Pharmacokinetics of desloratadine in children between 2 and 11 years of age

Abstract

Aims

The aim of the studies was to characterize the pharmacokinetics of desloratadine in healthy children and to determine the appropriate dose for paediatric patients 2–11 years old.

Methods

Two open-label, single-dose studies were carried out in healthy children between 2–5 (n = 18) and 6–11 years old (n = 18). On day 1, subjects received a single oral dose of desloratadine syrup (1.25 mg for 2–5 year olds or 2.5 mg for 6–11 year olds). Subjects were followed for an additional 4 days during which vital signs were measured daily and blood samples were collected periodically.

Results

Plasma desloratadine C_max occurred at a median of 2.0 h after dosing in both age groups. Median values for the younger (2–5 years old) and older (6–11 years old) groups were 2.28 and 2.05 ng ml⁻¹, respectively. Arithmetic (and harmonic) mean t_1/2 (h) values for each group, respectively, were 16.4 (13.9) and 19.4 (15.8). Exposure to desloratadine was similar in both the younger and older age groups, with a median AUC(last) of 38.8 and 38.2 ng ml⁻¹ h, respectively. These data were similar to values in adults, who received 5 mg doses of desloratadine. No adverse events or clinically significant abnormal laboratory values were noted in either group.

Conclusions

Single doses of desloratadine syrup (1.25 and 2.5 mg) were well tolerated in children 2–5 and 6–11 years old. Desloratadine exposure in children appears to be similar to that observed in adults, in whom efficacy has been established.

Introduction

Desloratadine, the principal metabolite of loratadine, is an orally active, nonsedating, peripheral histamine H₁-receptor antagonist indicated for the relief of the symptoms of seasonal allergic rhinitis, perennial allergic rhinitis and chronic idiopathic urticaria [1]. Studies in mice have shown that desloratadine is approximately four times as potent as loratadine, whereas human in vitro studies have indicated that it is up to 10 times more active [2]. Desloratadine causes few alterations in behaviour, or in neurological or autonomic function, at doses of up to 300 mg kg⁻¹ in mice and 12 mg kg⁻¹ in rats [3].

Following oral administration of desloratadine 5 mg once daily to healthy adults for 10 days, the mean time to maximum plasma concentrations (t_max) was approximately 3 h. The mean steady-state plasma concentration (C_max) and area under the plasma concentration–time curve 24 h after dosing (AUC(0,24 h)) were 4 ng ml ⁻¹ and 56.9 ng ml⁻¹ h, respectively [4]. Values for C_max and AUC increase in a dose-proportional manner following single oral doses of between 5 and 20 mg [4]. The meanelimination t_1/2 of desloratadine was approximately 27 h [4]. The results of two large placebo controlled trials in adults and adolescents with seasonal allergic rhinitis and chronic idiopathic urticaria [5, 6] showed that once-daily dosing with 5 mg desloratadine provided 24 h relief of symptoms.

Desloratadine is extensively metabolized to 3-hydroxydesloratadine, an active metabolite that is subsequently glucuronidated [7]. The enzyme(s) responsible for the formation of 3-hydroxydesloratadine has not been identified. Data from clinical trials indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine and are ‘poor metabolizers’ of desloratadine [8].

Antihistamines are frequently used in the management of allergic conditions, such as chronic idiopathic urticaria and allergic rhinitis, in children [9, 10]. It is thought that the pathophysiologies of these conditions and the activity of antihistamines are similar in adults and children [11, 12]. Therefore, a dose of desloratadine that matches the systemic exposure seen in adults receiving the approved dose of 5 mg is expected to be efficacious in children. The present studies were conducted to characterize the pharmacokinetic profile of a single dose of oral desloratadine syrup in healthy children between 2 and 11 years of age, in order to establish the appropriate dose of the drug.

Methods

Study protocol

Two separate open label, single dose studies were performed in children 2–5 and 6–11 years of age.

Both studies were carried out at Arkansas Research, Little Rock, AR, USA. The protocols and informed consent forms were reviewed and approved by an Institutional Review Board (Arkansas Research Human Volunteer Research Committee), and the studies were conducted in accordance with good clinical practice and the principles of the Declaration of Helsinki. Written informed consent was obtained from a parent or legal guardian of each subject at the screening visit before conducting any study-related activities.

