Lack of subsensitivity to terfenadine during long-term terfenadine treatment

J. ALLERGY CLIN. IMMUNOL. DECEMBER 1988

Van Metre et al.

Allergen-induced increase in nonallergic bronchial reactivity. Clin Allergy 1977;7:503-13. 27. Cattier A, Thomson NC, Frith PA, Roberts R, Hargreave FE. Allergen-induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber. J ALLERGY CLIN IMMUNOL1982;70:170-77. 28. Boulet L-P, Carder A, Thomson NC, Roberts RS, Dolovich

J, Hargreave FE. Asthma and increases in nonallergic bronchial responsiveness from seasonal pollen exposure. J ALLERGYCLIN IMMUNOL

1983;71:399-406.

29. Cockcroft DW, Murdock KY, Kirby J, Hargreave FE. Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine. Am Rev Respir Dis 1987;135:264-7.

Lack of subsensitivity to terfenadine long-term terfenadine treatment F. Estelle R. Simons, and Keith J. Simons,

MD, FRCP(C),* Wade T. A. Watson, PhD** Winnipeg, Manitoba, Canada

during

MD, FRCP(C),*

Eleven healthy male volunteers ingested terfenadine, 60 mg, every 12 hours for 56 days. Compliance was monitored strictly throughout the study. Before the first terfenadine dose on day 0, and I2 hours after the evening tet$enadine dose every seventh day and on randomly selected “unscheduled” days, wheal-and-Jlare areas were measured after intradermal injections of 0.01 ml of histamine phosphate (I .O mglml and 0.1 mglml). On days 0, 28, and 56, six volunteers had skin tests hourly for 12 hours after the morning terfenadine dose. On all study days, serum tetfenadine metabolite I concentrations were measured each time histamine skin tests were performed. On days 7, 14, 21, 28, 35, 42, 49, and 56, the mean areas of the histamine-induced wheals did not differ significantly from each other but were significantly decreased compared to the mean wheal area on day 0 (p < 0.01). On these days, the mean areas of the histamine-induced flares also did not differ signt@antly from each other but remained significantly suppressed compared to the mean flare areas on day 0 (p < 0.01). Wheal-and-pare suppression was noted in all unscheduled histamine skin tests per$ormed 12 hours after the evening terfenadine dose. In the subgroup of volunteers who had hourly tests, on day 0, the mean wheal-and-Jare areas were signtjicantly suppressed from 2 to 12 hours after the dose, with maximal wheal suppression occurring at 5 hours (p < 0.05) and maximal flare suppression occurring from 3 to 9 hours (p < 0.01). On day 28 in the subgroup, the mean wheal area was significantly larger 12 hours after the dose than before the dose or at any other time (p < 0.01) but the mean jare areas did not dtyer significantly at any time (p = 0.01). On a’ay 56 in the subgroup, the mean wheal areas did not dtfer signiJicantly from before the dose to 12 hours after the dose, nor did the mean flare areas differ significantly at any time (p = 0.01). The mean serum concentration of retienadine metabolite I 12 hours after the evening dose did not differ significantly on days 7, 14, 21, 28, 35, 42, 49, and 56 (p = 0.01). Unscheduled serum terfenadine metabolite I concentrations measured 12 hours after the dose provided additional confirmation of compliance. In the subgroup, the mean serum elimination half-life value and the mean area under the serum concentration versus time curve of terfedine metabolite I did not differ significantly on day 0, day 28, or day 56 (p = 0.01). We conclude that subsensitivity to the antihistaminic effect of terfenadine did not develop during 56 days in compliant subjects, as evidenced by continued suppression of the histamine-induced wheals and fires. Also, the pharmacokinetics of terfenadine metabolite I remained unchanged after 56 days of terfenadine treatment. (J AL,LERGY CLIN IMMUNOL 1988;82:1068-75.) From the Health Sciences Clinical Research Center, *Faculty of Medicine and **Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada. Supported by Merrell Dow Pharmaceuticals (Canada) Inc., Richmond Hill, Ontario, Canada, and Schering-Plough Corp., Kenilworth, N.J. Received for publication Feb. 25, 1988. Accepted for publication May 28, 1988. Reprint requests: F. Estelle R. Simons, MD, 840 Sherbrook St., Winnipeg, Manitoba, Canada R3A 1S1. 1068

