Clinical Pharmacokinetics of Sertraline

DRUG DISPOSITION

Clin Pharmacokinet 2002; 41 (15): 1247-1266 0312-5963/02/0015-1247/$25.00/0 © Adis International Limited. All rights reserved.

Clinical Pharmacokinetics of Sertraline C. Lindsay DeVane, Heidi L. Liston and John S. Markowitz Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Analytical Methods . . . . . . . . . . . . . . . . . . . . . . 2. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . 2.1 Oral Absorption and Bioavailability . . . . . . . . . . 2.2 Protein Binding and Distribution . . . . . . . . . . . . . 2.3 Metabolism and Elimination . . . . . . . . . . . . . . . 3. Pharmacokinetics in Special Populations . . . . . . . . . . 3.1 Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Paediatric Population . . . . . . . . . . . . . . . . . . 3.3 Pregnancy and Lactation . . . . . . . . . . . . . . . . 3.4 Renal Disease . . . . . . . . . . . . . . . . . . . . . . . 3.5 Hepatic Disease . . . . . . . . . . . . . . . . . . . . . 4. Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Pharmacokinetic Interactions . . . . . . . . . . . . . . 4.1.1 Warfarin . . . . . . . . . . . . . . . . . . . . . . . 4.1.2 Diazepam . . . . . . . . . . . . . . . . . . . . . . 4.1.3 Alprazolam . . . . . . . . . . . . . . . . . . . . . 4.1.4 Clonazepam . . . . . . . . . . . . . . . . . . . . 4.1.5 Digoxin . . . . . . . . . . . . . . . . . . . . . . . . 4.1.6 Tricyclic Antidepressants . . . . . . . . . . . . . . 4.1.7 Tolbutamide . . . . . . . . . . . . . . . . . . . . . 4.1.8 Anticonvulsants . . . . . . . . . . . . . . . . . . . 4.1.9 Antipsychotics . . . . . . . . . . . . . . . . . . . 4.1.10 Other Drugs . . . . . . . . . . . . . . . . . . . . 4.2 Pharmacodynamic Interactions . . . . . . . . . . . . 4.2.1 Monoamine Oxidase Inhibitors . . . . . . . . . . 4.2.2 Lithium . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3 β-Blockers . . . . . . . . . . . . . . . . . . . . . . 5. Sertraline Plasma Concentrations and Clinical Response 6. Overdosage . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

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Sertraline is a naphthalenamine derivative with the predominant pharmacological action of inhibiting presynaptic reuptake of serotonin from the synaptic cleft. It was initially marketed for the treatment of major depressive disorder and is now approved for the management of panic disorder, obsessive-compulsive disorder and post-traumatic stress disorder. Sertraline is slowly absorbed following oral administration and undergoes

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DeVane et al.

extensive first-pass oxidation to form N-desmethyl-sertraline, a weakly active metabolite that accumulates to a greater concentration in plasma than the parent drug at steady state. Sertraline is eliminated from the body by other metabolic pathways to form a ketone and an alcohol, which are largely excreted renally as conjugates. The elimination half-life of sertraline ranges from 22–36 hours, and once-daily administration is therapeutically effective. Steady-state plasma concentrations vary widely, up to 15-fold, in patients receiving usual antidepressant dosages between 50 and 150 mg/day. However, only sparse data have been published that support useful correlations between sertraline plasma concentrations and therapeutic or adverse effects to justify therapeutic drug monitoring. Sertraline has minimal inhibitory effects on the major cytochrome P450 enzymes, and few drug-drug interactions of clinical significance have been documented. Like other selective serotonin reuptake inhibitors, sertraline is well tolerated in therapeutic dosages and relatively safe in overdosage.

After the introduction of the selective serotonin reuptake inhibitors (SSRIs) into clinical practice, they rapidly surpassed the use of the tricyclic antidepressants (TCAs) as first line choices for the treatment of depression. Fluvoxamine was introduced in Europe in 1983 and fluoxetine in the US in 1990. Since 1990, three additional SSRIs (sertraline, paroxetine and citalopram) have become available and others are under clinical development. In addition to showing antidepressant efficacy comparable to that of the TCAs, the SSRIs have a broader spectrum of efficacy for treating anxiety disorders.[1,2] The benefits of sertraline and other SSRIs over older agents include an improved tolerability and adverse effect profile and relative safety in overdosage.[3,4] Sertraline is designated as (1S,4S)-N-methyl-4(3,4-dichlorophenyl) -1,2,3,4- tetrahydro -1-naphthylamine and contains two asymmetric carbon atoms (figure 1). The cis (1S,4S) enantiomer is the more potent serotonin reuptake inhibitor and is the marketed pharmaceutical form. The affinity of sertraline for other neurotransmitter receptor sites is low, and with the possible exception of binding to the dopamine transporter, are not considered to be of therapeutic consequence.[5] Initially marketed for the treatment of depression, sertraline is also approved in the US for the treatment of obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder.  Adis International Limited. All rights reserved.

