F. Estelle R. Simons, MD, a Gordon L. Sussman, MD, b Keith J. Simons, PhD c Winnipeg, Manitoba, and Toronto, Ontario, Canada

Transcription

1 Effect of the H2-antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the HI-antagonists hydroxyzine and cetirizine in patients with chronic urticaria F. Estelle R. Simons, MD, a Gordon L. Sussman, MD, b Keith J. Simons, PhD c Winnipeg, Manitoba, and Toronto, Ontario, Canada Background: Concomitant administration of an Hi-receptor antagon&t with an Ha-receptor antagonist may enhance the wheal and flare suppression produced by the Hi-antagonist. This synergism may be due, at least in part, to a pharmacokinetic effect. Methods: In a randomized, double-blind, parallel-group study in 16 patients with chronic urticaria, we investigated the pharmacokinetics and suppressive effect on the histamineinduced wheal and flare of a single dose of hydroxyzine 25 mg or cetirizine 10 rag, given before and after treatment with cimetidine 600 mg every 12 hours for 10 days. Results: When hydroxyzine was administered with cimetidine, the partial hydroxyzine area under the curve increased significantly (p < 0.05) to 303-2_ 92 ng/ml/hr from ng/ ml/hr after administration of hydroxyzine alone, and the concentration of cetirizine arising from hydroxyzine was lower. When hydroxyzine was given with cimetidine, wheal and flare suppression increased compared with when hydroxyzine was given alone, but the differences were not statistically significant (p > 0.05). When cetirizine was administered with cimetidine, the pharmacokinetics of cetirizine did not change significantly, and no enhancement of wheal and flare suppression was observed. Conclusions: In this study co-administration of hydroxyzine with cimetidine resulted in significantly increased serum hydroxyzine concentrations and increased wheal and flare suppression, thus confirming the rationale for a trial of concomitant administration of these medications in some patients with chronic urticaria umesponsive to treatment with an Hjantagonist alone. We found no therapeutic rationale for co-administration of cetirizine with cimetidine in urticaria treatment. These medications may be co-administered safely without fear of medication interaction. (J ALLERGY CLIN 1MMUNOL 1995;95: ) Concomitant administration of an Ha-receptor antagonist with an H2-receptor antagonist may be more effective in suppressing the histamine- or allergen-induced wheal and flare than administration of an Hi-antagonist or an Ha-antagonist alone. 1-n In patients with chronic urticaria or dermatographism, combined therapy with an H 1- receptor antagonist and an H2-receptor antagonist is generally more effective in reducing itching and From afaculty of Medicine, University of Manitoba; bfaculty of Medicine, University of Toronto; and CFaculties of Pharmacy, Medicine, and Science, University of Manitoba. Supported by UCB Pharma, Belgium. Received for publication May 6, 1993; revised Oct. 18, 1993; accepted for publication Aug. 18, Reprint requests: F. Estelle R. Simons, Room AE101, Children's Hospital of Winnipeg, 840 Sherbrook St., Winnipeg, Manitoba, Canada, R3A 1S1. Copyright 1995 by Mosby-Year Book, Inc /95 $ /1/60059 Abbreviation used AUC: Area under the curve whealing than is treatment with an H 1- or H 2- receptor antagonist alone, s2-18 although this synergistic effect has not been found in all studies. 19, 2o The mechanism of the enhanced suppression has been postulated to be due to a direct effect of the Ha-antagonist on H2-receptors in the blood vessels of the skin and prevention of vasodilation. On the basis of preliminary evidence obtained in an animal model 21 and in human subjects, = however, we hypothesized that synergism between H 1- receptor antagonists and H2-receptor antagonists might be at least partly due to a pharmacokinetic interaction. We tested this hypothesis in a double- 685