Patients who receive a first-generation HI-receptor antagonist regularly for weeks or months often appear to develop subsensitivity to the drug.le6 Subsensitivity may be manifest as diminished efficacy in relieving symptoms; that is, a larger dose of the HI-receptor antagonist is required to elicit an antihistaminic effect of similar magnitude to the effect produced by the initial H, receptor-antagonist dose at the onset of treat-

VOLUME 87

Lack of subsensitivity to te~e!~~~~~e 1069

NUMBER 6

Abbreviations

used

Area under the serum terfenadine metabolite I concentration versus time curve ANOVA: Analysis of variance b.i.d.: Twice daily AUC,:

merit. ‘. * Subsensitivity may also be evidenced by a decrease in central nervous system adverse effects, such as sedation’ or by waning suppression of the wheal-and-flare response in the skin during longterm treatment with first-generation H,-receptor antagonists .4-6 Subsensitivity to H,-receptor antagonists has been attributed to increased numbers of receptors in the end organ, to modulation of receptor binding, or to reduced drug concentrations at end organ receptor sites because of autoinduction of enzyme systems responsible for H, receptor-antagonist metabolism,‘. 8 increased clearance, and lower concentrations of drug in serum and tissue. The present investigation was designed to investigate the phenomenon of subsensitivity to the widely used, nonsedating H,-receptor antagonist, terfenadine. The pharmacodynamics and the pharmacokinetics of terfenadine were investigated concurrently throughout the study, and great emphasis was placed on assessment of compliance of volunteers. METHODS This study was approved by the Faculty Committee on

the Use of Human Subjects in Research of the University of Manitoba. Signed, informed consent was obtained from each subject before study entry. Subjects were eligible for study if they were nonobese male volunteers, aged 20 to 45 years, who had never smoked, were in good health, had never required long-term medication, including long-term antihistamine treatment, and had never ingested astemizole. Subjectswere excluded from the study if they consumed more than two cups of coffee per day or more than four cans of beer or four glasses of wine per week. Before study entry, volunteers had a physical examination and were weighed. Laboratory tests, including urinalysis, complete blood count, and blood chemistry tests, including serum electrolytes, blood urea nitrogen, creatinine, glucose, aspartate transaminase, alanine transaminase, alkaline phosphatase, y-glutamyltransferase, cholesterol, and triglycerides, were within the normal range. All volunteers also had a positive intradermal test (>5 cm* flare) to 1.Op,g of histamine phosphate injected intradermally. Subjects ingested terfenadine, 60 mg, every 12 hours regularly for 56 days. On days 0, 7, 14, 21, 28, 35, 42, 49. and 56. they arrived at the Clinical Investigation Unit

at 8 AM. Intradermal tests with 0.01 ml of solutions containing 1.O mg/mJ (stock solution) and 0. I mg. ml of histamine phosphatle (stock solution freshly diluted on each study day with sodium chloride, 0.9%) wt~e performed before ingestion of terfenadine, 60 mg. with 250 ml of water. The last six consecutivevolunteers in the study were asked to take part in a more intensive promcol on days 0, 28, and 56. They reported fasting on these days and had intradermal tests with the 1.O mg/ml solution of histamine phosphate before and hourly for 12 hours afrcr terfenadine ingestion. On all study days, histamine was injected on the volar surfaces of the forearms with a preselected order of sites that was identical in each subject. The resulting wheal-andflare areas were outlined with a liquid ink pen on the skin 10 minutes after each injection. The outlines were transferred to tracing paper. The areas of the wheals and flares were measured with an Apple II + computer (Apple Macintosh, Cupertino, Calif.), graphics tablet, and stereometric software.g.I” One investigator performed all the skin tests, and another investigator traced all the wheals and flares on the graphics tablet. During the time this study was performed, the coefficient of variation was 7.5% for areas of 0.35 cm2, representative of the smallest uheal areas traced, and 1.9% for areasof approximately 4.00 cm’. representative of the smallest flare areas traced. On day 0, a control blood sample was obtained before terfenadine ingestion, and on days 7. 14, 11( 2X. 35. 42, 49, and 56, 12 hours after the evening dose of tcrfenadine, a blood sample was obtained for serum terfenadine metabelite I measurements. On days 0, 2X. and 56, in the six subjectstaking part in the intensive protocol. blood samples were collected hourly for 12 hours via an indwelling venous catheter with a “heparin lock.” The first I .0 ml of each blood sample was discarded, and after the sanrplc was obtained, the heparin lock was rinsed with 1.O ml of 0.9% saline, followed by 0.5 ml of a solution containing heparin, 10 U/ml, and 0.9% saline. All blood sampleswere collected in plain glass tubes and centrifuged at 1700 rpm (1370 g). Serum was transferred to glassvials. which were securely capped and stored at - 20” C. Serum terfenadine metabotite I concentrations were determined via highperformance liquid chromatography at LAB. New Illm, Federal Republic of Germany.‘” On study days 0, 28, and 56, a light snackwas provided 2 hours after terfenadine ingestion, and standardizedmeats and snackswere provided for the rest of the IZhour study. Compliance was monitored closely with frequent phone calls, personal contact, and weekly tablet counts, in addition to frequent monitoring of skin reactivity to histamine and frequent concurrent monitoring of serum terfenadine metabolite I concentrations. On all study days, and during the phone contacts,the:exact times of terfenadine ingestion were reviewed, and the subjects were questioned about possible adverse effects, such as sedation, disorientation, or dry mouth, and about caffeine and alcohol intake and the use of other medications. All information was entered systemically in the subject’s record. The histamine-induced wheal-and-flare area’
1070