Shortly after fluoxetine was marketed, case reports of drug-drug interactions, particularly in combination with the TCAs, appeared in the literature.[9,10] Such reports stimulated interest in the comparative pharmacological properties of the SSRIs, including their drug interaction potential, the clinical significance of elimination half-lives, and the role of active metabolites.[11] Previous reviews have compared the salient pharmacokinetic properties of the marketed SSRIs and summarised the drug interaction data for sertraline.[11-16] The purpose of this review is to update and provide a current survey of the published pharmacokinetic data for sertraline. 1. Analytical Methods Sertraline has been measured in animal tissues and fluids and in human plasma by chromatographic techniques.[6,17-25] A capillary gas chromatographic-mass spectrometric method[17] was employed for initial measurement of sertraline in plasma following single oral doses given to male volunteers. This method required extraction of 3ml of plasma for detection of 1 µg/L of drug, a requirement which was later reduced to 1ml.[6] High performance liquid chromatography (HPLC)[18,19] was the first method that could simultaneously quantify sertraline and its major metabolite, Ndesmethyl-sertraline (DMS; figure 1). Subsequent methods based on HPLC have been published Clin Pharmacokinet 2002; 41 (15)

Sertraline

1249

H

CH3

N

H

H N

CI CI

CI

N-Desmethyl-sertraline

Sertraline

HOOC N

CH3

HO N

CI

CH3

O

CI

CI

CI Carbamic acid

CI

CI

CI

N-Hydroxy-sertraline

Ketone

α-Hydroxy ketone (diastereomers)

Conjugated glucuronides

Biliary and urinary excretion

Fig. 1. Metabolic pathways of sertraline.[6-8]

(table I). The simpler, less costly, HPLC methods provide adequate sensitivity and specificity for pharmacokinetic studies. 2. Pharmacokinetic Properties The pharmacokinetic properties of sertraline are summarised in table II.  Adis International Limited. All rights reserved.

2.1 Oral Absorption and Bioavailability

Sertraline is slowly absorbed, reaching maximum concentrations in plasma at 4–8 hours after oral administration.[7,8] Absolute bioavailability was estimated to be >44%, but studies comparing oral to intravenous administration have not been Clin Pharmacokinet 2002; 41 (15)

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published. The relative bioavailability is reported to be equivalent between tablets and oral solution.[8] Coadministration of sertraline with food increased peak plasma concentration by approximately 25% and decreased time to peak concentration from 8–5.5 hours, with a net marginal increase in area under the concentration-time curve (AUC).[28] A partial explanation for this finding is that a food-induced increase in hepatic blood flow could allow more unabsorbed drug to escape first-pass hepatic uptake and metabolism. The significance of this food-drug interaction is doubtful, since the therapeutic or adverse effects of sertraline have not been correlated to peak concentrations, and therapeutic benefits are reported in association with long-term daily administration. Plasma concentrations of sertraline and DMS have been reported following single ascending oral doses of 100, 200, and 400mg in ten normal healthy volunteers.[18] Parent drug slowly appeared in plasma with peak concentrations (Cmax) occurring 4–6 hours after ingestion (tmax). The desmethyl metabolite appeared early in plasma, and its concentration increased throughout the 8hour post-dose observation period. Plasma concentrations appeared to be proportional to oral dose up to the maximum administered dose of 400mg.

These data are shown in figure 2. A linear relationship between sertraline dose and plasma concentration was also reported in 24 healthy men following single oral doses of 50, 100 and 200mg.[7] 2.2 Protein Binding and Distribution

Sertraline is highly bound, approximately 98%, to plasma proteins.[7,8,28] A statistically, but not clinically, significant difference in plasma protein binding was found in 22 elderly (age >65 years) compared with younger subjects (n = 22; 18–45 years) and between female and male subjects (11 subjects per group).[29] The mean percentage of unbound sertraline in the elderly (1.42%) was significantly smaller than that for young individuals (1.55%; p < 0.001) and the mean percentage unbound in females (1.44%) was significantly less than in males (1.52%; p < 0.012). The fraction unbound for DMS has not been reported. The volume of distribution (Vd) of sertraline from animal studies was approximately 25 L/kg,[7] a value similar to that of other available antidepressants[30] that suggests extensive tissue distribution. Published pharmacokinetic reports have not included values for Vd of sertraline in humans. Taking the published AUC, clearance and elimination rates from two human studies of sertraline taken orally in healthy volunteers,[28,29] values of Vd cal-

