CLINICAL

THERAPEUTICSWOL.

22, NO. 12,200O

Pharmacokinetic Comparison of Oral Solution and Tablet Formulations of Citalopram: A Single-Dose, Randomized, Crossover Study
Marcelo M. Gutierrez, PhD, and Wattanaporn Abramowitz,
Forest Laboratories, Inc, New York, New York

PhD

ABSTRACT Background: Citalopram tablets fulfill most dosing needs in the treatment of depression, but some patients may have difficulty swallowing tablets and thus may be less likely to comply with their medication regimen. A liquid formulation of citalopram could be beneficial for such patients. Objective: This study was undertaken to compare the pharmacokinetic profiles of oral solution and tablet formulations of citalopram in healthy volunteers. Methods: In this open-label, single-dose, randomized, crossover, bioequivalence study, healthy volunteers alternately received one 60-mg dose of citalopram as an oral solution (10 mg/5 mL) and one 60-mg dose as a tablet. Doses were separated by a 14-day interval. Results: Of 24 subjects enrolled (mean age 27 years), 24 (16 men and 8 women) received the citalopram oral solution and 23 (15 men and 8 women) received the tablet; 1 subject discontinued before receiving the tablet. Citalopram was rapidly absorbed, with peak plasma concentrations occurring at -4 hours with both formulations. The rate and extent of absorption were similar between the 2 formulations, and no statistically significant differences were observed in half-life or oral clearance between formulations. Similarly, the pharmacokinetic profile for demethylcitalopram (the major metabolite of citalopram) did not differ between the 2 formulations. Both formulations were well tolerated, with no serious adverse events reported. Conclusion: The oral solution and tablet formulations of citalopram 60 mg were determined to be bioequivalent in this population. Key words: bioequivalence, citalopram, oral solution, pharmacokinetics. (C&z Ther: 2000;22:1525-1532)
Accepted for publication October 11, 2000. in whole or part is not permitted.

Printed in the USA. Reproduction

0149.2918/00/$19,00

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INTRODUCTION Citalopram is a selective serotonin reuptake inhibitor. In 1998 a tablet formulation of citalopram was approved by the US Food and Drug Administration for the treatment of depression. Citalopram achieves maximum plasma concentrations 2 to 4 hours after dosing, and it displays linear kinetics over the therapeutic dosage range of 10 to 60 mgid. The absolute bioavailability of the tablet formulation of citalopram is -80%. The recommended starting dosage of citalopram for all patients is 20 mgid. Available data indicate that most patients have a good therapeutic response to citalopram at this dosage. In elderly or hepatically impaired patients,3 the maximum recommended dosage of citalopram is 40 mg/d; in all other patients. 60 mg/d is the maximum recommended dosage. In the general population of depressed patients in the United States, the available 20- and 40-mg scored tablets of citalopram fulfill most dosing needs. However, some patients may have difficulty swallowing tablets and thus may be less likely to adhere to their medication regimen. For such patients, a liquid formulation of citalopram could be beneficial. A peppermint-flavored, sugar- and alcohol-free, oral liquid formulation of citalopram (IO mg/5 mL) recently has been developed. The present study compared the pharmacokinetic characteristics of a single 60-mg dose of citalopram administered in oral liquid versus tablet form in healthy volunteers.

gave written informed consent and could understand information provided to them about the study, if they were nonsmokers. and if their body weight was normal (according to the 1983 Metropolitan Height and Weight Tablejj. Subjects were excluded if they had clinically significant neurologic, psychiatric, cardiovascular. renal, hepatic, pulmonary, metabolic, or hematologic disease or hypersensitivity to citalopram. Subjects were also excluded if they had taken a prescription or over-the-counter medication dul-ing the 14 days before the first day of dosing, or if they had consumed caffeine within 48 hours or alcohol within 72 hours before the start of the study. Subjects who participated in any other clinical investigation using an experimental drug or requiring repeated blood sampling within 30 days before screening were also excluded. Female subjects of childbearing potential were required to have a negative serum pregnancy test at screening and to use a medically accepted contraceptive method during the study. The screening evaluation consisted of a complete medical history, physical examination. vita1 signs (temperature, pulse. respiration, and blood pressure). electrocardiogram, and clinical laboratory tests (hematology. blood chemistry, urinalysis).