J. ALLERGY CLIN. IMMUNOL. DECEMBER 1988

Simons et al.

r”l

Flare (h&an+S.E.M.)

&

Wheal *

7

14

21

28

35

(Mean+S.E.M.)

p
42

49

56

A

r”l &

Flare (bhan+S.E.M.) Wheal (Mean+S.E.M.) * p
0

RG. 1. A, Mean study entry (day and 56. B, Mean study entry (day 42,49, and 56.

7

14

wheal-and-flare areas Oj, and 12 hours after wheal-and-flare areas 0), and 12 hours after

21

28

35

42

49

56

after intradermal injection of histamine, 1.0 mg/ml, at the dose of terfenadine on days 7,14,21,28,35,42,49, after intradermal injection of histamine, 0.1 mglml, at the dose of terfenadine dose on days 7,14, 21, 28,35,

lyzed as absolute valuesand aspercent reduction of predose

control valuesby two-way ANOVA and the lkkey and Bonferroni multiple range tests.** The mean serum terfenadine metabolite I concentrations, collected 12 hours after the evening dose on days 7, 14, 21, 28, 35, 42, 49, and 56, were also compared using a two-way ANOVA and the Tukey and Bonferroni multiple range tests. The serum elimination half-life values and the AU& on days 0, 28, and 56 were

calculated with the PKCAJX interactive computer program on sn IBM-PC (International BusinessMachines Corp., Armonk, N.Y.).12,13The ALJC, valueson days 28 and 56 were adjustedfor tbe serumterfenadine metabolite I concentration obtained at 0 time on these days. These values were compared using the two-way ANOVA and the Tukey and Bonferroni multiple range tests. Differences were consideredto be significant at p < 0.01 andp < 0.05.

VOLUME82 NUMBER6

tack of subsensitivity to t~~f~~adin~ 1071

i!i flare hmear

Q 100 iii j

Mean +SEM n =11 *p
80 I 7

14

21

28

35

42

49

56

A I3 Hare +rvi?leal

Mean +sEM n =ll * pco.01

T

-

14

21

28

35

42

49

56

Dav FIG. 2. A, Mean percent suppression of the wheal and flare produced by intradermal injection of histamine phosphate, 1 mg/ml, 12 hours after the dose of terfenadine on days 7, 14, 21, 26, 35,42,49, and 56. B, Mean percent suppression of the wheat and flare produced by intradermal dose on days 7, 14, 21, injection of histamine phosphate, 0.1 mg/ml, 12 hours postterfenadine 26, 35, 42, 49, and 56.

RESULTS Eleven male volunteers completed the 56-day study, and no volunteer dropped out. The mean age of the volunteers was 28.5 It SD 6.2 years, and the mean weight was 80.3 rt 9.7 kg. The mean histamineinduced wheal-and-flare areas at study entry on day 0, and as monitored weekly 12 hours postterfenadine dose from days 7 to 56, are illustrated in Fig. 1, A and B. Wheals and flares remained significantly suppressed (p < 0.01) throughout the study compared to predose values. After intradermal injection of histamine phosphate, 1 mg/ml, mean wheal

suppression ranged from 42.0 ? 7.0% to 51.8 -C 6.7%, and mean flare suppression ranged from 64.9 2 4.7% to 77.0 2 2.5% during 56 days (Fig. 2, A). After intradermal injection of histamine phosphate, 0.1 mg/ml, mean wheai suppression ranged from 43.6 + 4.3% to 50.2 r 3.41, and mean flare suppression ranged from 65.5 2 6.5% to 79.3 k 2.9% (Fig. 2, B). On day 0, after the initial dose of terfenadine in the six subjects studied hourly, the mean wheal area predose and at l-hour after the dose of terfenadine differed significantly from the mean wheal area at all

