Sertraline Pharmacokinetics and Dynamics in Adolescents

DAVID A. AXELSON, M.D., JAMES M. PEREL, PH.D., BORIS BIRMAHER, M.D., GEORGE R. RUDOLPH, B.S., SHARON NUSS, R.N., JEFFREY BRIDGE, PH.D., AND DAVID A. BRENT, M.D.

ABSTRACT Objective: To determine the pharmacokinetics of sertraline in adolescents and assess its effect on a surrogate marker of serotonin transport. Method: Pharmacokinetic parameters of a single 50-mg dose of sertraline were determined in 10 adolescents. Steady-state withdrawal kinetics were determined in 12 adolescents taking 50 mg/day and in 6 adolescents taking 100 to 150 mg/day.Platelet serotonin reuptake was measured before and after 2 weeks of daily 50mg dosing. Results: The mean steady-state half-life of 50 mg was significantly shorter (15.3 3.5 hours) than the single-dose half-life (26.7 5.2 hours; t = 6.4, p < .001) and the steady-state half-life at 100 to 150 mg/day (20.4 3.4 hours; t = 2.9, p = .01). Platelet serotonin reuptake was inhibited by 61 15% after approximately 2 weeks of sertraline 50 mg/day. Conclusions: The half-life of sertraline 50 mg becomes significantly shorter from the initial dose to steadystate, and many adolescents may benefit from twice-per-day dosing. The steady-state half-life increases as the dose increases. The moderate levels of platelet reuptake inhibition at 50 mg/day indicate that most adolescents may need sertraline doses higher than 50 mg/day to attain a therapeutic response. J.Am.Acad.Child Adolesc.Psychiatry, 2002, 41(9):10371044.

There is growing evidence from randomized controlled trials that selective serotonin reuptake inhibitors (SSRIs) have efficacy in treating pediatric depression (Emslie et al., 1997; Keller et al., 2001), anxiety disorders (Research Unit on Pediatric Psychopharmacology Anxiety Study Group, 2001), and obsessive-compulsive disorder (March et al., 1998). Use of SSRIs in the pediatric population has exploded recently, with 600,000 children and adolescents prescribed SSRIs in 1996 and SSRI prescriptions to children and adolescents increasing by 74% from 1995 to 1999 (IMS America, cited by Strauch, 1997). Early in the development of a new medication, the manner in which the body absorbs, distributes, metabolizes,

Key Words: pharmacokinetics, adolescents, platelets, sertraline, serotonin. DOI: 10.1097/01.CHI.0000020266.43550.FE

Accepted April 9, 2002. From the University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh. These data were presented in part at the American Society for Clinical Pharmacology and Therapeutics Annual Meeting, March 2000. This work was supported by NIMH grants MH-18591 and MH-55123 (PI: Dr. Brent), MH-70008 (PI: Dr. Birmaher), MH-30915 (Core PI: Dr. Perel), and MH01878 (PI: Dr. Axelson). Correspondence to Dr. Axelson, Western Psychiatric Institute and Clinic, 3811 OHara Street, Pittsburgh, PA 15213; e-mail: axelsonda@msx.upmc.edu. 08908567/02/410910372002 by the American Academy of Child and Adolescent Psychiatry.

and excretes the compound (the pharmacokinetics) is determined in a group of healthy adults. These data are used to help determine dosing frequencyif a medication has a short half-life (time for an individual to metabolize half of the medication in the body), then it generally is given more frequently. Medications with half-lives of less than 20 hours are typically given more than once per day, to avoid large fluctuations in medication blood concentration. The popularity of SSRIs in children and adolescents developed despite the fact that there was little significant pharmacokinetic or pharmacodynamic information for SSRIs in pediatric populations. Knowledge of the kinetics and dynamics is necessary for appropriate design of drugdosage regimens, monitoring of treatment outcome, and optimal use with regard to both efficacy and safety (Branch, 1994). Sertraline was the first SSRI to have published pediatric pharmacokinetic data. The mean steady-state withdrawal half-life of sertraline at a dose of 200 mg/day in 29 children and 32 adolescents was 26.2 and 27.1 hours, respectively (Alderman et al., 1998). This is essentially the same as the 27-hour steady-state half-life at 200 mg/day found in adults (Ronfeld et al., 1997). However, 200 mg/day is not the usual starting dose of

