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The Pharmacokinetics of Escitalopram After Oral and Intravenous Administration of Single and Multiple Doses to Healthy Subjects

From the Department of Clinical Pharmacology and Pharmacokinetics, H. Lundbeck A/S, Copenhagen, Denmark (B. Søgaard, H. Mengel, F. Larsen); and the Forest Research Institute, Forest Laboratories, Inc, Jersey City, New Jersey (N. Rao).

Address for reprints: B. Søgaard, Department of Clinical Pharmacology, H. Lundbeck A/S, Ottiliavej 7, DK-2500 Copenhagen-Valby, Denmark.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
The pharmacokinetics of escitalopram (S-citalopram) and its principal metabolite, S-demethylcitalopram (S-DCT), were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion of escitalopram, the mean systemic clearance and volume of distribution were 31 L/h and 1100 L, respectively. After oral administration of single or multiple doses, the absorption was relatively fast, with the maximum observed plasma or serum concentration (C_max) attained after 3 to 4 hours. The mean half-lives were 27 and 33 hours, respectively; steady state was attained within 10 days. The area under the plasma or serum concentrationtime curve from time zero to 24 hours and C_max was both linear and proportional to the dose. The apparent volume of distribution was around 20 L/kg. Comparison of the systemic and oral clearance implied a high absolute bioavailability. There was no evidence of interconversion from S-citalopram to R-citalopram either in plasma or in urine. Concurrent intake of food had no effect on the pharmacokinetics of escitalopram or its metabolite. All treatments were well tolerated.

Key Words: Escitalopram • citalopram • enantiomer • healthy volunteers • single dose • multiple dose • cross-over • pharmacokinetics • bioequivalence • tolerability

Clinical trials with escitalopram have consistently shown better efficacy with escitalopram than with racemic citalopram, including higher rates of response and remission, but with comparable tolerability profiles.^3-6

The principal metabolite of escitalopram is S-demethylcitalopram (S-DCT), which may be further metabolized to S-didemethylcitalopram (S-DDCT) in small quantities. The metabolism involves the cytochrome P450 isozymes CYP2C19, CYP3A4 and CYP2D6.^7,8 Compared with the parent compound, both metabolites show only weak pharmacological activity in vitro and no activity in vivo.^4,9

The present article describes the pharmacokinetic profile of escitalopram and its principal metabolite after oral and intravenous administration of single and repeated doses to healthy subjects in 4 separate phase I studies. In 3 of the reported studies, citalopram was administered for comparison, but these results are only briefly mentioned, as they do not add new information.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
Subjects
Local Independent Ethics Committees (see Appendix) approved the studies, and all subjects gave written informed consent. The studies were carried out in accordance with the Declaration of Helsinki and the Principles of Good Clinical Practice.

The healthy subjects (either men, or men and women, depending on the study), aged 18 to 45 years, were recruited if they were within 20% of ideal body weight, in good physical condition, and had no clinically significant illness or abnormal laboratory values.

Study Designs
Study 1 was a single-dose study comparing the pharmacokinetics of escitalopram after intravenous infusion of escitalopram (10 mg over 60 minutes) or citalopram (20 mg over 60 minutes). Eight healthy male subjects were randomly assigned to 1 of 2 treatment sequences: escitalopram followed by citalopram or vice versa. Each administration was separated by a washout period of at least 2 weeks.

Study 2 was a single-dose study of the pharmacokinetics of escitalopram after an oral dose of 20 mg escitalopram or 40 mg citalopram given in random order to 2 groups of 12 healthy male subjects. The 2 treatment periods were separated by a 21-day washout period.