Study Design This was an open-label, single-dose, ran domized, crossover, bioequivalence study in healthy volunteers. The ctinical portion of the study was conducted at Clinical Studies, Ltd. Fort Lauderdale, Florida. and was approved by the independent investigational review board. The study was performed in accordance with the Declaration of Helsinki guidelines on biomedical research involving human subjects as adopted by the 18th World Medical Assembly in 1964 and sub-

SUBJECTS

AND METHODS

Subjects in good medical health aged I8 to 35 years were eligible for the study if they

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M.M. GUTIERREZ AND W. ABRAMOWITZ

sequent amendments (Tokyo, 1975; Venice, 1983; Hong Kong, 1989). Each subject was randomly assigned to receive 2 treatments-one 60-mg dose of citalopram as an oral solution (10 mg/5 mL) and one 60-mg citalopram tablet. The oral liquid formulation contained citalopram in sorbitol solution USP 70%, with propylene glycol USP, preservatives, and natural peppermint flavor #104. The 60mg dose was chosen because it is the highest recommended dose for citalopram. In bioequivalence studies, the highest recommended dose is often tested. Because citalopram displays dose-proportional pharmacokinetic characteristics over a range of 10 to 60 mg/d, the results obtained with the 60-mg dose are applicable to lower doses. The 2 treatments were separated by a 14-day interval. Xanthine-containing food or beverages were prohibited for 48 hours before dosing until the last blood sample was collected. Alcohol was prohibited for 72 hours before and throughout the course of the study. In addition, grapefruit or grapefruit juice was prohibited throughout the course of the study. Subjects fasted overnight for 8 hours before the 8 AM dosing and blood sampling. Water was allowed as needed until 2 hours before drug administration, at which time it was restricted until 4 hours after dosing. Standardized, bland, low-fat meals and snacks were provided to subjects at predetermined times while they were housed for this study. All meals and snacks were free of xanthine-containing compounds (including caffeine) and contained ~20 g of fat each.

Blood Sampling and Assay Blood samples were collected by a qualified phlebotomist using prechilled 7-

mL lavender-top Vacutainer@ (BectonDickinson, Franklin Lakes, New Jersey) tubes containing 15% K,EDTA. Samples were collected beginning on each day of dosing at 0 hours (before dosing) and at 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, and 192 hours after dosing. The actual clock times of all blood samples were recorded and reported for each subject, and blood samples were kept at 4C before processing. Whole-blood samples for the determination of citalopram, its major metabolite demethylcitalopram (DCT), and a minor metabolite, didemethylcitalopram (DDCT), were centrifuged at 4C at 1500g for 10 minutes. A minimum of 3 mL of plasma was transferred into a prechilled polypropylene tube and frozen immediately using a dry-ice isopropyl alcohol bath. The samples were then stored upright at -70C. Plasma concentrations of citalopram, DCT, and DDCT were determined using high-performance liquid chromatography with fluorescence. The plasma sample was extracted with 1.5 mL butyl chloride containing 0.1% triethylamine. The sample was vortexed for 2 minutes and centrifuged at 200g for 5 minutes. The top layer was separated and 200 pL O.OlN HCl added. The tube was vortexed for 2 minutes, the organic layer evaporated, and 45 yL of HCl solution was injected into the chromatograph using Waters Intelligent Sample Processor (Waters, Milford, Massachusetts). Separation was achieved with an AllsphererM (Alltech, Deertield, Illinois) ODS 1 (250 x 4.6 mm) column using Phenomenex (Phenomenex, Torrance, California) ODS 2 Cl8 (3.9 x 30 mm) as a precolumn. The mobile phase consisted of 60% acetonitrile:40% 0.1 M phosphate buffer with 0.1% triethanolamine. This