2 686 Simons, Sussman, and Simons J ALLERGY CLIN IMMUNOL MARCH 1995 blind, parallel-group study in 16 patients with chronic idiopathic urticaria. METHODS This study was approved by the Ethics Committee of the Ontario Allergy Society. Each patient gave written, informed consent to participation. Patients were age 18 to 65 years and had urticaria of moderate severity, defined as symptoms present 3 or more days weekly for a minimum of 6 weeks. Patients were excluded from the study if they had ingested an H~- or H2-receptor antagonist during the 2 weeks before study entry or if they had ingested astemizole within 3 months, ketotifen within 4 weeks, or oral glucocorticoids within 4 weeks. At study entry, history was obtained, and each patient had a physical examination, complete blood count, and assessment of hepatic function (total bilirubin, total protein and albumin, aspartate transaminase, alanine transaminase), renal function (urinalysis, urine creatinine, blood urea nitrogen), and electrolytes (sodium, potassium, calcium). Study protocol With a computer-generated random code, 16 patients were assigned to receive either hydroxyzine or cetirizine. Each patient had a complete pharmacokinetic study of a single dose of either hydroxyzine or cetirizine before and after 10 days of cimetidine treatment. On the first study day, patients reported to the Clinical Research Laboratory at 7:00 am, having fasted for at least 8 hours. Hydroxyzine 25 mg or cetirizine 10 mg (Pfizer Canada Inc., Pointe Claire, Quebec, Canada) was administered with 120 ml water in a third-party, doubleblind manner. Serial blood collections and intradermal tests with histamine phosphate 0.01 ml of a 0.1 mg/ml solution (Glaxo Canada, Mississauga, Ontario, Canada) were performed before the dose, hourly for 12 hours, and at 24 and 48 hours after the dose. A standardized snack was served 2 hours after dosing, and standardized meals were served 4 and 8 hours after the dose. Patients then took cimetidine 600 mg every 12 hours for at least 10 days, after which they returned to the Clinical Research Centre for a second dose of the Htreceptor antagonist they had received on the first study day, either hydroxyzine 25 mg or cetirizine 10 mg, again administered in a third-party, double-blind manner along with the cimetidine dose. The same schedule for collection of blood samples and skin tests was followed. Cimetidine 600 mg was continued every 12 hours until the study concluded, 48 hours after the Hi-antagonist dose. Compliance with cimetidine treatment was monitored by means of tablet counts and random blood sampling for measurement of serum cimetidine concentrations. Each time a blood sample was obtained and skin tests were performed, the patients were asked how they felt, and any adverse experiences were noted. Collection of blood samples and measurement of hydroxyzine or cetirizine in serum Before H~-antagonist dosing, an indwelling venous catheter with a heparin "lock" was inserted. At the scheduled times, 10 ml blood samples were obtained after the first 1.0 ml had been discarded. After each blood sample was obtained, the catheter was rinsed with 1.5 ml of 0.9% saline solution, followed by 0.5 ml of a solution containing 10 units of heparin per milliliter of saline solution. The blood samples were allowed to clot and were centrifuged; the serum was transferred into appropriately labeled disposable polypropylene tubes with screw caps and frozen promptly at -20 C. Serum samples were stored at -20 C until serum hydroxyzine and cetirizine concentrations were determined by highperformance liquid chromatography methods developed previously in our laboratory. 23,24 The lower limits of sensitivity of the high-performance liquid chromatography assays for hydroxyzine and cetirizine were 1.0 ng/ml and 2.0 ng/ml, respectively, with a coefficient of variation of 9.5% % over 6 months. Skin tests for assessment of antihistaminic effect After collection of each blood sample, an intradermal test with histamine was performed. A different site on the volar surfaces of the patients' forearms was used for each test, and the sequence of testing was the same for all patients. The wheal and flare circumferences were traced with a felt-tip pen at 10 minutes and transferred to paper with transparent tape. The wheal and flare areas were measured with a computerized digitizing system. 