1072

Simons

J. ALLERGY CLIN. IMMUNOL. DECEMBER 1988

et al.

tvkan+SEM n=6 ** p-z 0.01 tmnl Oil ottws *pcO.Ol maxlmum supplesskm A p < 0.05 modmlifll suppression

E

8 4

A

Th-m(h) d *

T

T

Flare wheal Mean+SEM n-6

*p
T

-

T

a

9

10

I

T

s! i4 E

2 0

6

zzl -

T

Mean+SEM n=6

T

2 0

1

234567

11

12

0

Time (h)

C FIG. 3. A, Day 0: Mean wheal-and-flare and hourly from 1 to 12 hours after the areas induced by histamine, 1 mg/ml, dose, in six subjects. C, Day 56: Mean before the dose, and hourly from 1 to

Time (h)

areas induced by histamine, 1 mg/ml, before the dose, dose, in six subjects. B, Day 28: Mean wheal-and-flare before the dose, and hourly from 1 to 12 hours after the wheal-and-flare areas induced by histamine, 1 mg/ml, 12 hours after the dose, in six subjects.

other times (p < 0.01). The mean flare area before the dose of terfenadine differed from the mean flare areas at all other times (p < 0.01). Maximum suppression of the mean wheal areas occurred at 5 hours (p < 0.05). Maximum suppression of the mean flare areas occurred from 3 to 9 hours, inclusive (p < 0.01) (Fig. 3, A). On day 28 of treatment with terfenadine, 60 mg every 12 hours, the mean wheal area 12 hours after the morning dose of terfenadine was significantly larger than the mean wheal area before the dose and from 1 to 11 hours after the dose, inclusive (p < O.Ol), but the mean flare areas did not differ significantly from predose terfenadine to 12 hours after the dose of terfenadine (p = 0.01) (Fig. 3, B) . On day 56 of terfenadine treatment, mean wheal areas did not differ significantly from before the dose to 12 hours after the dose, nor did mean flare areas differ significantly from before the dose to 12 hours after the dose (p = 0.01) (Fig. 3, C). Mean serum terfenadine metabolite I concentrations

obtained 12 hours after the previous dose on days 7, 14, 21, 28, 35, 42, 49, and 56 ranged from 57.1 ?z 6.8 to 80.0 + 20.1 rig/ml (Fig. 4). There was no significant difference between the mean serum terfenadine metabolite I concentrations on any study day (p = 0.01). The interpatient variability in steadystate serum terfenadine metabolite I concentrations correlated inversely with body weight; that is, large subjects tended to have low serum terfenadine metabolite I concentrations, and small subjects, high concentrations. There was little intrapatient variation. Unscheduled serum terfenadine metabolite I concentrations obtained 12 hours after the dose fell within the range of the scheduled serum terfenadine metabolite I concentrations in each volunteer. A plot of the log of the mean hourly serum terfenadine metabolite I concentrations in six subjects on days 0, 28, and 56 versus time is illustrated in Fig. 5. The mean serum elimination half-life values and the mean AUC, values for terfenadine metabo-

VOLUME 82 NIJMBER 6

2

Lack

of subsensitivity

to terfenadine

1073

9 Mean+SEM

1007 /

n=ll

‘6

g o/e (, 0

7

, , , , (, 14

21

28

35

42

49

FIG. 4. Mean trough serum tetfenadine metabolite centrations 12 hours after the dose of tetfenadine 7. 14, 21, 28, 35, 42, 49, and 56.