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sertraline and it is 50 to 100 mg higher than the mean doses used in open titration studies for depression and obsessive-compulsive disorder (Ambrosini et al., 1999; Cook et al., 2001). Other pharmacokinetic studies of antidepressants in pediatric patients have generally shown that children and adolescents have shorter drug half-lives than adults. The singledose half-life of paroxetine in 24 children and adolescents was found to be 11.1 5.2 hours, compared with 21 hours in adults (Findling et al., 1999). The steady-state half-life of nefazodone at a dose of 100 mg b.i.d. (twice per day) was 4 hours in children and adolescents, compared with 7 hours in adults (Findling et al., 2000). Of note, the mean steady-state half-life of nefazodone was only 2.7 hours in children and adolescents at doses of 50 mg b.i.d., indicating that the half-life of nefazodone lengthened as the dose increased (Findling et al., 2000). Therefore, it is important to study the steady-state kinetics of a medication across the expected dose range. Sertraline and the other SSRIs are primarily metabolized by the hepatic cytochrome P450 (CYP450) system. Sertraline is metabolized to an inactive demethylated metabolitenorsertraline. Several of the CYP450 isozymes have been shown to have genetic polymorphisms that influence the activity of the enzyme. In addition, developmental or environmental factors may affect the activity of a particular CYP450 isoenzyme. Determining the relative activity of CYP450 isoenzymes through metabolic probes has been shown to be relevant in predicting SSRI levels in adults. Poor metabolizers of debrisoquin (a probe for 2D6 activity) showed significantly higher levels of fluoxetine and norfluoxetine (but not sertraline) compared with extensive metabolizers (Hamelin et al., 1996). In vitro studies using preparations of human liver microsomes predict that sertraline is likely to be metabolized by five different CYP isoenzymes (2C9, 3A, 2C19, 2B6, and 2D6) in humans, with no individual isozyme accounting for more than 20% to 40% of the overall metabolism (Greenblatt et al., 1999; Kobayashi et al., 1999). Whether the activity of various CYP isoenzymes is related to sertraline metabolism in children and adolescents has not been studied. Although the study of the kinetics of a medication is important, it is the pharmacodynamics (how the medication affects the individual) that is of ultimate relevance to the clinician and patient. Human platelets

have a serotonin reuptake pump that is identical with the one in serotonergic neurons (Lesch et al., 1993), so it can be used as a surrogate marker for the effect of SSRIs on serotonin neurons. Preskorn (1997) made the observation that at the usual recommended minimum therapeutic doses of SSRIs in adults (e.g., 20 mg of fluoxetine, 20 mg of paroxetine, 40 mg of citalopram, 150 mg of fluvoxamine, and 50 mg of sertraline), the mean reuptake inhibition of serotonin in patients platelets was 60% to 80%. Specifically for sertraline at 50 mg/day, the rate of inhibition was 76% (Preskorn and Harvey, 1996) and 80% (Preskorn and Lane, 1995) in two different studies. Data from Pfizer Pharmaceutical (cited by Preskorn and Lane, 1995) showed that the concentration of sertraline expected to result in 70% platelet serotonin reuptake inhibition was 15 ng/mL. We performed this study to determine the basic pharmacokinetic parameters of sertraline in adolescents at the usual starting dose of 50 mg. We examined the effects of 2 weeks of sertraline therapy at 50 mg/day on platelet serotonin reuptake inhibition and performed steady-state withdrawal pharmacokinetics. In addition, we examined whether there were any significant relations between sertraline kinetics and pretreatment CYP 2D6 and 3A activity as measured by the metabolic probe dextromethorphan (DEX). The results obtained from the 50-mg study led us to examine the steady-state pharmacokinetics of sertraline at higher doses (100150 mg) in an additional small group of subjects.
METHOD Subjects Subjects were adolescents who were referred to the study by their treating psychiatrist because they were about to start or were already taking sertraline for treatment of depression or anxiety. Informed consent was obtained prior to the start of study procedures. Subjects were included if they were younger than 18 years of age, were medically healthy, and it was clinically appropriate for the subject to receive sertraline monotherapy at a steady dose for at least 2 weeks. Potential subjects were excluded for any of the following reasons: anemia; past or current eating disorder; recent substance use disorder or a positive drug screen at study intake; significant cigarette smoking (more than 10 cigarettes per day); use of psychotropics or any medication likely to influence sertraline metabolism; and presence of a psychiatric condition that would preclude use of sertraline monotherapy for a 2-week period (e.g., current or past manic symptoms, psychosis, severe attentiondeficit/hyperactivity disorder, severe or psychotic depression). The study protocol was reviewed and approved by the University of Pittsburgh Institutional Review Board.