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GUTIERREZ

AND W. ABRAMOWITZ

-+-c-

Tablet Oral solution

Time (h) Figure 1. Mean citalopram plasma concentrations 10 mg/5 mL oral solution. after one 60-mg tablet and 60 mg of a

Table II. Pharmacokinetic variables (mean + SD) for citalopram and 60 mg of a 10 mg/5 mL oral solution.
Oral Solution Variable (n = 23) 79.54 2831.00 2975.28 33.36 21.54 c 18.19 k 856.15 + 895.80 f 6.33 f 5.04 Tablet (n = 23) 80.28 2855.25 2990.67 33.55 21.42 + 18.90 + 832.84 + 869.43 + 6.76 + 5.17

after one 60-mg tablet

90% CI or P 95-104 95-104 96-103 NS NS NS

C maxi
AUC,,,

ng/mL
ng.h/mL ng.h/mL

AU&,,,, T rnax h t,/z, h Cl/F, L/h

4.09 + 1.59

4.00 + 1.31

Cmax = maximum concentration; AUC,_,;I, = area under the curve from time zero to last measurable concentration; AUC,,, = AUC from time zero to infinity; Tmsx = time to Cmax; t,,? = half-life; Cl/F = oral clearance.

ject were not included in the pharmacokinetic analyses. Figure 1 shows mean citalopram plasma concentrations after a 60-mg tablet and after 60 mg of the 10 mg/5 mL oral solution. The 2 curves are superimposable. As shown in Table II, all pharmacokinetic variables for the oral liquid formulation are similar to those for the tablet, with no statistically significant differences detected between the 2 formulations. There-

fore, the rate and extent of absorption of citalopram with the liquid formulation are similar to those with the tablet. The pharmacokinetic variables for DCT were also similar for the 2 formulations (Figure 2 and Table III). Consistent with studies of citalopram tablets, the plasma levels of DCT after administration of the oral solution were -33% of those of the parent compound. Plasma levels of DDCT were below the lower

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CLINICAL THERAPEUTICS

+ + 14 12 10 8 6 4 2 0 72 96 120

Tablet Oral solution

144

168

192

Time (h)

Figure 2. Mean demethylcitalopram plasma concentrations 60 mg of a 10 mg/S mL oral solution.

after one 60-mg tablet and

Table III. Pharmacokinetic variables (mean f SD) for demethylcitalopram mg citalopram tablet and 60 mg of a 10 m&/.5 mL oral solution. Oral Solution (n = 23)
11.27 f. 2.98 97 I .4 1 t 228.97 1206.80 t 258.06 20.00 rtr20.62 60.93 + 20.02
Tablet

after one 60-

Variable
C_.

(n = 23) I I .74 + 3.20 983.12 + 334.16 1204.10 t 259.72 14.17 f 12.22 59.37 t 23. I4

90% Cl or P 90- 104 93-104 Y-1 06 NS NS

concentra-

ng/mL

AUC,,_,ZI,,, n&.h/mL AUC,,,. ng.h/mL T rn:,x. h tl/?. h

C,,Inx = maximum concentration; AK,,_, ,,, = area under the curve from time xro to last meawrahlc tion: AUC,,_, = AUC from time xro tu infinity: T,,,a, = time to C,,,I,; t, = half-lift.

limit of quantification for the assay (~2 ng/mL). The most frequent adverse events were nausea, abdominal pain, diarrhea, dizziness, vomiting, and somnolence (Table IV). All adverse events were considered mild to moderate. Although the dosage administered was 3 times the recommended starting dosage of 20 mg/d, no serious adverse events were reported.

