significant
differences were noted in the patient global evaluations. However, there was a
higher placebo response rate in this study compared to the aforementioned
studies. The 30 mg tid group showed a statistically significant increase in
salivary flow from pre-dose to post-dose compared to placebo (p=0.0017).
|