56

I conon days

lite I obtained on each study day are presented in Table I. There was no significant change in the mean serum elimination half-life or mean AUC, values of terfenadine metabolite I on days 28 or 56, compared to day 0 (p = 0.01). The only adverse effect of terfenadine reported was increased appetite in one subject, who did not gain weight during the 56-day study. DISCUSSION Compliance was monitored very closely in this study with personal or phone contact every few days, and, most importantly, unscheduled histamine skin tests and concurrent measurement of serum terfenadine metabolite I concentrations in addition to the regularly scheduled weekly tests and tablet counts. We demonstrated that subsensitivity to a conventional dose of terfenadine, 60 mg b. i .d., did not develop during 56 days, as assessed by monitoring of the histamine-induced wheal-and-flare response every 7 days. The mean wheal-and-flare areas appeared minimally larger on days 49 and 56, compared to days 7 to 42 (Fig. l), but this is probably not clinically important, since the subsensitivity reported by other authors has been of much greater magnitude and has been evident within 3 weeks.4-6 On day 0, we found that maximum wheal suppression occurred 5 hours after the initial dose of terfenadine, and maximum flare suppression occurred from 3 to 9 hours, confirming earlier studies of the effect of terfenadine on the histamine-induced wheal and flare. ‘O,14.l5 The mean maximal wheal suppression after 60 mg of terfenadine was approximately 50%, somewhat less than previously reported.14 The waning antihistaminic effect of terfenadine toward the end of the dosing interval, particularly on day 28, may be explained by the fact that terfenadine, in a dose of 60

Time Uwurs) FIG. 5. Log serum terfenadine on days 0, 28, and 66 versus

metabolite I concentrations time in hours (six subjects).

mg b.i.d., has modest potency as an II,-receptor antagonistg. I6 and may not significantly suppress the wheal and flare in the evening, when, in untreated patients, the wheal-and-flare sizes are larger than at other times of the day because of circadian variation. Is Serum terfenadine metabolite I levels obtained 12 hours after the evening doses of terfenadine remained constant in each subject. Terfenadine metabolite I was measured, rather than terfenadine itself, because after conventional doses of terfenadine, the peak serum terfenadine concentrations of 1 to 2 ng/ ml achieved are at the lower limit of sensitivity of high-performance liquid chromatography assay techniques.‘O Terfenadine metabolite I is similar in structure to the parent drug, one of the methyl groups on the terminal carbon of terfenadine having been oxidized to carboxylic acid. I7 After administration of “‘Cterfenadine, 11% to 13% and 22% to 32% of the dose is eliminated as metabolite I in urine and feces, respectively, during 24 hours. I7 The mean serum elimination half-life values and mean areas under the curve of the pharmacologically active terfenadine metabolite I did not change during 56 days. In the postabsorption and distribution phase after drug administration, the elimination half-life of a metabolite calculated from the linear terminal portion of the serum metabolite concentration versus time curves may reflect the elimination half-life of the unchanged drug. I2 Similarly, AUC, corresponds to the amount of drug that is converted to that metabolite at

1074 Simons et al.

TABLE I. Pharmacokinetic

J. ALLERGY CLIN. IMMUNOL. DECEMBER 1988

values of terfenadine Dav

Serum elimination half-life (hr) AUC, (ng/ml/hr)

metabolite I (mean + SD)

0

2.93 e 0.53

1088.9 + 242.0

Dav

28

4.55 -r- 1.08

1159.3 + 277.2 *

Dav

58

3.81 * 0.54

NS*

1156.9 ? 411.8

NS*

*NS, No significant difference; p = 0.01.

any dosing interval.‘* In the present study, there was no significant difference (p = 0.01) in the mean halflife values and mean AUC, values obtained on days 0, 28, and 56, indicating that there was probably no change in the rate of formation or elimination of terfenadine membolite I during the 56 days of the study. As terfenadine metabolite I accounts for only about 40% of an administered dose of terfenadine, the lack of change in the metabolite I disposition suggests, but does not prove, that there is no autoinduction of terfenadine disposition during long-term administration for 56 days. This study adds to a growing body of evidence that autoinduction of enzyme systems for hepatic metabolism of H,-receptor antagonists does not occur after weeks or months of H, receptor-antagonist treatment, as suggested decades ago, based on limited evidence.‘, ? We have recently demonstrated in dogs who received hydroxyzine intramuscularly daily for 150 days that the mean clearance rates obtained on days 30, 60, 90, 120, and 150 were significantly lower (p < 0.05) than the hydroxyzine clearance rate of 25.12 ? 4.13 ml/min/kg obtained before the dogs had ever been administered hydroxyzine and that the clearance rates on days 30, 60, 90, 120, and 150 did not differ significantly from each other. The mean serum elimination half-life values for hydroxyzine on days 30, 60, 90, and 120 were significantly longer than on the first study day, and mean serum hydroxyzine concentrations were significantly higher on later study days. ” In a study of chlorpheniramine subsensitivity in humans, the serum elimination half-life values for chlorpheniramine did not differ significantly when the drug was administered for 3 weeks, compared to when it was administered for 3 days, although subsensitivity to chlorpheniramine did occur, as evidenced by waning wheal-and-flare suppression. Subsensitivity could not be explained by changes in drug metabolism, and the authors speculated that poor compliance may have contributed to subtherapeutic results during long-term chlorpheniramine treatment. In the 3-week phase of chlorpheniramine treatment, 9/ 14 subjects missed six or more of 63 chlorpheniramine tablets.6 In an ear&r

