The Journal of Allergy and Clinical Immunology
Volume 103, Issue 2 , Pages 223-226, February 1999

The clinical pharmacology of brompheniramine in children☆☆☆★

Winnipeg, Manitoba, Canada

From the Department of Pediatrics and Child Health, aFaculty of Medicine and bFaculty of Pharmacy, University of Manitoba,Winnipeg

Received 30 June 1998; received in revised form 14 August 1998; accepted 17 August 1998.

Article Outline

Abstract 

Background: Brompheniramine has been widely used in the treatment of allergic rhinitis and other disorders during the past 4 decades. There are no published studies of its clinical pharmacology in children. Objectives: This study was performed to test the hypothesis that brompheniramine would have a prompt onset of action and a 24-hour duration of action in children. Methods: Before brompheniramine 4 mg was ingested, and at intervals from 0.5 to 30 hours thereafter, blood samples were obtained for quantitation of plasma brompheniramine concentrations by means of HPLC. Concurrently, epicutaneous tests with histamine phosphate were performed; wheals and flares were traced at 10 minutes, and the areas were measured by using a computerized digitizing system. Results: In 14 children, mean age 9.5 ± 0.4 years (SEM), the peak brompheniramine concentration was 7.7 ± 0.7 ng/mL, and the time at which peak concentrations occurred was 3.2 ± 0.3 hours. The terminal elimination half-life was 12.4 ± 1.1 hours, and the oral clearance was 20.2 ± 2.1 mL/min/kg. Compared with predose areas, the wheals and flares produced by histamine phosphate 1 mg/mL were significantly decreased from 0.5 to 30 hours and from 1 to 30 hours, respectively (P < .05), with mean maximum inhibition at 12 (52% ± 9%) and 6 hours (72% ± 10%), respectively. Conclusions: In children a single dose of brompheniramine produces prompt, long-lasting peripheral H1 -blockade. Revised dosage regimens may be needed in this population. (J Allergy Clin Immunol 1999;103:223-6.)

Keywords: H 1 -receptor antagonists, antihistamines, allergic rhinitis, pharmacokinetics, children, wheal and flare

Abbreviations:  Emax, Maximum effect attributable to medication, EC50, Plasma concentration producing 50% of Emax

 

For 4 decades, the antihistamine (H1 -receptor antagonist) brompheniramine has been widely used in the treatment of allergic rhinitis and other upper respiratory tract disorders in children. In this population there are fewrandomized, controlled studies of its efficacy and safety 1, 2, 3, 4, 5 and no published studies of its clinical pharmacology because it was introduced before such documentation was required by government regulatory agencies. Recently, the Food and Drug Administration has addressed the necessity for appropriate study of medications that are used, but not optimally investigated, in the pediatric population.6

Our objective was to characterize the pharmacokinetics and pharmacodynamics of brompheniramine in young subjects. We hypothesized that in children, as in adults,7 it would have a prompt onset of action and would produce peripheral H1 -blockade for at least 24 hours after a single dose.

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METHODS 

We studied the clinical pharmacology of brompheniramine in children by using a prospective, single-dose study design.

Patient selection 

Children were eligible to participate if they were age 6 to 12 years, weighed 20 to 40 kg, and had allergic rhinitis. They were excluded if they had any recent acute illness or any chronic illness, except for the rhinitis and mild concurrent asthma, or if they required any medication by mouth. They were permitted to use a low-dose (≤100 μg) intranasal glucocorticoid for rhinitis and a low-dose (≤400 μg) inhaled glucocorticoid and/or an inhaled short-acting β2 -adrenergic agonist as needed for asthma before and during the study.

The protocol was approved by the University of Manitoba Faculty Committee on the Use of Human Subjects in Research. Before study entry, assent was obtained from each child, and written, informed consent was obtained from the parent.

During a preliminary visit to the Health Sciences Clinical Research Centre Pediatric Allergy Laboratory, the children were assessed for their ability to meet the inclusion criteria of the study. A medical history was obtained, and a physical examination was performed. They were given the opportunity to become familiar with the test procedures. They had a complete blood count, urinalysis, and sequential multiple analysis-12 for assessment of hepatic and renal function.

Children abstained from H1 -receptor antagonist use for at least 1 week before study entry and did not use astemizole within 3 months of study entry. Before dosing, and for 30 hours after dosing, they refrained from ingesting methylxanthine-containing substances (eg, cola, chocolate, or cocoa). On the first study day, at 7:30 AM and after an 8-hour overnight fast, a single oral dose of brompheniramine 4 mg (10 mL of Dimetapp Allergy Dye-Free Elixir [Whitehall Robins, Inc, Mississauga, Ontario] containing 2 mg brompheniramine maleate per 5 mL)8 was administered, followed by 150 mL of water. Fasting was continued for 2.5 hours after dosing. Clear juice and water were permitted during this time.