24 Data analysis Pharmacokinetic analysis of serum hydroxyzine and cetirizine concentrations versus time plots was performed with standard equations and the PKCALC interactive computer program on an IBM-PC (IBM Corp., Armonk, N.Y.) 25, 26 All data were listed as means --- SD. Statistical comparisons were done with a one-way analysis of variance for parallel groups and Student's t test. Differences were considered to be statistically significant at a p value of less than The histamine-induced wheal and flare areas were analyzed as absolute values and as percent reduction of premedication values. The primary variables were the areas under the absolute wheal and flare area versus time curve and the areas under the percent reduction of wheal and flare area versus time curve during the 48 hours after dosing. To assess the effect of cimetidine alone on suppression of the cutaneous response to histamine, the data obtained before the Ha-antagonist dose was given on study days, before and after cimetidine administration, were compared. Two-way analysis of variance and the Tukey and Bonferroni multiple range tests, with patient and sample

3 J ALLERGY CLIN IMMUNOL Simons, Sussman, and Simons 887 VOLUME 95, NUMBER 3 A I Hydroxyzine with Cimetidine + SEM ~ Hydroxyzine alone ~ - SEM xxlil 10- "1" 5- E FIG. 1. Serum hydroxyzine concentration versus time plots after a single dose of hydroxyzine 25 rag, before and after treatment with cimetidine 600 mg every 12 hours for 10 days in eight patients. time, or patient sample time and study (with and without cimetidine) as criteria of classification, were used for all comparisons. On the basis of previous studies of hydroxyzine and cetirizine, and assuming eight patients per treatment group, there was a power of at least 90% to detect a 25% suppression of histamine-induced wheals and flares before and after administration of cimetidine. A type 1 error of 0.05 was used in one-sided tests. 27 Safety was assessed by evaluating the subjective reports of adverse experiences and changes in physical examination findings and laboratory measurements. RESULTS The demographics of the eight patients in each group including age, sex, weight, and duration of urticaria are listed in Table I. There was a significant difference in patient age (p < 0.05) between subjects receiving hydroxyzine, 53.5 _+ 7.0 years, and those receiving cetirizine years. Also, the range in subject age in the cetirizine group was greater. Because subjects served as their own controls before and after cimetidine administration, these differences were not relevant to the outcome of the study. Pharmacokinetics Mean hydroxyzine serum concentrations before and after administration of cimetidine for 10 days TABLE I. Demographics Hydrexyzine group Cetirizine group n 8 8 Age (yr) 53.5 ± Male/female 4/4 5/3 Weight (kg) 80.7 ± _ Duration of urticaria (yr) are shown in Fig. 1. Before cimetidine administration, the mean peak serum hydroxyzine concentration was ng/ml, occurring at hours. After cimetidine administration, the mean peak serum hydroxyzine concentration was ng/ml, occurring at 2.9 _+ 1.0 hours. Before cimetidine administration, the mean partial area under the curve (AUC) for hydroxyzine was ng/ml/hr, increasing significantly (p < 0.05) to 303 _+ 92 ng/ml/hr after cimetidine administration. Before and after cimetidine administration, serum hydroxyzine concentrations were below the limits of analytic detection 12 or more hours after hydroxyzine administration; therefore, no other pharmacokinetic values were calculated. Before cimetidine administration, the mean

4 688 Simons, Sussman, and Simons J ALLERGY CLIN IMMUNOL MARCH "~ 200- E o 00- "E 50- U t= o 30-0 I= 2o- "R q o to- E 5- el) CetlrizJne from Hydroxyzlne alone + SEM Cetirizine from Hydroxyzine, with Clmetidine - SEM I I i I I FIG. 2. Serum concentrations of cetirizine arising from hydroxyzine in vivo after a single dose of hydroxyzine 25 rag, before and after treatment with cimetidine 600 mg every 12 hours for 10 days. peak serum cetirizine concentration arising from hydroxyzine in vivo was ng/ml, occurring at 3.8 +_ 1.8 hours; after cimetidine administration, these values were lower, ng/ml, and later, 7.7 +_ 2.0 hours, respectively, but the differences were not statistically significant (Fig. 2). Before cimetidine administration, the AUC of cetirizine arising from hydroxyzine, _ 1502 ng/ml/hr, was higher than after cimetidine administration, 3666 _ 1654 ng/ml/hr, but the difference was not statistically significant (p > 0.05). Mean cetirizine serum concentrations before and after administration of cimetidine for 10 days are shown in Fig. 3. Before cimetidine administration, the mean peak serum cetirizine concentration of ng/ml was obtained at 3.0 _+ 0.5 hours. The mean area under the serum cetirizine concentration versus time curve was 4022 _ ng/ml/hr, the mean serum elimination half-life was 7.6 _+ 1.6 hours, the total body clearance was 0.63 _ 0.24 ml/min/kg, and the apparent volume of distribution was 0.39 _ L/kg. The mean residence time was hours. After cime- tidine administration, the mean peak cetirizine concentration of ng/ml was obtained at hours. The mean area under the serum cetirizine concentration versus time curve was ng/ml/hr, the mean elimination halflife was hours, the total body clearance was ml/min/kg, and the apparent volume of distribution was 0.36 _ L/kg. The mean residence time was hours. The values obtained after co-administration of cimetidine and cetirizine were not significantly different (p > 0.05) from those obtained after administration of cetirizine alone. Wheal and flare suppression The 10-day course of cimetidine did not suppress the mean histamine-induced wheal and flare areas obtained before Hi-antagonist dosing (p > 0.05). The effects of hydroxyzine on suppression of the histamine-induced wheal and flare before and after cimetidine administration are shown in Fig. 4. Compared with pretreatment values, significant suppression (p < 0.05) of wheals occurred from 6

5 J ALLERGY CLIN IMMUNOL Simons, Sussman, and Simons 689 VOLUME 95, NUMBER 3 I000 = 50o o " 50- O - o E 2 5- Cetirizine with Cimetidine E + SEM Cetirizine alone,~ - SEM I ' I I ' I I I I I I I / ~'T'- ' ///------'T- O FIG. 3. Serum cetirizine concentration versus time plots after a single dose of cetirizine 10 rag, before and after treatment with cimetidine 600 mg every 12 hours for 10 days in eight patients. to 24 hours after hydroxyzine had been administered alone and from 5 to 12 hours after cimetidine had been administered with hydroxyzine. Compared with pretreatment values, significant suppression (p < 0.05) of flares occurred from 4 to 24 hours after hydroxyzine had been administered alone and from 4 to 12 hours after cimetidine had been administered with hydroxyzine. Co-administration of cimetidine with hydroxyzine generally produced higher percent wheal and flare suppression than administration of hydroxyzine alone (e.g., at 5 hours, 56 _+ 13 vs 49% _+ 12% wheal suppression and 77 _+ 9 vs 51% _+ 14% flare suppression), but the differences were not statistically significant (p > 0.05). The effects of cetirizine on suppression of the histamine-induced wheal and flare before and after cimetidine administration are shown in Fig. 5. Compared with pretreatment values, significant suppression (p < 0.05) of wheals occurred from 2 to 12 hours after administration of cetirizine alone and from 2 to 12 hours after cimetidine was administered with cetirizine; significant suppression of flares occurred from 2 to 24 hours after administration of cetirizine alone and from 2 to 24 hours after cimetidine was administered with cetirizine. Co-administration of cimetidine with cetirizine did not produce statistically significant enhancement of wheal and flare suppression at any time (p > 0.05). On the control study days, cetirizine 10 mg had a more rapid onset of action and produced greater percent wheal and flare suppression than hydroxyzine 25 mg, but the differences were not statistically significant (p > 0.05). Adverse effects After hydroxyzine was administered alone, and when hydroxyzine was given with cimetidine, seven of eight patients experienced transient somnolence. After cetirizine was given alone, and when cetirizine was given with cimetidine, transient somnolence occurred in five of eight patients. DISCUSSION Cimetidine, through its imidazole ring, binds to the heine portion of the hepatic cytochrome P450 system and in a dose-related manner, inhibits oxidation, hydroxylation, dealkylation, demethylation, and other mixed-function oxygenase system