Table I. Summary of assay techniques for measuring sertraline Analytical method

Samples assayed

Metabolite analysis

Minimum extraction volume (ml)

Limit of detection

Reference

GC-MS

Brain tissuea

No

3

1 µg/L

17

GC-MS

Plasmaa

No

1

1 µg/L

6

GC-EC

Plasmab

Yes

NA

5 µg/L

18

HPLC

Brain tissuea

Yes

1

25 µmol

19

HPLC

Plasmab

Yes

0.5

10 µg/L

20

HPLC

Serumb

Yes

1

10 µg/L

21

HPLC

Brain tissuea

Yes

1

NA

22

HPLC

Plasmab, red blood cellsb

Yes

0.5

15 nmol

23

HPLC

Plasmab

No

1

10 µg/L

24

HPLC

Plasmaa

Yes

0.2

10 µg/L

25

a

Animal tissue.

b

Human samples.

GC-EC = gas chromatography-electron capture; GC-MS = gas chromatography- mass spectrometry; HPLC = high-performance liquid chromatography; NA = data not available.

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Clin Pharmacokinet 2002; 41 (15)

Sertraline

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Table II. Summary of mean (± SD, or range) pharmacokinetic parameter values for sertraline Dose (mg)

Population description

Cmax (µg/L)

tmax (h)

AUCa (µg • h/L)

t1⁄2β (h)

100 single

8 male, 2 female, healthy volunteers

20.6 (12.6–27.5)

6 (4–6)

546 (215–960)

25.4 NA (13.2–45.2)

26

100 single

8 male, 2 female, hepatic dysfunction

35.2 (20–40.8)

4 (2–6)

2166 (345–3864)

81.7 NA (15.6–116.5)

26

50 single

29 children

23.5 ± 10.9

5.8 ± 2.1

299 ± 145

26.2

NA

27

50 single

32 adolescents

16.3 ± 5.8

6.2 ± 3.0

214 ± 60

27.1

NA

27

CL/F (L/h/kg)

Reference

100 single

10 healthy males

24.5 ± 65

7.0 ± 2.1

664 ± 203

20.0

NA

28

200/day × 21 days

11 young males

118 ± 22

6.9 ± 1.0

2076 ± 549

22.4

1.41 ± 0.36

29

200/day × 21 days

11 young females

166 ± 65

6.7 ± 1.8

3063 ± 1413

32.1

1.35 ± 0.67

29

200/day × 21 days

11 elderly males

135 ± 35

7.8 ± 2.3

2590 ± 720

36.7

1.09 ± 0.38

29

200/day × 21 days

11 elderly females

147 ± 43

6.4 ± 1.5

2667 ± 948

36.3

1.26 ± 0.29

29

a

AUC24 or AUC∞.

AUC = area under the concentration-time curve; Cmax = maximum plasma concentration; CL/F = total body clearance adjusted for bioavailability; NA = data not available; tmax = time of Cmax occurrence; t1⁄2β = elimination half-life.


fold increase over peripheral plasma concentrations for both sertraline and DMS, reflecting their high lipophilicity.[31] With antidepressants like the TCAs, an extensive tissue distribution prevented haemodialysis or haemoperfusion from being an effective treatment from toxic ingestions; fortunately, this is of minor significance for sertraline and other SSRIs due to their safety profile in overdosage.[3,4]

400 350 Concentration (µg/L)

culated for sertraline using standard pharmacokinetic equations were 55.3 and 45.6 L/kg, respectively. These values are somewhat larger than the Vd reported in animals; however, calculations of Vd using the AUC from oral dose studies results in an overestimation of Vd for drugs such as sertraline that are subject to extensive hepatic firstpass metabolism. If these calculated values are adjusted to account for the reported bioavailability of 44%, then new estimates of Vd of sertraline are obtained which are consistent with the values for other SSRIs.[11,13] The significance of a relatively large Vd for sertraline is that much of the accumulated drug in the body at steady-state resides outside of the systemic circulation. The concentration of sertraline in rat brain after single dose administration was 40to 50-fold higher than in plasma.[6] In addition, DMS, the major metabolite, has been found in a higher concentration than sertraline in rat brain.[22] Data from human post-mortem cases have shown liver tissue concentrations to range from 3.9–20 mg/kg for sertraline and 1.4 to 11 mg/kg for DMS. These values represent an approximate 20- to 50-