Study 3 was a multiple-dose, double-blind pharmacokinetic study of escitalopram after the administration of 10 or 30 mg/d escitalopram and 20 or 60 mg/d citalopram. Eighteen male and 18 female subjects were randomly allocated to 2 parallel groups (18 in the lowdose group and 18 in the high-dose group). Half of the low-dose group received 10 mg/d escitalopram in sequence 1 followed by 20 mg/d citalopram in sequence 2. The other half of the group received treatments in the opposite order. The high-dose group received either escitalopram (3 days at 10 mg/d, 3 days at 20 mg/d, and 18 days at 30 mg/d) in sequence 1 followed by citalopram (3 days at 20 mg/d, 3 days at 40 mg/d, and 18 days at 60 mg/d) in sequence 2 or vice versa. Each of the 2 sequences lasted 24 days at both dose levels, separated by a 14-day washout period.

Study 4 investigated the effect of food on the bioavailability of a single oral dose of escitalopram (20 mg). Eight male and 10 female subjects received, in a randomized order, 3 treatments: a single oral dose of 20 mg of escitalopram (as the commercialized tablet) in the fed state (treatment A) and in fasted state (treatment B) and 20 mg of escitalopram as the tablet formulation used in clinical trials in the fasted state (treatment C). The treatments were separated by an interval of at least 14 days. For treatments B and C, subjects fasted for at least 10 hours before dosing and for another 4 hours after dosing. For treatment A, subjects fasted for 10 hours before a standardized high-fat, high-calorie breakfast (approximately 1000 calories, 50% fat) given 30 minutes before drug administration. Treatment C was included for regulatory purposes, and the results will not be presented here.

In all 4 studies, most subjects were white.

Genotyping
In studies 1 and 3, the genotype of each subject, in terms of polymorphic cytochrome P450 isozymes 2D6 (CYP2D6) and 2C19 (CYP2C19), was determined by analysis of the CYP2D6 (^*3, ^*4 and ^*6 [only study 1] alleles) and CYP2C19 (^*2 and ^*3 alleles) genotypes. In study 2, only the CYP2D6 genotype was determined. Genotype was determined using polymerase chain reaction amplification with fluorescence detection.

Safety and Tolerability
Safety and tolerability were assessed throughout all the studies by the monitoring of adverse events (AEs), by physical examinations, by electrocardiograms (ECGs), and by laboratory and vital signs assessments.

Blood Sampling
Venous blood samples were drawn from an antecubital vein either in plain glass tubes (for serum) or in prechilled Lavender Top Vacutainer (Becton, Dickinson and Co, Franklin Lakes, NJ) tubes containing potassium EDTA as an anticoagulant (for plasma) for determination of escitalopram, R-citalopram, and their metabolites.

In each study sequence, blood samples (5-10 mL) were drawn at predefined time points from before dosing up to 120 to 240 hours after dosing, depending on the study. In the multiple-dose study (study 3), blood samples were collected on both day 1 and day 24. In addition, predose samples were drawn on days 2, 10, 16, 21, 22, and 23 for assessment of steady state.

Urine Collection
In study 2, urine was collected at the following intervals: 0 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48 hours and thereafter every 24 hours up to 168 hours after dosing.

Drug Analysis
Serum or plasma concentrations of escitalopram, S-DCT, and S-DDCT were determined using enantioselective (except study 4) high-performance liquid chromatographic methods.^10,11 In study 1, mass-spectrometric detection was performed on a Quattro LC from Micromass (Manchester, United Kingdom) using positive electrospray ionization in multiple reaction-monitoring mode. In studies 2 and 3, mass-spectrometric detection (TSQ 7000, Thermo Finnegan, San Jose, Calif) was performed in selective reaction-monitoring mode. In study 4, fluorescence detection was used (excitation 240 nm, emission 296 nm). The internal standard was a citalopram analogue, (±)-1-(3-dimethylaminopropyl)-1-(4-chlorophenyl)-1, 3-dihydroisobenzofuran-5-carbonitrile (Lu 10-202-O). The lower limit of quantification (LLOQ), using 0.5 mL of serum or plasma for analysis, was 3.08, 3.22, and 3.37 nmol/L for escitalopram (and R-citalopram), S-DCT (and R-DCT), and S-DDCT (and R-DDCT), respectively. In study 4, the LLOQ was twice these values. The bioanalytical method for the urine samples was essentially the same as the method for analyzing plasma.¹⁰