6 690 Simons, Sussman, and Simons J ALLERGY CUN IMMUNOL MARCH 1995 'i 2 O 10 IX'l Flare Hyd i~l Wheal Hyd 8 i~ Flare Hyd + Cim Wheal Hyd + Cim 6 +SEM n=8 * p < 0.05 from baseline 0.8 *, ' 1 i 0.~ 0 I FIG. 4. Wheal and flare areas after intradermal injection of 0.01 ml of histamine phosphate (0.1 mg/ml), before and from 1 to 48 hours after a single dose of hydroxyzine 25 mg. The effect of treatment with cimetidine 600 mg every 12 hours on wheal and flare suppression is shown. Hyd, Hydroxizine; Cim, cimetidine. m actions. This effect is found to a greater extent with cimetidine than with other H2-antagonists. Even when cimetidine doses as low as 400 to 800 mg daily are ingested, elimination of many commonly prescribed medications is significantly reduced Cimetidine would be expected to inhibit the oxidation of hydroxyzine to its carboxylic acid metabolite in the hepatic mixed-function oxygenase system. Cimetidine may also reduce the renal clearance of organic basic compounds by competition for renal tubular secretion and theoretically could influence the elimination of cetirizine by this mechanism. Approximately 60% of a cetirizine dose is excreted primarily unchanged through the kidneys during the first 24 hours after a single dose. The hydroxyzine dose selected for use in this study, 25 mg, was relatively low, not only to ensure double-blinding, but also because administration of higher hydroxyzine doses results in almost total suppression of the histamine-induced wheal and flare response and any potential effect of coadministration of cimetidine would be undetectable. After administration of 25 mg of hydroxyzine, hydroxyzine concentrations were below the limit of analytic detection at 24 and 48 hours; thus, it was not possible to calculate hydroxyzine pharmacokinetic values such as clearance rate, apparent volume of distribution, or total AUC (0 to infinity). A 10-day course of cimetidine inhibited the metabolism of a single dose of hydroxyzine to cetirizine in vivo, as demonstrated by higher serum hydroxyzine concentrations and significantly higher partial mean AUC (0 to 12 hours) and by a decrease in the cetirizine arising from hydroxyzine in vivo and the mean AUC (0 to 36 hours) of cetirizine arising from hydroxyzine. Cimetidine enhanced the wheal and flare suppression produced by hydroxyzine, but the effect was not statistically or clinically significant. Because cetirizine concentrations arising from hydroxyzine were reduced after cimetidine administration, any enhanced suppression of the cutaneous response was probably due to the increased hydroxyzine concentrations in serum and, presumably, the skin. In an earlier, multiple-dose study, serum hydroxyzine concentrations were reported to be higher in patients concomitantly treated with hydroxyzine and cimetidine than in patients treated with hydroxyzine alone, but no pharmacokinetics were described. 2a In a rabbit model, co-administration of hydroxyzine or cetirizine with cimetidine resulted in significantly increased serum hydroxyzine or cetirizine concentrations, respectively, and in sig-

7 J ALLERGY CLIN IMMUNOL Simons, Sussman, and Simons 691 VOLUME 95, NUMBER I~ Flare Cet i Wheal Cet i~ Flare Cet + Cim I~I Wheal Cet + Cim ~, + SEM * p < 0.05 from baseline 2 1.2,k I 2 i 'i p FIG. 5. Wheal and flare areas after intradermal injection of 0.01 ml of histamine phosphate (0.1 mg/ml), before and from 1 to 48 hours after a single dose of cetirizine 10 rag. The effect of treatment with cimetidine 600 mg every 12 hours daily on wheal and flare suppression is shown, Cet, Cetirizine; Cim, cimetidine. nificantly increased suppression of the histamineinduced wheal. 2a In an earlier H1-H2-interaction study, mean wheal suppression increased by 9% when cimetidine 300 mg every 6 hours was added to hydroxyzine 25 mg every 6 hours for 24 hours, compared with the wheal suppression produced by hydroxyzine 25 mg every 6 hours alone, and the effect was statistically significant? In this study, cimetidine did not inhibit the elimination of cetirizine. Cetirizine pharmacokinetic values obtained before and after cimetidine were similar to those reported in healthy adults. 