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CYP 2D6 and 3A Phenotyping Procedure After an intake interview, subjects took 30 mg of DEX. DEX has been safely and effectively used at a dose of 30 mg in two phenotyping trials of more than 500 children and adolescents (Evans et al., 1989; Relling et al., 1991). Subjects then collected their urine during a 4-hour period and a sample was taken for analysis. Subjects continued to collect their urine over a 24-hour period. The 4-hour urine samples were analyzed for the concentration of DEX and its metabolite dextrorphan (DET). The ratio of the molar concentrations of DEX to DET in the urine was calculated and CYP 2D6 metabolic activity was determined according to the guidelines described by Evans et al. (1989). The 24-hour samples were analyzed for the molar concentrations of DEX and its metabolite 3-methoxymorphinan (3-MM). CYP 3A activity was explored using the ratio of DEX/3-MM molar concentrations as described by Jones et al. (1996). Single-Dose Kinetics Phase Subjects arrived at the laboratory in the morning to have an intravenous (IV) line placed and a blood sample drawn to measure platelet serotonin reuptake. Between 8:45 and 10:15 A.M., the subjects took a 50-mg sertraline tablet; blood samples were drawn through the IV line at 1.5, 2.5, 3.5, 4.5, 6, 7.5, 8.5, 9.5, 11, and 12 hours after the sertraline dose. Subjects returned the next day for a blood draw from 26 to 34 hours after the sertraline dose. Steady-State Kinetics Phase Sertraline was dispensed in weekly pillboxes with individual compartments for each 50-mg dose. Subjects took 50 mg every morning for a period of 14 days (n = 9), 19 days (n = 2), or 36 days (n = 1). Subjects were instructed to leave any missed doses in the pillbox, and compliance was assessed via pill counts. The subjects returned to the laboratory in the morning and had an IV line placed and blood drawn to determine the trough sertraline concentration and platelet serotonin reuptake inhibition. Subjects took a 50-mg sertraline tablet between 8:45 and 10:15 A.M. and then had blood samples drawn at 1, 3, 4.5, 6, 7.5, 9, 10.5, 12, 13, and 28 to 34 hours after the dose. Six of the subjects stayed overnight and also had samples drawn at 17, 20, 22, and 24 hours after the dose. Higher Sertraline Doses A separate group of subjects taking sertraline 100 to 150 mg/day participated only in the steady-state kinetics phase. Subjects had to be taking either 100 mg or 150 mg of sertraline in a single daily dose for at least 2 weeks. The kinetics procedure for subjects taking sertraline 100 to 150 mg/day was identical with that for the subjects taking 50 mg. All subjects taking 100 to 150 mg stayed overnight and had samples drawn at 17, 20, 22, and 24 hours after the dose and returned for a draw 28 to 34 hours postdose. Procedure for Dextromethorphan and Metabolite Measurements DEX and DEX concentrations in urine were measured by the highperformance liquid chromatography (HPLC)/fluorescence method of Lam and Rodriguez (1993). The coefficients of variation (CVs) ranged from 2.0% to 7.0% for DEX and 1.1% to 2.1% for DET. 3MM was concurrently measured by HPLC/fluorescence as modified from Jones and colleagues (1996).