Pharmacokinetic Analysis
Pharmacokinetic parameters of escitalopram and S-DCT including the maximum observed plasma or serum concentration (C_max), the time to C_max (t_max), the apparent elimination half-life in plasma or serum (t_1/2), the area under the plasma or serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUC_0-t), the area under concentration-time curve from time zero to infinity (AUC_0-inf), clearance (either systemic [CL] or oral [CL/F] of escitalopram were estimated as dose/AUC_0-inf) and the apparent volume of distribution (V_z or V_z/F) was estimated using standard noncompartmental methods and the software package WinNonlin (Pharsight Corporation, Calif).

From the urine data, the renal clearance (CL_R, amount excreted in urine/AUC_0-inf), the percentage of the dose excreted unchanged in urine and the halflives of escitalopram and S-DCT were calculated.

Statistical Analysis
For study 4 (influence of food), the statistical model contained terms for sequence, subject nested within sequence, period, treatment, and residual effects. The bioequivalence was assessed using the 2 one-sided test procedures with a 90% confidence interval (with acceptance limits of 80%-125% for AUC_0-inf and 70%-143% for C_max) on log-transformed data (according to Note for Guidance on Investigation of Bioavailability and Bioequivalence, CPMP/EWP/QWP/1401/98).

For the multiple oral dose study, the statistical model included a term for gender.

The statistical software used was SAS version 6.12 or later (SAS Institute Inc, Cary, NC).

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
Pharmacokinetics
The values of the pharmacokinetic parameters for escitalopram and S-DCT are presented in Tables I and II, and the mean serum concentration versus time profile of escitalopram and S-DCT after an oral single dose of escitalopram (study 2) is presented in Figure 1.

View larger version (16K): [in this window] [in a new window]   Figure 1. Mean serum concentration versus time profiles (± SD) of escitalopram and S-DCT (S-demethylcitalopram) after a single oral dose of 20 mg escitalopram.

Escitalopram. Consistent with the systemic clearance (mean 31.1 L/h) and the V_z (mean 1100 L), a mean t_1/2 of 27 hours was found for escitalopram after intravenous administration (Table I).

Following both single and multiple oral doses, escitalopram was rapidly absorbed reaching C_max at 3 to 4 hours. Comparing C_max and AUC_0-24 after the first administration on day 1 (10 mg: about 28 nmol/L and 425 nmol•h/L, respectively) and at steady state (day 24, Table I), the values for escitalopram were 2.3-fold to 2.6-fold higher at steady state, which is consistent with a t_1/2 of about 30 hours. In general, for escitalopram, steady state was attained within 10 days of dosing, as there was no statistical significant difference between trough concentrations on day 10 and on day 24.

Coadministration of food with escitalopram did not affect the pharmacokinetic parameter values (Table II). For escitalopram, the calculated 90% confidence interval range for C_max, AUC_0-t, and AUC_0-inf for fed and fasted subjects fell within the 80% to 125% limits required to conclude bioequivalence. Values for t_max and t_1/2, as well as CL/F and V_z/F, for escitalopram were not significantly different after administration of escitalopram to fasted or fed subjects.

The CL/F and the V_z were similar after single and multiple doses at different dose levels (Table I). The mean body weight normalized V_z at steady state was about20L/kg, ranging from 12 to 36 L/kg.

S-DCT metabolite. After intravenous administration, the mean values of C_max and AUC_0-t for S-DCT were about 8% and 28%, respectively, of the corresponding escitalopram values. After a single oral dose of 20 mg escitalopram, the mean C_max for the metabolite was about 19% of that of the parent drug and was reached after approximately 14 hours. After multiple oral dosing, the mean C_max and AUC_0-24 of the metabolite S-DCT were about 35% and 40% of the parent compound, respectively, with t_max occurring 6 to 8 hours after dosing. The t_1/2 of S-DCT was about twice that of escitalopram.