Within 3 weeks of screening, children who met the study entry criteria received a single dose of desloratadine syrup (0.5 mg ml⁻¹) administered orally via syringe (2.5 ml (1.25 mg) in the children 2–5 years old, and 5 ml (2.5 mg) in the children 6–11 years old). All subjects attended the study site at least 12 h before dosing, which occurred the following morning in the presence of a physician. Upon confinement, laboratory tests performed at screening were repeated for each subject. Within each study, all subjects received treatment on the same day, and remained awake and ambulatory for 4 h after dosing.

Vital signs were measured daily, and blood samples (5 ml) were collected immediately prior to drug administration and at 1, 1.5, 2, 4, 8, 12, 24, 48, 72 and 96 h after dosing. Subjects were discharged from the study site after 24 h and returned on days 3, 4 and 5 for the remaining samples and procedures.

Subjects

Healthy male and female children between 2–5 or 6–11 years old, were eligible for inclusion in one of the two studies. Subjects were free from any disease or condition that required medical attention, or that would have interfered with participation in the study. For inclusion, the results of the laboratory tests and a 12-lead electrocardiogram (ECG), recorded at 25 mm s⁻¹ and ventricular rate and PR, QRS, QT and QTc intervals, were required to be within normal limits or clinically acceptable to the investigator.

Children with a local or systemic infectious disease within 4 weeks of treatment, or who tested positive for hepatitis B surface antigen or hepatitis C antibody, were excluded from the studies. Those with a clinically significant food or drug allergy (in particular to loratadine) were also ruled out. Additional exclusion criteria included participation in a clinical trial of an investigational drug within the previous 30 days, use of terfenadine or astemizole within 30 days (or other medications, including loratadine, within 14 days) prior to the study, and consumption of caffeine or xanthine-containing substances within 72 h. No concomitant medications except paracetamol were permitted during the course of the study period without prior approval, except in the event of a medical emergency.

Drug and metabolite analysis

Anticoagulated blood samples were stored on ice and centrifuged within 30 min after collection at approximately 4°C and 4000 g for 20 min. Plasma was transferred into two tubes, stored frozen at or below −20°C, and shipped in dry ice to the analytical laboratory (PPD Pharmaco, Richmond, Virginia, USA). Plasma samples were then assayed for desloratadine and 3-OH-desloratadine concentrations using liquid chromatography with tandem mass spectrometric detection [13]. The lower limit of quantification was 0.025 ng ml⁻¹ for both desloratadine and 3-OH-desloratadine. All values below the lower limit of quantification were reported as zero. For desloratadine, between run coefficient of variation (%CV) was 7.5, 3.5 and 2.4% for low, medium andhigh QC concentrations, respectively. For 3OH-desloratadine, between run %CV was 6.3, 3.9 and 3.2% for low, medium and high QC concentrations, respectively.

Pharmacokinetic analysis

Plasma concentration data were used to estimate pharmacokinetic parameters for desloratadine and 3-OH-desloratadine, using model-independent methods (WinNonlin Professional, Version 2.1; Pharsight Corp, CA, USA) [14]. The maximum plasma concentration (C_max) and time to maximum plasma concentration (t_max) were the observed values. The terminal-phase rate constant (λ_z) was calculated using linear regression from the slope of the log-linear terminal portion of the plasma concentration–time curve. The terminal-phase half-life (t_1/2) was determined from the expression 0.693/λ_z. The area under the plasma concentration–time curve from time zero to the time of the last quantifiable sample [AUC(last)] was calculated using the linear trapezoidal method. Where appropriate, the value of AUC(last) was extrapolated to infinity from equation:

where C(est) was the estimated concentration determined from linear regression at the time of the last quantifiable sample. The apparent clearance, CL/F, was determined from the equation:

The apparent volume of distribution, V_d/F, was calculated from the CL/F using the equation:

The AUC(last) ratio of 3-OH-desloratadine (3-OH-DL):desloratadine (DL) was determined from the equation:

Statistical analysis

Summary statistics were used to describe the pharmacokinetic data and included means and medians, standard deviations, percentage coefficient of variation (%CV) and 95% confidence intervals. The influence of demographic factors on the pharmacokinetic parameters of desloratadine was examined using a stepwise linear regression model, with the former being entered into the model at the 10% level of probability and removed at the 5% level.

Assessments of adverse events

Physical examinations, vital signs, ECG recordings and clinical laboratory tests were conducted at screening, and at the end of the studies (96 h after treatment). Routine laboratory tests (blood count, blood chemistry and urinalysis) were also carried out prior to treatment, and vital signs were measured daily during the study period. Subjects were observed and questioned throughout the study to detect the occurrence of adverse events or signs of discomfort. Details of all reported adverse events were recorded, including their severity and relationship to treatment (unlikely, possible or probable).