Procedure for Sertraline and Desmethylsertraline Measurements Concentrations of sertraline and its metabolite norsertraline were assayed with previously validated analytical methods using HPLC. The methods entailed solvent extraction from alkaline solution of 1-mL plasma samples, followed by back-extraction into dilute acid. With an automated sample processor, these extracts were injected onto a C-18 column and resolved with a phosphate buffer/acetonitrile mobile phase. The levels were determined with a variable-wavelength UV detector and automatic integration. The CVs ranged from 0.4% to 6.1% for sertraline and 1.1% to 5.9% for norsertraline, with a lower limit of quantitative detection of 1.5 ng/mL. Procedure for Platelet Serotonin Reuptake Assay The method of Tuomisto and colleagues (1979) was used, but modified by reducing the blood volume collected to 20 mL. The intrapatient CV of the assay based on nine standard concentrations of [3H]5-hydroxytryptamine (5-HT) per assay ranged from 9.1% to 14.6%. Determination of Pharmacokinetic and Pharmacodynamic Parameters Sertraline and norsertraline concentration versus time data were fit to one- and two-compartment first-order pharmacokinetic models with PKAnalyst version 1.1 (MicroMath, Inc.) and WinNonlin versions 1.5 and 3.1 (Scientific Consulting Inc./Pharsight). Secondary parameters were either provided by the program or calculated with standard formulas. All elimination phases were also studied with noncompartmental analysis, a mode of WinNonlin. The results of the three analyses were averaged to determine the final pharmacokinetic parameters. For the calculation of Vmax of 5-HT uptake into the platelet, the raw data (from a scintillation counter) was converted into V versus [5-HT] plot (9 points for each assay), which was fit to the MichaelisMenten equation by nonlinear regression using Enzfitter version 2.0.8 (Biosoft). Platelet 5-HT reuptake inhibition was determined by the change in Vmax from pre- to posttreatment. The percentage of platelet inhibition versus sertraline concentration was fit to a simple Emax model using the dynamics mode of WinNonlin. The concentrations of sertraline required to cause 70% and 80% inhibition (IC70 and IC80) were calculated from the fit. Statistical Comparisons All statistical comparisons were performed with SPSS-PC version 10.1. The distributions of the variables of interest were examined with the Shapiro-Wilks test, and variables were logtransformed if necessary to achieve normality. The primary analysis examined the following sertraline pharmacokinetic parameters: half-life, maximum concentration (Cmax), and the area-under-thecurve of the concentration versus time plot for a 24-hour postdose period (AUC24). Differences between single-dose and steady-state kinetics at 50 mg/day were examined within subjects by using a paired t test. Our sample size allowed us to detect only associations of large effect size between pharmacokinetic parameters, CYP activity, and demographic variables; therefore, these analyses were strictly exploratory in nature. Associations between sertraline pharmacokinetic parameters at 50 mg/day (single-dose and steadystate) and CYP activity, age, weight, and body mass index (BMI) were explored with Pearsons correlation analysis. Our findings

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from the 50-mg study led us to run another steady-state phase with an additional group of subjects taking intermediate sertraline doses (100150 mg/day). Comparison of sertraline steady-state kinetics in the 50-mg and 100- to 150-mg groups was performed by using t tests. RESULTS Subject Characteristics