Comparing C_max and AUC_0-24 after the first administration on day 1 (about 5 nmol/L and 90 nmol•h/L, respectively) and at steady state (day 24, Table I), the values for the metabolite increased approximately 5-fold.

Coadministration of food did not affect the pharmacokinetic parameters of S-DCT either (Table II).

S-DDCT metabolite. The serum or plasma concentrations of this metabolite were below the LLOQ after single dose administration. During multiple oral dosing with escitalopram, the concentrations in a significant part of the samples were below the LLOQ. The overall mean indicated that the S-DDCT levels were approximately 2% to 4% of the parent compound.

Urinary Excretion
The CL_R values of escitalopram and S-DCT were 2.7 and 6.9 L/h, respectively, corresponding to excretion of about 8% and 10% of the dose in the urine (Table I). The t_1/2 assessed from urine concentration data were consistent with the values obtained from plasma.

Influence of Gender
Numerically higher mean AUC_0-24 values for escitalopram were seen in women compared with men. When the values were normalized for weight, however, there were no differences attributable to gender. Neither non-weight-normalized nor weight-normalized AUC_0-24 values showed any statistically significant differences between men and women.

Interconversion
There was no evidence of interconversion from S-enantiomers to R-enantiomers in either plasma or urine in any of the studies.

Influence of Genotype
The single dose studies included 1 (study 1) and 2 subjects (study 2) who were CYP2D6 poor metabolizers, but they showed no consistent differences in the pharmacokinetic parameters compared with the rest of the subjects, who were extensive metabolizers. In the multiple dose study, there were 3 CYP2D6 and 3 CYP2C19 poor metabolizers. None were double poor metabolizers. Again, there were no consistent differences in the pharmacokinetics when CYP2D6 poor metabolizers were compared with the other subjects; only 1 of the 3 subjects had a lower CL/F (14 L/h). The CYP2C19 poor metabolizers were among those with the highest plasma concentrations of escitalopram. In these subjects, the CL/F on day 24 ranged from 10 to 12 L/h.

Safety and Tolerability
Escitalopram was well tolerated in all 4 studies. There were no serious AEs, and none of the reported AEs were considered severe. Two subjects (receiving 20 and 60 mg citalopram) withdrew because of treatment-related AEs (anxiety and loss of concentration or headache). Nausea, headache, dizziness, and somnolence were consistently among the 5 most common AEs in all studies. Neither escitalopram nor citalopram treatment caused any clinically significant changes in vital signs, ECG values, or clinical laboratory parameters.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
The present article describes the pharmacokinetic profile of escitalopram and S-DCT after oral and intravenous administration of single and repeated doses to healthy subjects. After single and multiple oral administrations, C_max values for escitalopram and S-DCT were proportional to the doses administered. The t_max of escitalopram (3 to 4 hours) corresponds to the values reported previously for escitalopram after administration of citalopram.¹² Based on the 90% confidence intervals for C_max, AUC_0-t, and AUC_0-inf for escitalopram, there was no evidence for any food effect. Indeed, none of the pharmacokinetic parameters showed any significant differences between fed and fasted subjects.

CL/F, V_z, and terminal t_1/2 of escitalopram were constant across doses and were similar after single dose administration and at steady state. This result was also true for the relevant parameters for the metabolite (S-DCT).

The mean t_1/2 values (27 and 33 hours) of escitalopram were slightly shorter than those described previously (about 35 hours) after administration of citalopram¹² but remain essentially comparable. For the S-DCT metabolite, the mean values of C_max, t_max, AUC, and t_1/2 after multiple dosing of escitalopram were also in agreement with values reported previously.¹²

The t_1/2 of escitalopram would predict steady state to be attained within about a week (5 times t_1/2). However, in this study, the first trough samples were drawn after 10 days, confirming that steady state was attained within 10 days of dosing. For escitalopram and S-DCT, the accumulation factors were about 2.5 and 5, respectively.