300 250 200 150 100 50 0 0

100

200

300

400

500

Dose (mg)

Fig. 2. Peak plasma concentrations of sertraline following in-

creasing oral doses. Data from Saletu et al.[18]


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2.3 Metabolism and Elimination

The major metabolic pathways of sertraline have been established in animal studies and are presumed to be similar in humans. They are shown in figure 1. The metabolism of sertraline has been studied in the rat and dog using [14C]sertraline administration. Mass balance studies were conducted using urinary, biliary and faecal drug excretion. Elimination of sertraline proceeds by hepatic metabolism to oxidated and glucuronidated metabolites. Multiple cytochrome P450 (CYP) isoforms appear to be responsible for the metabolism of sertraline.[32] The role of CYP2C19 in sertraline N-demethylation was investigated in human microsomes of six extensive and three poor metabolisers.[33] This in vitro study found only CYP2C8/9 and CYP2C19 to be substantially affected by CYP inhibitors and/or CYP antibodies. The formation of DMS was also significantly slower in CYP2C19 poor metabolisers.[33] Minimal effect on sertraline demethylation was observed with the inhibition of CYP1A2, 2A6, 2D6, 2E1 or 3A4/5. Other reports have shown sertraline N-demethylation to be more interspersed among different CYP isoforms in vitro by taking into account the relative abundance of each CYP isoform.[32,34] Sertraline was shown to be N-demethylated by several CYP enzymes in human microsomes and cDNA-expressed human CYP isoforms, including CYP2D6, CYP2C9, CYP2B6, CYP2C19 and CYP3A4. Among these five isoforms, CYP2D6 had the highest estimated intrinsic clearance (maximum velocity/Michaelis constant; Vmax/Km) of 0.309 µg/min/pmol. The percentage contribution of each isoform relative to Vmax/Km values was

35, 29, 14, 13 and 9% for CYP2D6, CYP2C9, CYP2B6, CYP2C19 and CYP3A4, respectively.[34] Previously, sertraline metabolism was reported to be unaffected when compared between poor and extensive CYP2D6 metabolisers.[35] This finding is not surprising, since CYP2D6 accounts for approximately 3% of the liver’s CYP activity and several CYP enzymes presumably metabolise sertraline in vivo.[32] Given the modest contribution of each isoform to the N-demethylation of sertraline in vitro,[33] alternative pathways could compensate in subjects genetically deficient for CYP2D6 metabolising activity. Recently, in a human study using six poor metabolisers and six extensive metabolisers of the CYP2C19 gene, the oral clearance (CL/F) of sertraline was significantly lower in the poor metabolisers.[36] The major metabolite, DMS, is modestly pharmacologically active in vitro[37] and in vivo.[22] Receptor binding profiles in human brain using [3H]citalopram and [3H]serotonin have shown inhibition at these receptors by sertraline to be 25- to 60-fold greater than for DMS.[5] Table III summarises in vitro serotonin receptor inhibitory values for sertraline and DMS in comparisons with other SSRIs.[5,22,37-39] In studies analysing animal brain tissue and human plasma, concentrations of DMS were greater than those of sertraline.[20,22] Under steady-state administration conditions, plasma concentrations of sertraline have varied widely, nearly 15-fold, between individuals receiving the same daily dose.[20] This variability is consistent with the known interindividual CYP isoenzyme activity in humans and the assumption that multiple CYP isoforms appear to be involved in the metabolism

Table III. Comparison of serotonin receptor inhibitory potencies of the selective serotonin reuptake inhibitors[5,22,37-39] Tissue source

Ki (nmol/L)a SER

DMS

FLX

NFLX

PAX

FLV

Rat brain synaptosomes

0.29

0.46

2.0

1.9

0.05

1.5

0.75

Human transfected brain cells

3.3

187

20

54

0.83

14

8.9

a

CIT

Lower values indicate greater potency.

CIT = citalopram; DMS = desmethylsertraline; FLV = fluvoxamine; FLX = fluoxetine; Ki = inhibition constant; NFLX = norfluoxetine; PAX = paroxetine; SER = sertraline.