A total of 19 subjects participated in the study. Thirteen subjects participated in the 50-mg dose protocol. Six additional subjects who were taking 100 to 150 mg/day participated in the steady-state withdrawal kinetic phase. Of the 13 subjects in the 50-mg protocol, 5 were male and 8 were female. Nine subjects were white and four were African American. Subject ages ranged from 13.1 to 17.7 years (mean SD = 15.2 1.5 years). One subject was Tanner stage 3, one subject did not participate in Tanner staging, and the remaining subjects were Tanner stages 4 or 5. Subject weights ranged from 45.7 to 92.4 kg (61.8 13.1 kg), and mean BMI was 22.6 4.7. Three subjects smoked up to 10 cigarettes per day. One subject took concomitant loratadine (Claritin) and used an albuterol inhaler during the study, and one subject took levothyroxine

supplementation and was euthyroid at the time of study. No subjects who completed the steady-state kinetic procedure missed more than two doses during the protocol, and all doses were taken in the 3 days prior to the procedure. One subject dropped out after the single-dose phase. Technical difficulties with blood sampling prevented determination of complete singledose kinetics for two subjects. Six additional subjects (four male, two female) who were taking 100 or 150 mg of sertraline participated in the steady-state withdrawal kinetic phase. The mean age of these subjects was 15.1 1.7 years. Two subjects were white, two were African American, and two were Latino. These subjects did not have CYP phenotyping, 50-mg kinetics, or determination of platelet reuptake inhibition.
Single-Dose Pharmacokinetics

The mean half-life of sertraline after the initial 50mg dose was 26.7 5.2 hours (n = 11; see Table 1).The mean peak sertraline concentration was 15.1 7.5 ng/mL (Cmax) and the AUC24 was 198 97 nghr/mL.
Steady-State Pharmacokinetics at 50 mg/day

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The mean half-life of sertraline after approximately 2 weeks of taking 50 mg every morning was 15.3 3.5 hours (n = 12; see Table 1). In subjects who had both single-dose and steady-state kinetics, the steady-state half-life was sigTABLE 1 Steady-State Weight (kg) 64.0 83.6 56.7 45.7 54.1 59.5 57.5 58.0 58.3 59.2 92.4 53.1 68.2 62.3 (12.7) 5 2 5 4 5 5 55.1 44.2 63.4 55.4 93.3 63.4 62.5 (16.7) t1/2 29.2 33.8 23.1 27.2 32.8 28.3 25.4 27.2 23.5 14.6 28.9 26.7 (5.2) Single-Dose Cmax 9.1 7.6 30.1 10.5 29.6 18.4 14.9 7.4 16.8 10.4 13.5 11.0 17.6 15.1 (7.5) AUC24 111 437 161 212 293 234 110 117 160 174 164 198 (97) Platelet 5-HT Inhibition Sertraline Pharmacokinetics and Dynamics: All Subjects t1/2 13.7 15.2 17.4 15.8 24.2 14.5 17.5 11.8 13.6 11.4 16.3 12.4 15.3 (3.5) 15.4 17.8 20.6 22.5 25.1 20.8 20.4 (3.4) Cmax 20.6 13.7 57.4 22.0 24.2 34.1 16.9 22.3 19.7 11.6 14.4 23.5 23.4 (12.3) 43.6 100 61.1 96.6 88.0 90.1 70.9 (22.5) Cmin 10.1 5.9 31.6 9.5 14.7 19.4 8.0 12.7 8.6 3.8 6.3 9.3 11.7 (7.5) 20.3 48.9 34.5 57.0 57.3 51.9 45.0 (14.7) AUC24 314 158 1002 360 432 598 299 416 325 174 245 394 393 (226) 710 1580 1085 1637 1649 1681 1390 (401) (%) 52 63 73 62 33 87 55 71 55 61 (15)

Sertraline Dose (mg) 50 mg qA.M. 50 50 50 50 50 50 50 50 50 50 50 50 50 Mean (SD) 100150 mg qA.M. 100 100 100 150 150 150 Mean (SD) F M M M M F Sex F M F M F M M F F F F F M

Demographics Age Tanner (yr) 14.0 13.3 14.9 15.3 15.4 15.1 13.1 16.4 17.1 16.6 13.5 17.7 15.1 15.2 (1.5) 16.4 13.9 14.7 13.6 14.3 17.9 15.1 (1.7) Stage 5 3 45 45 5 4 4 5 45 45 45 4

Note: 5-HT = 5-hydroxytryptamine.