As there was no crossover between the intravenous and oral administrations of escitalopram, it is not possible to calculate the absolute bioavailability directly. However, the t_1/2 for escitalopram was similar following intravenous infusion and oral administration. In the present studies, based on the mean CL after oral and intravenous administration (36 L/h vs 31 L/h, respectively), the estimate of the absolute bioavailability for escitalopram appears to be in the order of approximately 80%, implying limited first-pass metabolism. This finding is in agreement with the value reported for citalopram (ie, the S-enantiomer plus R-enantiomer).¹³

The urine analysis revealed that a relatively small amount of the dose (8%) was excreted as unchanged escitalopram. This finding compares well with previous results¹² and reflects a relatively low CLR of about 3L/h.

There was no evidence, in any study, of interconversion from the S-enantiomer to the R-enantiomer.

After multiple doses of escitalopram, the CL/F in the 3 CYP2C19 poor metabolizers was about one third of the overall mean values. This finding did not result in an increase in the frequency of the AEs in comparison with the other subjects. For the 3 CYP2D6 metabolizers, no consistent pattern was observed.

All treatments were well tolerated. Nausea, headache, and dizziness were among the most frequent AEs found with escitalopram, which are similar to those previously described for citalopram.¹⁴ No dose-dependent effect was observed. There were no clinically significant, treatment-related findings in clinical laboratory data, vital signs, ECG values, or physical examinations.

	CONCLUSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
The pharmacokinetics of escitalopram and its principal metabolite were linear and dose proportional in the range 10 to 30 mg. The mean t_1/2 was about 30 hours. Escitalopram was well absorbed, and the pharmacokinetics was not influenced by food intake. There was no evidence of interconversion from the S-enantiomer to the R-enantiomer.

	ACKNOWLEDGEMENTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
We thank M. Briley, PhD, for assistance with the manuscript.

A preliminary account of part of this work was presented as posters at the 41st and 42nd Annual New Clinical Drug Evaluation Unit Meeting 2001 and 2002.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 

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7. von Moltke LL, Greenblatt DJ, Giancarlo GM, Harmatz JS, Shader RI. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Disp. 2001;29: 1102-1109.[Abstract/Free Full Text]

8. Herrlin K, Yasui-Furukori N, Tybring G, Widén J, Gustafsson LL, Bertilsson L. Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. Br J Clin Pharmacol. 2003;56: 415-421.[CrossRef][Medline] [Order article via Infotrieve]

9. Baumann P, Larsen F. The pharmacokinetics of citalopram. Rev Contemp Pharmacother. 1995;6: 287-295.

10. Gutierrez MM, Rosenberg J, Abramowitz W. An evaluation of the potential for pharmacokinetic interaction between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir. Clin Ther. 2003;25: 1200-1210.[Medline] [Order article via Infotrieve]

11. Malling D, Poulsen MN, Søgaard B. The effect of cimetidine or omeprazole on the pharmacokinetics of escitalopram. Br J Clin Pharmacol. 2005;60: 287-290.[Medline] [Order article via Infotrieve]

12. Sidhu J, Priskorn M, Poulsen M, Segonzac A, Grollier G, Larsen F. Steady state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans. Chirality. 1997;9: 686-692.[Medline] [Order article via Infotrieve]

13. Joffe P, Larsen FS, Pedersen V, Ring-Larsen H, Aaes-Jørgensen T, Sidhu J. 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.[CrossRef][Medline] [Order article via Infotrieve]

14. Hyttel J, Bøgesø KP, Perregaard J, Sánchez C. The pharmacological effect of citalopram resides in the (S)-(+)-enantiomer. J Neural Transm Gen Sect. 1992;88: 157-160.[CrossRef][Medline] [Order article via Infotrieve]
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