Pharmacology: Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI) antidepressant. Its mechanism of action is presumed to be linked to its inhibition of the central nervous system (CNS) neuronal uptake of serotonin (5HT). At clinical doses, sertraline blocks the uptake of serotonin into human platelets.
In vitro studies in animals suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (α1, α2, β), cholinergic, gamma aminobutyric acid (GABA), dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular effects for other psychotropic drugs. The chronic use of sertraline was found in animals to downregulate brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of major depressive disorder (MDD). Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics: Sertraline exhibits dose proportional pharmacokinetics in the range of 50 to 200 mg. Its peak plasma concentration (Cmax) occurs between 4.5 to 8.4 hours after ingestion of 50 to 200 mg once a day for 14 days. The average terminal half-life (t1/2) of plasma sertraline is about 26 hours. Steady-state concentrations of sertraline are achieved after approximately one week of once-a-day dosing. Consistent with the terminal elimination t1/2, there is an approximately two-fold accumulation, compared to a single dose, with repeated sertraline dosing over a 50 to 200 mg dose range. Sertraline's area under the curve (AUC) was slightly increased when sertraline was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from eight hours post-dosing to 5.5 hours.
Approximately 98% of the circulating drug is bound to plasma proteins. Animal studies showed that sertraline has a large apparent volume of distribution.
Sertraline undergoes extensive first-pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination t1/2 of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. Desmethylsertraline exhibits time-related, dose-dependent increases in AUC (0-24 hour), Cmax and Cmin, with about a 5 to 9 fold increase in these pharmacokinetic parameters between day 1 and day 14.
In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40 to 45% of the administered radioactivity was recovered in the urine in nine days; unchanged sertraline was not detectable in the urine. For the same period, about 40 to 45% of the administered radioactivity was accounted for in the feces, including 12 to 14% unchanged sertraline.
Special Population: Hepatic Impairment: Sertraline's clearance was reduced in patients with chronic mild liver impairment (Child-Pugh score of 5 to 6 and 7 to 8) who received 50 mg per day of sertraline for 21 days, resulting in approximately 3-fold greater exposure compared with age-matched volunteers with no hepatic impairment; the exposure to desmethylsertraline was approximately 2-fold greater. No significant differences in plasma protein binding were observed between the two groups. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. A lower or less frequent dose should be used in patients with liver impairment.
Renal Impairment: In patients with mild to moderate (CLcr = 30 to 60 mL/min), moderate to severe (CLcr= 10 to 29 mL/min) or severe (receiving hemodialysis) renal impairment, the pharmacokinetics and protein binding of sertraline 200 mg per day for 21 days were not altered compared with age-matched patients with no renal impairment. Sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment.
Age: Sertraline's plasma clearance is about 40% lower in elderly patients compared with younger individuals. Decreased desmethylsertraline clearance is seen in older males but not in older females.
Children: The pharmacokinetics of sertraline was evaluated in children with a DSM-III-R diagnosis of MDD or obsessive-compulsive disorder. During 42 days of chronic sertraline dosing, sertraline was titrated up to 200 mg per day and maintained at that dose for a minimum of 11 days. On the final day of sertraline 200 mg per day, mean sertraline AUC0-24hr, mean Cmax, and mean t1/2 were 3,107 ng.hr/mL, 165 ng/mL, 26.2 hours, respectively, in patients 6 to 12 years old. The 13 to 17 years old group exhibited a mean sertraline AUC0-24hr of 2,296 ng.hr/mL, mean Cmax of 123 ng/mL, and mean t1/2 of 27.8 hours. The higher plasma levels in the 6 to 12 years old group were largely attributable to patients with lower body weights. No gender-associated differences were observed. Both the 6 to 12 years old and 13 to 17 years old showed 22% lower AUC0-24hr and Cmax values when plasma concentration was adjusted for weight relative to adults. Reduced doses may be advisable for pediatric patients (particularly very young patients) given their lower body weights in order to avoid excessive plasma levels.