EMLA local anesthetic cream (Astra, Mississauga, Ontario) was applied to potential venipuncture sites. An indwelling intravenous catheter (Critikon, Tampa, Fla) was inserted, and 2.5-mL blood samples were obtained before dosing and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 28, and 30 hours afterwards. The first 1 mL of blood was discarded. After each sample was obtained, the catheter was rinsed with 1.5 mL of 0.9% saline. Some of the blood samples taken at 24, 28, and 30 hours were obtained by venipuncture.

The blood was centrifuged at room temperature at 3700 rpm for 10 minutes. The plasma was transferred to polypropylene tubes, which were sealed and frozen at –20°C. Brompheniramine concentrations were determined by using an HPLC assay, as previously described,7 which was modified to improve sensitivity. Calibration curves were linear over the range of 2 to 10 ng/mL, with a between-day mean coefficient of variation of 13% ± 2%.

After each blood sample was collected, peripheral H1 -blockade was evaluated by using epicutaneous tests with histamine phosphate 1 mg/mL and 10 mg/mL.9 Different sites on the volar surfaces of the forearms were used for each skin test; the same site was not reused. The sequence of test sites was identical in all children. At baseline, the tests were performed in duplicate. Wheal and flare circumferences were traced with a pen at 10 minutes and transferred to paper with transparent tape, and areas were calculated by using Sigma-Scan (Jandel Scientific, San Rafael, Calif) with a computer-linked digitizer. By using this system, with wheal and flare sizes ranging from 0.05 to 5.0 cm2 and a sample size of 14 children, sufficient accuracy was achieved to detect differences of 20% with a 95% level of confidence.

Data analysis 

Individual plasma brompheniramine concentration versus time plots were analyzed by using compartmental modeling (PCNONLIN, Scientific Consulting, Apex, NC)10 and also by using noncompartmental analysis.

Absolute wheal and flare areas over time were analyzed with 1-way ANOVA with subject and time as variates, analysis of covariance with predose wheal or flare areas as the covariates, and the Tukey and Bonferroni multiple-range tests. Differences were considered to be significant at P values of less than or equal to .05.11

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RESULTS 

Fourteen children (8 boys), with a mean age of 9.5 ± 0.4 years, mean weight of 31.9 ± 1.7 kg, and mean height of 136 ± 2.6 cm, completed the study. The mean plasma brompheniramine concentration versus time plot is shown in Fig 1.

All the plots could be fitted accurately to a 1-compartment model with first-order absorption and elimination; no higher level models could be fitted. The elimination rate constants calculated by using compartmental analysis and noncompartmental analysis were not significantly different.12 Other pharmacokinetic parameters, including area under the plasma concentration versus time curve, oral clearance, and apparent volume of distribution, were therefore calculated from the compartmental analysis data.

The mean maximum plasma brompheniramine concentration of 7.7 ± 0.7 ng/mL occurred at a mean time of 3.2 ± 0.3 hours. The mean terminal elimination half-life was 12.4 ± 1.1 hours, the mean area under the plasma brompheniramine concentration versus time plot was 127 ± 18 ng/mL/h, the mean oral clearance rate was 20.2 ± 2.1 ng/mL/h, and the mean apparent volume of distribution was 20.0 ± 1.8 L/kg.

Wheal and flare areas after testing with histamine phosphate 1 mg/mL are shown in Fig 2.

  • View full-size image.
  • Fig. 2. 

    Effect of brompheniramine 4 mg on wheals and flares produced by epicutaneous tests with histamine phosphate 1 mg/mL. Wheals were suppressed from 0.5 through 30 hours (P ≤ .05), and flares were suppressed from 1 through 30 hours (P ≤ .05).

The wheals were significantly suppressed (P < .05) compared with predose values from 0.5 to 30 hours, with the mean maximum suppression of 52% ± 9% occurring at 12 hours. The flares were suppressed (P < .05) from 1 to 30 hours compared with predose values, with the mean maximum suppression of 72% ± 10% occurring at 6 hours.

After testing with histamine phosphate 10 mg/mL, the wheals were significantly suppressed (P < .05) at 2, 4, 8, and 12 hours compared with predose values, with the mean maximum suppression of 50% ± 10% occurring at 12 hours. The flares were not significantly suppressed compared with predose values at any time, with the mean maximum suppression of 44% ± 8% occurring at 12 hours.