DISCUSSION Citalopram has been shown to be an effective and well-tolerated antidepressant in adult patients. Several studies have shown that it is also effective and well tolerated in elderly patients? In conjunction with these positive clinical findings, citaloprams favorable pharmacokinetic profile and relative lack of effect on the

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M.M. GUTIERREZ AND W. ABRAMOWITZ

Table IV. Adverse events. Oral Solution (n = 23) Nausea Abdominal pain Diarrhea Dizziness Vomiting Somnolence Headache Fatigue Dyspepsia Flatulence Fever Tremor Anxiety Insomnia Paresthesia 12 10 10 8 5 5 3 2 2 1 1 1 0 0 0

Tablet (n = 23) 13 7 7 7 4 4 3 0 2 0 0 2 1 1 I

oral liquid formulation has the potential to extend the benefits of citalopram and to improve outcomes in some patients who already are taking this drug. Finally, the liquid formulation of citalopram, unlike the liquid formulations of some other antidepressants (eg, fluoxetine), contains no sugar or alcohol. This may be a significant consideration for some patients.

CONCLUSIONS The oral solution and tablet formulations of citalopram were determined to have the same pharmacokinetic profile in this population of healthy adult volunteers. Thus, the citalopram oral solution may help to meet the therapeutic needs of a wider range of patients with depression.

cytochrome P450 enzyme systemss9 make it a suitable choice of antidepressant for a wide variety of patients. This study of healthy volunteers showed that a 60-mg dose of an oral liquid formulation of citalopram (10 mg/ 5 mL) has the same pharmacokinetic profile as does one 60-mg citalopram tablet. Because citalopram displays linear kinetics across the lo- to 60-mg dose range, these results should apply across the full therapeutic dosing range. Thus, the oral solution of citalopram retains the favorable qualities of the tablet formulation while providing an alternative for patients who have difficulty swallowing tablets and potentially aiding compliance. Because long-term treatment of depression is recommended to prevent the relapse or recurrence of symptoms,0 compliance is a critical component of successful antidepressant pharmacotherapy. Therefore, the

Address correspondence to: Marcel0 M. Gutierrez, PhD, Department of Pharmacokinetics, Forest Laboratories, Inc, 909 Third Avenue, New York, NY 10022.

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Hirschfeld RMA. Citalopram dosing of

depressed patients by US psychiatrists. Poster presented at: Annual Meeting of the American Psychiatric Association; May 15-20, 2000; Washington, DC. 687. Joffe P, Larsen FS, Pedersen V, et al. Single-dose pharmacokinetics of citalopram in patients with moderate renal insufficiency or hepatic cirrhosis compared with healthy subjects. Eur J Clin Pharmacol. 1998;54:237-242.

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4.

Metropolitan New

Height

~rrd

Weight

Tuhles.

York: Metropolitan
1983.

Life Insurance

co;

citalopram and amitriptyline in elderly depressed patients treated in general practice. Depr-<,.s.siort All.%-iefy. I998;8: 147-l S?. 8. Jeppeaen U, Gram L. Vibtisen K. DosedependentinhibitionofCYP1 A2, CYP2C19. and CY P2D6 by citalopram, tluoxetine. fluvoxamine. and paroxetine. Et&t-.I Clifr Phitrmncal. 1996:5 1:71-78. 9. Greenblatt DJ. van Moltke LL, Harmatz JS, Shader RI. Human cytochromes and some newer antidepressants: Kinetics. metabolism. and drug interactions. J Clifl Psy~hophtrri~~trc,nl. 1999: 19(Suppl I ):2?&3SS. IO. Keller MB. The long-term treatment ofdepression. J Cliti Psyc,lzicrtry. I999:6O(Suppl 17):41-45; discussion 36-48.

5. Nyth AL, Gottfries CG, Lyby K, et al. A controlled multicenter clinical study of citalopram and placebo in elderly depressed patients with and without concomitant dementia. Actu fsvdtiatr. Stand.
l992:%: 1X-145.

6. Nyth AL, Gottfries CG. The clinical effcacy of citalopram in treatment of emotional disturbances in dementia disorders. A Nordic multicentre study. Ar .I P.ILY%my. 1990; 157:894-90 I. 7. Kyle CJ, Petersen HE. Over@ KF. Comparison of the tolerability and efficacy of

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