32, 33 Co-administration of cimetidine with cetirizine did not enhance the wheal and flare suppression produced by cetirizine alone. Other H~-antagonists besides hydroxyzine and cetirizine, studied pharmacokinetically after coadministration with cimetidine, include teffenadine and ebastine; cimetidine did not have a significant effect on elimination of either of these medications.34, 35 Wheal and flare suppression was not reported in these studies. In this study, no significant H2-antagonist suppression of the histamine-induced wheal and flare response was observed, because baseline values before and after cimetidine administration did not differ significantly in the hydroxyzine or cetirizine studies. In previous studies by others, administra- tion of cimetidine or other H2-receptor antagonists alone has had a variable, weak, dose-related suppressive effect on the histamine-induced cutaneous response Addition of cimetidine or ranitidine to Hi-antagonist treatment has significantly enhanced the suppressive effect of the HI-antagonist in some studies, but not in others. 11 The enhanced effect is not entirely pharmacokinetic in origin, because it has been observed when H1- and H2-receptor antagonists are administered concurrently by local intradermal injection, and in this instance, is due entirely to a direct effect of the H2-antagonist on H2-receptors in the cutaneous vasculature. 6, s0 No patient in this study reported adverse effects from cimetidine alone; however, long-term cimetidine therapy is not free of the risk of adverse effects.36, 37 Many patients reported transient subjective somnolence after administration of hydroxyzine or cetirizine, but the incidence did not increase when cimetidine was added. There are no objective studies of central nervous system adverse effects or cardiovascular system adverse effects when H~- and H2-receptor antagonists are given concurrently. Hydroxyzine is widely known to cause somnolence, impair performance, and increase sleep latency38-41; and it has rarely, when given alone in very large doses, been reported to prolong the QTc interval. 4a In contrast, cetirizine

8 692 Sirnons, Sussman, and Simons J ALLERGY CLIN IMMUNOL MARCH 1995 does not impair performance or increase sleep latency 3s-41 and does not cause a dose-related prolongation of the QTc interval. 43 In some patients with urticaria or dermatographism refractory to treatment with an Hi-receptor antagonist alone, the addition of an H2-receptor antagonist to the Hi-receptor antagonist may enhance relief of pruritus and suppression of wheal formation. A 3-week trial of concomitant HI- and H2-antagonist treatment is recommended, 44 after which the H2-antagonist should be discontinued if improvement has not occurred. Combinations that have been tested include cimetidine with hydroxyzine, chlorpheniramine, or cyproheptadine, and ranitidine with terfenadine? 2-2 The results of this study certainly do not justify a more prolonged trial of cimetidine with hydroxyzine and do not provide any therapeutic rationale for concomitant use of cimetidine with cetirizine. An important corollary of this is, however, that patients requiring an Hi-receptor antagonist for treatment of an allergic disorder and an H2-rece p- tor antagonist for treatment of gastroesophageal reflux or other gastric hypersecretory disorders could receive cetirizine and cimetidine concurrently without fear of medication interaction or increased toxicity. We acknowledge the assistance of Billie Purcell, RN, Quon Mai, BSc, Pharm, Medical Research Council of Canada summer student, and Zheng Yi, BSc Pharm, who measured the serum hydroxyzine and cetirizine concentrations. REFERENCES 1. Marks R, Greaves MW. Vascular reactions to histamine and compound 48/80 in human skin: suppression by a histamine H2-receptor blocking agent. Br J Clin Pharmacol 1977;4: Smith JA, Mansfield LE, Nelson HS. The effect of cimetidine on the immediate cutaneous response to allergens. Ann Allergy 1979;42: Johnson CE, Weiner JS, Wagner DS, McLean JA. 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