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Fig.1 Sertraline half-life at 50 mg: single-dose versus steady-state. ***Singledose > steady-state, p < .001.

nificantly shorter than the single-dose half-life (t9 = 6.3, p < .001; see Fig. 1). The mean trough sertraline concentration (Cmin) was 11.7 7.5 ng/mL, the mean Cmax was 23.4 12.3 ng/mL, and the mean sertraline AUC24 was 393 226 ng/mLhr. (See Fig. 2 for mean sertraline concentrations over the 30-hour sampling period.) The mean Cmin of the desmethyl metabolite (norsertraline) was 27.4 14.9 ng/mL, and the mean norsertraline Cmax was 33.5 ng/mL. The AUC24 for norsertraline was 611 126 ng/mLhr. The mean ratio of the AUC24 for norsertraline to sertraline was 1.89 0.23.
Steady-State Kinetics at 100 to 150 mg/day

taking 50 mg. Sertraline clearance was significantly higher in the subjects taking 50 mg than in those taking 100 to 150 mg (2.5 0.9 versus 1.6 0.5 L/hr/kg; t16 = 2.3, p = .03). The mean ratio of the norsertraline to sertraline AUC24 for the subjects taking 100 to 150 mg was significantly lower than for the subjects taking 50 mg (1.39 0.45 versus 1.89 0.23; t12 = 2.8, p = .02).
Platelet 5-HT Reuptake

Fig.3 Sertraline steady-state half-life across the dose range. **100150 mg/

The mean steady-state half-life in the six subjects taking intermediate sertraline doses was significantly higher than that in the subjects taking 50 mg (20.4 3.4 hours versus 15.3 3.5 hours; t16 = 2.9, p = .01; see Table 1 and Fig. 3). Mean Cmax, Cmin, and AUC24 for sertraline and

One subject had an extremely low baseline Vmax, so there was little room for change with treatment and a high uncertainty in the platelet serotonin reuptake inhibition. Therefore, this subject was dropped from the analysis. Platelet uptake of serotonin after 2 weeks of treatment with sertraline 50 mg/day was a mean 61 15% less than at baseline. Six of the nine subjects with platelet data had less than 70% reuptake inhibition. Pharmacokinetic/ pharmacodynamic modeling examining the relation of trough sertraline concentration at steady-state and platelet serotonin reuptake inhibition showed that the IC50 (trough concentration necessary to cause 50% inhibition of platelet serotonin reuptake) was 6.2 ng/mL. The IC70 was 14.4 ng/mL, and the IC80 was 24.7 ng/mL.
Exploratory Analyses: CYP Phenotyping and Demographic Factors

Fig. 2 Mean concentrations of sertraline 50 mg/day at steady-state. day > 50 mg/day, p = .01. Results from Alderman et al. (1998) for comparison.

norsertraline were all significantly higher in the subjects taking 100 to 150 mg compared with those

As noted above, the study was not powered to detect anything but large associations between sertraline pharmacokinetic parameters (half-life, Cmax, or AUC24) and demographic factors or CYP 2D6 activity. All of the 50mg phase subjects (n = 13) were extensive metabolizers for CYP 2D6. The mean molar urinary metabolic ratio of DEX/DET was 0.014 0.028 (range, 0.00080.0829); this was far below the usual cutoff of 0.3 used to differentiate extensive from poor metabolizers. The concentration of 3-MM in the 24-hour urine collection was quantifiable for only four subjects. Therefore, we could not perform any analyses relating to CYP 3A activity. There were no statistically significant associations between CYP 2D6 activity and 50-mg single-dose sertraline pharmacokinetic parameters (r < 0.42, p > .20 for all comparisons) or

