Sertraline

Absorption

Absorption
Following oral once-daily sertraline hydrochloride dosing over the range of 50 mg to 200 mg for 14 days, mean peak plasma concentrations (C
max) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation up to steady-state concentrations, which are achieved after one week of once- daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the C
maxand area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 mg to 200 mg. The single dose bioavailability of sertraline hydrochloride tablets is approximately equal to an equivalent dose of sertraline hydrochloride oral solution. Administration with food causes a small increase in C
maxand AUC.
Metabolism
Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both
in vitrobiochemical and
in vivopharmacological 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. 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 urine in 9 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 feces, including 12 to 14% unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0 to 24-hour), C
maxand C
min, with about a 5- to 9-fold increase in these pharmacokinetic parameters between day 1 and day 14.
Protein Binding
In vitroprotein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 ng to 500 ng/mL. However, at up to 300 ng and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, warfarin and propranolol.
Studies in Specific Populations
Pediatric Patients
Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6 to 12 years, 32 aged 13 to 17 years) including both males (N=28) and females (N=33). Relative to the adults, pediatric patients aged 6 to 12 years and 13 to 17 years showed about 22% lower AUC (0 to 24 hr) and C
maxvalues when plasma concentration was adjusted for weight. The half-life was similar to that in adults, and no gender-associated differences were observed
[See Dosage and Administration (2.1),
Use in Specific Populations (8.4)]
.
Geriatric Patients
Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated with 100 mg/day of sertraline hydrochloride for 14 days was approximately 40% lower than in a similarly studied group of younger (25 to 32 year old) individuals. Steady-state, therefore, was achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females
[See
Use in Specific Populations (8.5)]
.
Hepatic Impairment
In patients with chronic mild liver impairment (N=10: 8 patients with Child-Pugh scores of 5 to 6; and 2 patients with Child-Pugh scores of 7 to 8) who received 50 mg of sertraline hydrochloride per day for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with normal hepatic function (N=10). The exposure to desmethylsertraline was …