Results

Thirty-six children between 2–5 years (n = 18) and 6–11 years of age (n = 18) were enrolled in and completed the two studies. Baseline demographic characteristics are presented in Table 1.

Table 1.

Baseline demographic characteristics of the subjects studied

	Age 2–5 years (n = 18)	Age 6–11 years (n = 18)
Mean age (years) (range)	3.4 (2–5)	8.5 (6–11)
Gender, male/female	10/8	9/9
Race, Caucasian/Black	16/2	16/2
Mean weight (kg) (range)	17.4 (13–23)	30.7 (18.6–50.5)
Mean height (m) (range)	0.99 (0.86–1.12)	1.32 (1.18–1.45)

The pharmacokinetic parameters for desloratadine and 3-OH-desloratadine are summarized in Table 2. Plasma concentrations of both desloratadine and 3-OH-desloratadine decreased slowly after reaching the maximum concentration in both age groups. Exposure to desloratadine based on AUC was similar in both age groups.

Table 2.

Pharmacokinetic parameters for the subject studied

	Children aged 2–5 years (n = 18) 1.25 mg desloratadine			Children aged 6–11 years (n = 18) 2.5 mg desloratadine
Variable	Arithmetic meana	Geometric mean	Median	Arithmetic meana	Geometric mean	Median
Desloratadine
Cmax (ng ml−1)	2.68 (50)	2.44	2.28	2.23 (35)	2.10	2.05
tmax (h)	3.17 (63)	2.74	2.00	3.67 (79)	2.93	2.00
t1/2 (h)	16.4 (55)	13.9b	–	19.4 (61)	15.8b	–
AUC(last) (ng ml−1 h)	42.0 (49)	37.5	38.8	48.6 (88)	38.1	38.2
CL/F (l h−1)	35.8 (50)	31.6	31.4	73.7 (55)	60.8	64.5l
Vd/F (l)	707 (31)	679	686	1619 (39)	1507	1565
3-OH-desloratadine
Cmax (ng ml−1)	0.644 (49)	0.508	0.656	0.764 (54)	0.546	0.785
tmax (h)	4.89 (35)	4.67	4.00	4.44 (42)	4.25	4.00
t1/2 (h)	26.2 (78)	20.6b	–	28.1 (65)	23.7bc	–
AUC(last) (ng ml−1 h)	17.3 (42)	14.5	18.4	20.5 (50)	13.0	21.0
AUC(last) ratio (%)	53.1 (58)	38.7	44	68.6 (59)	34.2	74.6

^aValues in parentheses are the percentage coefficients of variation.

^bHarmonic mean.

^cn = 17.

Peak plasma concentrations of desloratadine occurred at a median t_max of 2 h after dosing in both age groups, with a range of 1.5–8 h in children 2–5 years old and 1.5–12 h in children 6–11 years old (Figure 1A). Peak plasma concentrations of 3-OH-desloratadine occurred later at 4–8 h after dosing in the 2–5-year-old group and 4–12 h in the 6–11-year-old group, with a median t_max of 4.0 h in both groups (Figure 1B).

Figure 1.

Arithmetic mean concentration–time profiles for desloratadine (•) and 3-hydroxy (3-OH)-desloratadine (○) in children aged 2–5 years (1.25 mg dose; Figure 1A) and 6–11 years (2.5 mg dose; Figure 1B)

Children 2–5 and 6–11 years old had median AUC values of 38.7 and 38.4 ng ml⁻¹ h, respectively, compared with 35.3 ng ml⁻¹ h in adults receiving 5 mg desloratadine as a syrup, and 38.5 ng ml⁻¹ h in adults receiving 5 mg of desloratadine as tablets (data on file at Schering-Plough, Kenilworth, NJ, USA). The C_max values for the drug as well as systemic exposure to its metabolite 3-OH desloratadine observed in the two paediatric studies reported here were also comparable with those seen in the adults.

No significant relationships between pharmacokinetic variables and age or body weight were found within the 2–5 years olds. However, in the 6–11 years olds, there was a statistically significant (P = 0.01) relationship between body weight and C_max, which explained 34% of the variability in the latter (Figure 2).

Figure 2.