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50-mg parameters at steady-state (r < 0.34, p > .31 for all comparisons). There were no statistically significant associations between 50-mg single-dose pharmacokinetic parameters and age, weight, or BMI. The strongest potential correlation existed between BMI and singledose half-life (r = 0.48); no other associations were greater than r = 0.40. Associations between weight and 50-mg steady-state pharmacokinetic parameters ranged from r = 0.47 (half-life) to r = 0.56 (AUC24), though p > .05 for all comparisons. Associations between BMI and 50-mg steady-state parameters ranged from r = 0.38 (half-life) to r = 0.61 (AUC24). None of these had an uncorrected p < .05 except AUC24 (p = .04); this is not significant after correcting for multiple comparisons. Inspection of the data did not reveal any clinically relevant differences in 50-mg steadystate parameters between males and females (e.g., halflife for males = 14.5 1.5 hours versus females = 15.7 4.2 hours) or due to racial background (half-life for African Americans = 17.7 6.4 versus whites = 14.5 1.9). No clinically relevant differences due to sex or race were seen in the 50-mg single-dose parameters.
DISCUSSION

In summary, the plasma half-life of sertraline 50 mg in adolescents significantly changes from a mean of 26.7 hours after the initial dose, to a mean of 15.3 hours at steady-state. The steady-state half-life at 50 mg/day is significantly shorter than at intermediate doses of 100 to 150 mg/day (mean = 20.4 hours). After a stable dose of 50 mg/day over a 2-week period, the rate of platelet 5-HT reuptake was reduced a mean of 61%, with six of nine subjects exhibiting less than 70% reuptake inhibition.
Limitations

The results of this study must be viewed in the context of the following limitations. The number of subjects, though typical for a pharmacokinetic study, was too small to allow for meaningful assessment of the relation of sertraline kinetics to demographic variables or CYP 2D6 activity. Several potential associations between sertraline kinetics and demographic factors (i.e., weight and BMI) may be significant in future studies with larger sample sizes. We did not phenotype for CYP 2C9 or 2C19 and

could not successfully phenotype for CYP 3A. The absence of Asian subjects and the relatively small number of Latino subjects is a limitation. There were no prepubertal subjects, so we could not assess for potential effects of pubertal development. One potential criticism is that we did not measure plasma levels beyond 34 hours after withdrawal of sertraline. This was done in part for ethical reasons, as it may not be appropriate to withhold a potentially therapeutic medication from a subject for an extended period of time. Because we had many samples taken at least 6 hours after the dose and our final point during steadystate was generally two half-lives after the dose, we had more than enough measurements in the elimination phase to construct accurate kinetic curves. Finally, the small sample size precluded any examination of platelet reuptake data and pharmacokinetic parameters. The results of the single-dose kinetics were not surprising: the 26- to 27-hour half-life was consistent with prior published values for adults. However, the steady-state halflife of sertraline 50 mg/day was substantially shorter than that found in other studies of adolescents at 200 mg/day (27.1 8.2 hours; Alderman et al., 1998) or young adults at 200 mg/day (27.2 hours; Ronfeld etal., 1997). The halflife at 100 to 150 mg/day was in between the results for 50 mg and 200 mg. In addition, the ratio of the AUC24 of the norsertraline metabolite to sertraline also decreased as the dose increased. The AUC24 ratio of metabolite to parent compound reveals the relative concentration of the metabolite to the parent drug over the day. The norsertraline AUC24/sertraline AUC24 was significantly lower in the subjects who received 100 to 150 mg than those who received 50 mg (1.39 0.45 versus 1.89 0.23), and similar to the results found by the Alderman group at 200 mg (1.3). These results suggest that proportionally more sertraline is being converted to norsertraline at 50 mg than at higher doses. These findings indicate that sertraline exhibits nonlinear or saturation kinetics at steady-state in adolescents. The nonlinear kinetics lead to disproportionately higher plasma levels at higher doses than would be predicted if a linear relationship existed between dose and plasma levels. For instance, the mean Cmax in our study at 50 mg/day was 23.4 ng/mL, or a dose-normalized level of 0.47 ng/mL per mg of sertraline. However, the dosenormalized Cmax at 100 to 150 mg was 0.65 ng/mL per mg, which is 38% higher than what would be expected if sertraline kinetics were