1253

of sertraline.[32,34] The ratio of DMS to sertraline varied from 1.1–4.1 among 27 patients receiving sertraline 100–300 mg/day.[20] All patients had a higher DMS concentration in plasma compared with parent drug. The mean and range of steadystate sertraline plasma concentrations from a program of therapeutic drug monitoring are shown in figure 3 and figure 4. Congruent with a higher plasma concentration of DMS than of sertraline, the mean elimination half-life of DMS exceeded that of sertraline in most reports. A summary of the pharmacokinetic parameters for DMS is given in table IV. In mice, brain DMS concentrations were nearly as high following parenteral sertraline administration as they were following DMS administration. The administration of preformed DMS was found to decrease the brain concentration of 5-hydroxyindoleacetic acid (5-HIAA). 5-HIAA concentration serves as a measurement of brain serotonin turnover as a consequence of inhibiting the serotonin transporter. This finding in rats suggests that DMS contributes to serotonin reuptake inhibition.[22] A separate study found no effect of DMS on serotonin reuptake in rats.[39] DMS appeared to have 5–10% of the potency of sertraline on serotonin uptake inhibition.[5] Although DMS has been regarded as lacking antidepressant activity, these observations suggest that DMS contributes modestly to the overall pharmacological effects of sertraline in hu-

Concentration (µg/L)

70 60 50

Concentration (µg/L)

Sertraline

160 140 120 100 80 60 40 20 0 25

50

75

100

125

150

200

Dose (mg)

Fig. 4. Mean and range of N-desmethyl-sertraline plasma con-

centration following steady-state administration of sertraline 25–200 mg/day. Number of patients varied from 6 for 25 mg/day to 156 for 50 mg/day.[40]

mans. DMS is the only metabolite reported to be pharmacologically active and the only metabolite whose concentration has been reported in human pharmacokinetic studies. An unequivocal assessment of whether DMS is an antidepressant in humans would require direct administration of DMS. Other metabolic pathways of sertraline result in the formation of sertraline carbamic acid, Nhydroxy-sertraline and the deaminated ketone of sertraline (figure 1). These metabolites are conjugated with glucuronic acid and undergo biliary and urinary excretion, accounting overall for 82% of radioactivity excreted in the bile and urine of dogs following administration of [14C]sertraline.[6] Clearance of sertraline is consistent with a high hepatic extraction (table II). The elimination half-life (t 1⁄2β) in healthy volunteers varied from 13–45 hours with a mean of approximately 26 hours. [7,25]

40 30

3. Pharmacokinetics in Special Populations

20 10 0 25

50

75

100

125

150

200

Dose (mg)

Fig. 3. Mean and range of sertraline plasma concentration fol-

lowing steady-state administration of sertraline 25–200 mg/day. Number of patients varied from 6 for 25 mg/day to 156 for 50 mg/day.[40]


The pharmacokinetics of SSRIs in special populations can vary in potentially clinically relevant ways.[11,13] Only sparse data are available for sertraline in populations at high risk for compromised drug disposition. Clin Pharmacokinet 2002; 41 (15)

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DeVane et al.

Table IV. Pharmacokinetic parameter values for N-desmethyl-sertraline Dose (mg)

Population description

Cmax (µg/L)

tmax (h)

AUC (µg • h/L)

t1⁄2β (h)

200/day

6–12 years

210 ± 108

14.6 ± 16.1

4143 ± 1818

78.5 ± 50.6

38

200/day

13–17 years

153 ± 56.3

10.8 ± 8.02

3091 ± 1080

75.4 ± 37.1

38

100 single

10 healthy volunteers

11.2

6

NA

NA

26

100 single

10 hepatic dysfunction

7.9

168

NA

NA

26

200/day

22 elderly

255 ± 94

11.0 ± 13.9

4959 ± 1487

NA

29

200/day

22 young volunteers

200 ± 75

7.5 ± 3.4

4054 ± 1369

70.9

29

Reference

AUC = area under the concentration-time curve; Cmax = maximum plasma concentration; NA = data not available; tmax = time of Cmax occurrence; t1⁄2β = elimination half-life.

3.1 Elderly

Sertraline clearance was reported to be approximately 40% lower in 16 elderly (eight males, eight females; >65 years) than in younger (25–32 years) subjects following 14 days of treatment of sertraline 100mg, suggesting that steady-state plasma concentration would not be reached until 2–3 weeks in this population.[7,8] Following 21 days at a sertraline dose of 200 mg, peak plasma sertraline concentrations and AUC were higher, and t1⁄2β longer, in elderly (>65 years) versus younger male (18–45 years) subjects. No difference was found among elderly male, elderly female and younger female subjects. Elderly males had a mean t1⁄2β of 36.7 versus 22.4 hours in young males.[29] An analysis of AUC normalised for single doses of 50, 100 and 200mg indicated linearity in the elderly within this dose range. As this relationship can be expected to apply to long-term administration, increases in daily dose should produce proportional increases in steady-state concentrations. The decreased clearance and prolonged t1⁄2β suggest that steady-state concentrations of sertraline would be higher and achieved later during long-term administration to elderly compared with younger male patients. Whether higher steadystate sertraline or DMS concentrations for a given daily dose in the elderly have clinical significance is unknown. 3.2 Paediatric Population