The relationship between dose-adjusted C_max and body weight of the paediatric subjects studied

Two subjects in the younger age group had plasma concentrations and AUC values that were higher for desloratadine and lower for 3-OH-desloratadine than the other subjects. Thus, their rate of metabolism of desloratadine appeared to be lower than that of the other 16 subjects (Table 2). The AUC ratios (metabolite to parent) in these two children were 2% and 3%, compared with 28%−123% in the others. Similarly, three subjects in the older age group were ‘poor metabolizers’ of desloratadine, with AUC ratios of 3.7%, 0.05% and 0.9%, compared with 39.9%−140% in the other 15 children. The metabolite to parent ratio profile in Figure 3 was fairly flat with two small deeps. Deeps were associated with five ‘poor metabolizers’ of desloratadine in both age groups.

Figure 3.

The trend in AUC of metabolite (3-OH desloratadine) to the parent drug (desloratadine) ratio as a function of age in the paediatric subjects studied

To make a valid comparison of AUC in paediatric vs. adult subjects, common desloratadine concentration–time points (0, 1, 2, 4, 8, 12, 24, 48 and 72 h) were extracted from the present data and from a previous phase 1 pharmacokinetic study of desloratadine in 30 adults following a single dose of 5 mg given as a syrup (data on file at Schering-Plough, Kenilworth, NJ, USA), and the AUC values were calculated. As the comparisons were being made across studies, and owing to the presence of ‘poor metabolizers’ in some studies, median as opposed to mean AUC values were used to compare exposure (Figure 4). Doses of 1.25 mg and 2.5 mg in children 2–5 and 6–11 years of age, respectively, resulted in median desloratadine AUC values that were comparable with the values observed in adults following a 5 mg dose.

Figure 4.

Comparison of desloratadine AUC in children and adult volunteers following administration of desloratadine as a syrup. The bold horizontal line inside the box represents the median, the top and bottom portions of box the 75th and 25th percentile of the data, respectively, and the top and bottom whiskers represent the 95th and 5th percentile, respectively. The horizontal lines outside the box represent values beyond the 95th percentile. *data on file at Schering-Plough, Kenilworth, NJ, USA

No adverse events were reported in either age group, and no subjects withdrew from the study prematurely. Laboratory values remained within the normal ranges. There were no consistent clinically relevant changes in blood pressure, pulse rate or oral body temperature, and all values remained within the normal range for each age group.

Discussion

In the two studies described in this paper, systemic exposure to desloratadine after administration of 1.25 mg in children 2–5 years olds or 2.5 mg in 6–11 years olds, in an oral syrup formulation, was similar to that observed in previous studies of adults receiving 5 mg desloratadine.

Results from two additional small studies in children of 2–5 years (n = 18) and 6–11 years (n = 18) of age, using higher doses of desloratadine gave AUC and C_max values about twice as high as those observed in adults taking 5 mg of drug. Thus, it was recommended that the dose be reduced by 50% to 1.25 and 2.5 mg in children 2–5 and 6–11 years olds, respectively.

It has been established that some individuals have an impaired ability to form the active metabolite of desloratadine. In the present work, two of the 18 2–5 years olds (11%) and three of the 18 6–11 years olds (17%) were found to be ‘poor metabolizers’ of desloratadine. A much larger study in older children and adults has recently established that the prevalence of the ‘poor metabolizer’ phenotype (defined as having a ratio of 3-OH-desloratadine to desloratadine of less than 0.1) in the population is approximately 6% in both groups [8]. This study also showed that the prevalence of ‘poor metabolizers’ is greater in the Black (16%) than in the Caucasian paediatric population (3%) [13]. Exposure to desloratadine has been shown to be approximately six-fold greater in ‘poor metabolizers’ than in the rest of the population, with a similar magnitude of a decrease in the formation of 3-OH-desloratadine in adults and in children receiving age-appropriate doses [15].

Findings from previous studies in children with allergic rhinitis and chronic idiopathic urticaria indicated that desloratadine syrup was well tolerated. The incidence of adverse events was low and no clinically relevant changes in vital signs were observed [11, 16]. In the present work, there were no adverse effects in any of the five ‘poor metabolizers’ of desloratadine, despite their greater exposure. Again, this is consistent with previous findings in adults and children 2–11 years of age, which indicates that the adverse event profile of desloratadine in ‘poor metabolizers’ is similar to that of placebo in all age groups [8].

In conclusion, the present studies demonstrate that exposure to desloratadine in children is similar to that observed in adults, in whom the efficacy of the drug has been established. The findings provide further characterization of the pharmacokinetic profile of desloratadine given as a syrup and add to the evidence that 1.25 mg and 2.5 mg are appropriate doses for children 2–5 years and 6–11 years of age, respectively.