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completely linear. In the Alderman study, the mean Cmax at 200 mg/day was 123 ng/mL (0.62 ng/mL per mg), which is 32% higher than expected if sertraline kinetics were linear. One explanation for these findings is that the enzymes metabolizing sertraline become saturated at higher doses of sertraline. It is also possible that absorption and duration of exposure may be involved, but the fact that the clearance of sertraline is faster at 50 mg than at 100 to 150 mg implicates metabolism as the primary cause. The overall effect of the nonlinear kinetics on peak plasma levels (~35% higher than predicted by dose) may not be clinically relevant for most adolescents, but the effect on halflife (15.3 hours at 50 mg/day, 20.4 hours at 100150 mg/day, and 27.1 hours at 200 mg/day) is substantial and could result in an optimal dose frequency of twice per day at doses of 50 mg and once daily at 200 mg/day. Sertraline is not the only SSRI that has been shown to have nonlinear kinetics. In adults, fluoxetine, paroxetine, and fluvoxamine all exhibit nonlinear kinetics at steadystate (Preskorn, 1997). Sertraline in adults exhibits linear kinetics across the dose range in single-dose studies (Warrington, 1991), but we are unaware of any studies examining steady-state kinetics across the 50- to 200-mg dose range in adults. Therefore, it is not clear whether the nonlinear steadystate kinetics of sertraline are limited to adolescents. The platelet 5-HT reuptake inhibition that we found at 50 mg/day (61%) was lower than reported values in adults (76%80%), though direct statistical comparison is not possible (Preskorn and Lane, 1995). However, the IC70 (trough concentration necessary to cause 70% inhibition of platelet serotonin reuptake) was 14.4 ng/mL, and the IC80 was 24.7 ng/mL in our adolescents. These results were very similar to the IC70 (15 ng/mL) and IC80 (22 ng/mL) for sertraline in adults. This suggests that there is not any significant difference between adolescents and adults on the concentration of sertraline necessary to inhibit the pump.
Clinical Implications

reach a threshold concentration for a prescribed period of time at the site of therapeutic action (SOA) (see Preskorn, 1996). The critical concentrations and duration of exposure at the SOA vary for different patients, medications, and psychiatric disorders. We assume that wide variations in plasma concentration throughout the day would not be optimal, because part of the time the patient would be exposed to higher than necessary concentrations (potentially causing side effects) and part of the time the patient would have concentrations at the SOA below the therapeutic threshold, theoretically reducing the efficacy of the medication. There are some data to show that half-life might be clinically relevant for SSRI treatment. Rosenbaum and colleagues (1998) had clinically stable adult patients taking SSRIs undergo a double-blind placebo substitution of their SSRI for a 5-day period. Subjects were assessed continuously for physical and clinical symptoms. Subjects taking fluoxetine (very long halflife) had significantly less discontinuation-emergent events and a lower chance of reemergence of depressive symptoms compared to the shorter half-life SSRIs, paroxetine and sertraline. Although the potential inaccuracy of the assumptions used to relate pharmacokinetics to clinical care makes it improper to make a blanket recommendation that sertraline at a dose of 50 mg/day should be administered b.i.d. to all adolescents, it is logical for clinicians to start sertraline at b.i.d. dosing in new patients and consider switching patients already taking 50 mg/day to b.i.d. dosing if they have only a partial therapeutic response or appear to have withdrawal effects (i.e., nausea, irritability, or malaise) later in the day or if they miss a dose. We would expect that most adolescents would eventually need more than 50 mg of sertraline per day to achieve sufficient inhibition of the serotonin reuptake pump and for many of them, a b.i.d. dosing regimen may be optimal. Adolescents taking 200 mg/day most likely can be given sertraline once daily.
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Because we do not know exactly how SSRIs or other antidepressants exert their therapeutic effects, the clinical implications of this study have to be taken in the context of assumptions that we make about the relation between the kinetics and dynamics of medications. We assume that the medication must

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