The single- and multiple-dose pharmacokinetics, safety and efficacy of sertraline and DMS were  Adis International Limited. All rights reserved.

investigated in 29 children (6–12 years) and 32 adolescents (13–17 years) with depression and/or OCD.[27] The dosage range was 50–200 mg/day and two titration schedules were examined, one using 50mg increments, as recommended with adults, and one using 25mg increments. The t1⁄2β of both sertraline and DMS in children and adolescents was not significantly different from reported values in adults. The t1⁄2β for the paediatric group was 26.2 hours and for the adolescent group 27.1 hours. Cmax and AUC24 were found to be greater in the paediatric patients compared with the adolescent patients; however, this increase became insignificant when values were normalised for bodyweight. The two subjects with the lowest weights in the paediatric group demonstrated the highest values, which accounted for the statistical difference found. There was no difference in the rate of reported adverse effects in the two titration schedules. Likewise, the incidence of adverse effects was similar to that in the adult patients. Based on these results it was concluded that sertraline could be administered to paediatric patients to treat depression and/or OCD using a standard adult titration schedule. A multicentre randomised controlled trial assessed the efficacy of sertraline in 107 children (6–12 years) and adolescents (13–17 years) with OCD.[41] Trough plasma concentrations of sertraline and DMS were measured and normalised to bodyweight. No significant correlation was found between either sertraline or DMS plasma concentration and response rate, age or sex. Clin Pharmacokinet 2002; 41 (15)

Sertraline

Axelson et al.[42] recently reported various aspects of the pharmacokinetics of sertraline in dosages of 50–50 mg/day in adolescents. The steadystate elimination half-life at 50 mg/day was significantly shorter (15.3 ± 3.5 hours) than the half-life following a single 50mg dose (26.7 ± 5.2 hours). These data suggest adolescent patients may require twice daily doses, but at 150 mg/day, the half-life increased. Thus, at higher daily doses, adolescents may be effectively treated with single daily doses. 3.3 Pregnancy and Lactation

Studies have reported the concentration of sertraline and DMS in human breast milk and/or plasma of breastfed infants from mothers receiving sertraline.[43-48] Milk to plasma ratio (M/P) was estimated from area under the plasma and milk concentration-time curves from seven nursing women receiving sertraline 50 mg/day and one additional subject receiving 200 mg/day. The mean M/P for sertraline and DMS was 1.93 and 1.64, respectively.[43] Although the quantity of milk produced by the patients in this study was below normal values, infant exposure was estimated to be 0.90% and 1.32% for sertraline and DMS, respectively, when based on an average milk production of 0.151 kg/day (percentage of adult dose). Sertraline and DMS could not be detected in the four infants in whom plasma sampling was conducted.[43] A study of ten nursing women receiving sertraline at dosages of 50–150 mg/day found comparable results for sertraline.[45] The M/P was 1.76, with the average dose to infants estimated as less than 2% of the maternal daily dose. Plasma sertraline concentration in infants of nursing mothers receiving treatment with sertraline has ranged from 2–3 µg/L.[44,46-48] Like sertraline, DMS has generally been found in trace amounts ranging from 2–10 µg/L.[44,46-48] However, out of nine pairs of nursing mothers and infants, Wisner et al.[46] reported one infant with a DMS concentration of 24 µg/L and no measurable sertraline concentration, and another infant had sertraline and DMS concentrations of 64 and 68  Adis International Limited. All rights reserved.

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µg/L, respectively. These values reflected approximately one-half the concentration of the respective mothers. Out of a total of 26 infants reported from four studies, only low concentrations of sertraline and DMS were found and no adverse effects, developmental, or other health-related problems were identified during the period of observation.[44,46-48] Similarly, no differences in fetal malformations, rate of miscarriage, stillbirth, prematurity, birth weight, or gestational age were reported in 147 women treated with sertraline in a dosage range of 25–200 mg/day during pregnancy compared with controls.[49] Although sertraline use by pregnant women or nursing mothers appears to be safe, long-term investigation of the neurological and behavioural development of infants of mothers receiving sertraline during pregnancy or while breastfeeding is needed for confirmation. 3.4 Renal Disease