Pharmacodynamic analysis with the Emax model fitting of the percent wheal suppression versus plasma brompheniramine concentrations yielded a loop of hysteresis for both sets of wheal and flare data. There was a lag of 4 to 6 hours between peak plasma brompheniramine concentrations and peak wheal and flare suppression, which precluded the calculation of meaningful EC50 or Emax values.13

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DISCUSSION 

The recommended brompheniramine dosage regimen for children age 6 to 12 years is 2 mg every 4 to 6 hours.8 In this study we administered a single 4 mg brompheniramine dose and then collected blood samples and performed skin tests up to and including 30 hours afterwards. The rationale for selecting the 4 mg dose was that it is clinically relevant, yet high enough to result in measurable plasma brompheniramine concentrations for 30 hours after administration. The rationale for selecting the 30-hour study duration was based on our study of the elimination of the pharmacologically similar H1 -antagonist chlorpheniramine in children.14 At the final sample time, 30 hours after the dose, the mean plasma brompheniramine concentration of 1.5 ± 0.5 ng/mL was at the lower limit of the brompheniramine assay’s reproducible sensitivity. This, and the absence of blood samples between 12 and 24 hours after dosing, are the limitations of this study.

Brompheniramine appears to be well-absorbed in children, as it is in adults, with peak concentrations occurring at 3.2 ± 0.3 hours and 3.1 ± 1.1 hours.,7 respectively (Table I), although in the absence of an intravenous formulation, true bioavailability cannot be determined.

Table I. Brompheniramine pharmacokinetics
ChildrenAdults
Age (y)9.5 ± 0.428 ± 11
Weight (kg)31.9 ± 1.772.8 ± 13.5
Dose (mg)49.8 ± 1.7
cmax (ng/mL)7.7 ± 0.711.6 ± 3.0
tmax (h)3.2 ± 0.33.1 ± 1.1
t1/2 (h)12.4 ± 1.124.9 ± 9.3
AUC (ng/mL/h)127 ± 18293 ± 32
Cl (mL/min/kg)20.2 ± 2.16.0 ± 2.3
Vd (L/kg)20.0 ± 1.811.7 ± 3.1
cmax, Maximum plasma concentration; tmax, time of maximum plasma concentration; t1/2, terminal elimination half-life; AUC, area under the plasma concentration versus time plot; Cl, oral clearance; Vd, apparent volume of distribution.

Values are mean ± SEM.

The brompheniramine doses were approximately 1.3 mg/kg in both populations. The lower mean peak plasma brompheniramine concentration of 7.7 ± 0.7 ng/mL found in children compared with the peak plasma brompheniramine concentration of 11.6 ± 3 ng/mL7 found in adults is consistent with the more rapid clearance and shorter terminal elimination half-life in young subjects (12.4 ± 1.1 hours and 24.9 ± 9.3 hours, respectively).7 Differences of this magnitude in elimination half-life values between adults and children have been found previously for chlorpheniramine,14 diphenhydramine,15 hydroxyzine,16 ebastine,17 and other H1 -receptor antagonists metabolized in the cytochrome P450 system. In contrast, H1 -receptor antagonists such as cetirizine and fexofenadine, which are excreted largely unchanged in the urine18, 19 and the bile,19 have similar terminal elimination half-life values in children and in adults.

On the basis of the mean brompheniramine elimination half-life of 12.4 ± 1.1 hours found in this single-dose study, dosing every 12 hours on a regular basis in children would be predicted to result in plasma brompheniramine concentrations of about 1.5 times those reported here. Dosing every 4 to 6 hours regularly8 might lead to clinically relevant brompheniramine accumulation.

Brompheniramine produces prompt, effective, and prolonged wheal and flare suppression in children, as it does in adults.7 The objective, standardized, histamine-induced wheal and flare bioassay provides a rational basis for clinical study design, especially with regard to dose and dose interval. The new information provided in this article about the clinical pharmacology of brompheniramine in children will facilitate additional randomized, placebo-controlled trials of the efficacy and safety of revised brompheniramine dosage regimens in the pediatric population, similar to those recently performed in adults.20, 21

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Acknowledgements 

We thank Dr Allan Becker and Mrs Fay Ernst, RN, of the Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba for their assistance. We sincerely thank Dr Howard M. Druce and Mr William Thoden of Whitehall Robins Healthcare Inc for financial support of this project.

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References 

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☆ Supported by Whitehall Robins Healthcare Inc.

☆☆ Reprint requests: F. Estelle R. Simons, MD, FRCPC, Children’s Hospital of Winnipeg, 820 Sherbrook St, Winnipeg, Manitoba, Canada R3A 1R9.

★ 0091-6749/99 $8.00 + 0 1/1/94322

PII: S0091-6749(99)70494-X

The Journal of Allergy and Clinical Immunology
Volume 103, Issue 2 , Pages 223-226, February 1999

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