The pharmacokinetics of single doses of sertraline were unaffected by renal impairment. No data for multiple doses have been reported,[7] nor data from patients with severe renal dysfunction.[8] Caution is recommended when sertraline is prescribed for this population. Sertraline was analysed in plasma and in the dialysate of two anuric haemodialysis patients following a single 100mg dose. Initial sertraline plasma concentrations were found to be comparable to values for patients with normal renal function. Sertraline was not detected in the dialysate and t1⁄2β was found to be 42 and 92 hours in the two patients, suggesting that doses of sertraline may need to be reduced in individuals with end-stage renal disease.[50] Metabolites of sertraline are glucuronidated before excretion and they could be expected to circulate at higher plasma concentrations in patients with renal disease. Glucuronidated metabolites of most drugs are pharmacologically inactive unless they are hydrolysed in the gastrointestinal tract following biliary excretion and reabsorbed. Information about enterohepatic recycling of sertraline Clin Pharmacokinet 2002; 41 (15)

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metabolites is unavailable, but these species are likely to be unimportant given the lack of activity of the minor metabolites. 3.5 Hepatic Disease

Since sertraline undergoes oxidative metabolism as its major elimination pathway, severe hepatic dysfunction would be expected to impair drug elimination. Disposition of sertraline in patients with hepatic disease has been characterised in a small number of cases.[26] Ten patients with chronic stable hepatic insufficiency were compared with healthy matched controls following the administration of a single 100mg dose of sertraline. CL/F was found to be reduced, with t1⁄2β prolonged in the cirrhotic patients (81.7 hours) compared with healthy adults (25.4 hours). Cmax was also increased by 1.7-fold. Data from the manufacturer’s product information are also available.[8] In patients with mild, stable cirrhosis, the t1⁄2β of sertraline averaged 52 hours compared with 22 hours in patients without liver disease. This suggests that steady-state concentrations would be higher for a given daily dose and achieved much later during long-term administration. For patients with liver disease, initial dosages should be less than 50 mg/day and/or the dosage interval increased beyond 24 hours. No data are available for patients with more severe hepatic impairment or liver disease of different aetiologies (e.g. hepatitis versus cirrhosis). 4. Drug Interactions Sertraline drug-drug interactions have been investigated with prototypical drugs from different pharmacological classes. A summary is given in table V, with other interactions described in case reports.[51-59] 4.1 Pharmacokinetic Interactions

The high degree of plasma protein binding of sertraline (98.5%; table II [64]) suggests a potential for pharmacokinetic drug-drug interactions. Also, sertraline is a potent in vitro inhibitor of CYP2D6,  Adis International Limited. All rights reserved.

DeVane et al.

with an apparent inhibition constant (Ki) of 0.70 µmol/L for sparteine hydroxylase.[65] Several studies have examined the effect of sertraline on CYP2D6 through the use of probe drugs, primarily dextromethorphan, by measuring the dextromethorphan/dextrorphan ratio (DMR).[66-69] Although all have shown an increase in the DMR following sertraline administration, not all results have been statistically significant from baseline. This may be partially attributed to the doses of sertraline used and interindividual differences in baseline CYP2D6 activity. In comparison to other SSRIs such as fluoxetine and paroxetine, the inhibitory effect of sertraline on CYP2D6 in vivo can be considered mild and generally not clinically significant; however, individuals with high CYP2D6 activity may experience more pronounced effects. The time course for CYP2D6 inhibition to dissipate has been shown to be considerably shorter for sertraline and paroxetine (5 days) in comparison with fluoxetine (42 days), congruent with the shorter half-lives for sertraline and paroxetine.[69] In vitro data demonstrate that sertraline is a measurable CYP3A4 inhibitor.[70,71] In vivo data do not substantiate a consistent risk of clinically meaningful interactions involving CYP3A4 substrates.[72] Sertraline was found to have a 50% inhibitory concentration (IC50) of 3.2 µmol/L for inhibition of CYP2B6 in human liver microsomes.[73] Few substrates are known for this isoenzyme and no in vivo interactions with sertraline have been reported. 4.1.1 Warfarin

The effect of sertraline on the plasma protein binding and pharmacodynamics of warfarin was investigated in a parallel group study in 12 healthy men.[56] Single doses of warfarin were administered before and after 3 weeks of treatment with sertraline (up to 200 mg/day) or placebo. Warfarin was significantly displaced from plasma protein binding by sertraline, resulting in an increased prothrombin time in the active drug group which was significantly greater (p = 0.02) than the effects of placebo. No clinically relevant effects were noted. A slight delay in normalisation of prothrombin time occurred following the final dose of warfarin Clin Pharmacokinet 2002; 41 (15)

Sertraline

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Table V. Selected reports of drug interactions with sertraline Agent

Effect

References

Comment

Desipramine

Increased TCA Competitive enzyme concentration, usually inhibition of CYP2D6 minimal without significance

Possible mechanism

51-54

Possibly dose-related effect; monitoring of TCA concentrations is recommended

Imipramine

Nonsignificant change in AUC of imipramine or its metabolites

Competitive enzyme inhibition of CYP2D6

55

Single case report; see above

Warfarin

Increased anticoagulant effect; increased prothrombin time

Warfarin displacement from 56 plasma protein binding sites; possible inhibition of CYP2C

Monitoring of prothrombin time is recommended

Diazepam

Clinically significant decrease in clearance

Competitive inhibition of CYP2C binding

57

Increase vigilance with combination; clinical relevance unclear

Alprazolam

No effect

Lack of effect of sertraline on CYP3A4

60

Usual monitoring

Tolbutamide

Significant decrease in clearance

Competitive inhibition of CYP2C binding

8,30,61

Limited data; clinical relevance unclear

Carbamazepine

Increased carbamazepine plasma concentration decreased sertraline

Competitive inhibition of CYP3A4 binding

58,62,63

Single case reports and one volunteer study. Monitor effects of both drugs

Lithium

Nonsignificant decrease in Possible increased lithium clearance; presence serotonin concentration of tremors leading to serotonin syndrome-like effects

59

Reduce dosage of sertraline or treat tremor if persistent or bothersome

AUC = area under the concentration-time curve; CYP = cytochrome P450; TCA = tricyclic antidepressant.

in the sertraline group. Because these data were obtained from healthy volunteers taking single doses of warfarin, extrapolation to seriously medically ill individuals is difficult. It is advisable to carefully monitor prothrombin time when sertraline treatment is initiated or stopped in patients receiving anticoagulation with warfarin. 4.1.2 Diazepam

Sertraline-diazepam interaction data has been published in abstract form.[57] Twenty healthy volunteers were given intravenous infusions of diazepam 10mg before and after 21 days of treatment with oral sertraline at a dosage of 200 mg/day. A statistically significant reduction in systemic clearance of the benzodiazepine was observed, but was thought to be clinically insignificant. The apparent Vd, elimination rate and plasma protein binding of diazepam were not significantly altered. Despite the modest decrease in clearance observed in the healthy volunteers, it does not appear that diazepam and sertraline used in combination would  Adis International Limited. All rights reserved.

give rise to clinically significant drug-interaction effects. 4.1.3 Alprazolam

Previous in vitro data demonstrated that sertraline may inhibit the metabolism of alprazolam by CYP3A4.[71] However, a study of ten healthy normal volunteers found no significant effect of sertraline on alprazolam oxidative metabolism.[60] Six subjects received sertraline 50 mg/day, four subjects received 100 mg/day and six subjects received 150 mg/day in a modified crossover fashion for a minimum of 14 days. In addition, pharmacodynamic findings demonstrated that the addition of sertraline to alprazolam did not affect psychomotor performance except for a peak decrease in performance on the manual tracking test. A subsequent report found no significant effect on alprazolam pharmacokinetics in 12 male volunteers following steady-state administration with sertraline 50 mg/day.[74] In our laboratory, another study using sertraline at a dosage of 100 mg/day for 8 Clin Pharmacokinet 2002; 41 (15)

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days found no effect on alprazolam pharmacokinetics in 16 male subjects.[75] It appears that the metabolism of alprazolam by CYP3A4 is unaffected by sertraline at dosages up to 150 mg/day. 4.1.4 Clonazepam

Sertraline did not significantly affect the pharmacokinetics or pharmacodynamics of clonazepam in seven men and six women who completed a placebo-controlled, randomised, double-blind, crossover study of clonazepam 1mg with and without sertraline 100mg.[76] CL/F, Vd and t1⁄2β of clonazepam were not altered, and neither were scores on several pharmacodynamic measurements. 4.1.5 Digoxin

Sertraline did not alter digoxin pharmacokinetics in 20 healthy male volunteers who received concurrent oral digoxin 0.25 mg/day with either sertraline 200 mg/day or placebo for a period of 10 days.[77] Only the time to maximum digoxin concentration was significantly decreased over placebo (p = 0.0046). No significant effect was found on the renal clearance of digoxin and there were no meaningful differences in ECG measurements between the placebo and sertraline groups. Digoxin dosage adjustments are not likely to be necessary when the medication is combined with sertraline. 4.1.6 Tricyclic Antidepressants

The disparity between the potent in vitro effects of sertraline on inhibiting CYP2D6 (Ki