study, the same investigators found that doubling the dose of chlorpheniramine did not completely overcome the observed subsensitivity to the drug, and they postulated that an increase in the number of H, receptors had occurred.4 In a 28-day crossover study in patients confined to the treatment site to ensure compliance, neither chlorpheniramine, 12 mg b.i.d., nor loratadine, 10, 20, or 40 mg b.i.d., appeared to be associated with subsensitivity, as assessed by continued suppression of histamine-induced wheals and flares throughout the 28 days. Serum H, receptor-antagonist concentrations were not measured in this study.” Lack of subsensitivity to astemizole has been claimed by a number of investigators,*‘. ‘* but as this H,-receptor antagonist does not even produce maximal blockade until after 2 to 4 weeks of treatment, binds firmly to the H, receptors, and has a prolonged duration of action, design of studies primarily to assess astemizole subsensitivity poses some obstacles. Further studies of the phenomenon of subsensitivity to HI-receptor antagonists will be of great interest, since long-term treatment with medications in this class remains important for relief of itching, nasal discharge, and sneezing in patients with allergic rhinoconjunctivitis. and for relief of itching in patients with allergic skin disorders. REFERENCES

1. Monash S. Development of refractory condition of skin towards antihistaminic drugs after antihistaminic therapy as determined by histamine iontophoresis. J Invest Dermatol 1950;15:1. 2. Dannenberg TB, Feinberg SM. The development of tolerance to antihistamines. J ALLERGY 1951;22:330. 3. Bye CE, Claridge R, Peck AW, Plowman F. Evidence for tolerance to the central nervous effects of the histamine antagonist, triprolidine, in man. Eur J Phannacol 1977;12:181_ 4. Taylor RJ, Long WF, Nelson HS. The development of subsensitivity to chlorpheniramine. J ALLERGY CLIN IMMUNOL 1985;76:103.

5. Long WF, Taylor RI, Wagner CJ, Leavengood DC, Nelson HS. Skin test suppression by antihistamines and the development of subsensitivity. J ALLERGY CLIN IMMUNOL 1985;76:113. 6. Bantz FW, Dolen WK, Chadwick EW, Nelson HS. Chronic chlorpheniramine therapy: subsensitivity, drug metabolism, and compliance. Ann Allergy 1987;59:341.

VOLtiME 82 NUMBER 6

Lack of subsensitivitv

7. Burns JJ. Conney AH, Koster R. Stimulatory effect of chronic drug administration on drug-metabolizing enzymes in liver microsomes. Ann NY Acad Sci 1963;104:881. 8. Conney AH. Michaelson IA, Burns JJ. Stimulatory effect of chlorcyclizine on barbiturate metabolism. J Pharmacol Exp Ther 1961;132:202. 9. Gendreau-Reid L, Simons KJ, Simons FER. Comparison of the suppressive effect of astemizole, terfenadine, and hydroxyzinc on histamine-induced wheals and flares in humans. J ALLERGY CLIN IMMUNOI.

1986;77:335.

10. Simons FER, Watson WTA. Simons KJ. The pharmacokinetics and pharmacodynamics of terfenadine in children. J ALLERGY CLIN IMMUNOL 1987;80:884. 11. Steel RGD, Torrie JH, eds. Principles and procedures of statistics New York: McGraw-Hill, 1980: 172-94. 12. Gibaldi M, Petrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker. 1982. 13. Shumaker RC. PKCALC: a BASIC interactive computer program for statistical and pharmacokinetic analysis of data. Drug Metab Rev 1986;17:331. 14. Huther KJ, Renftle G, Barraud N, Burke JT, Koch-Weser J. Inhibitory activity of terfenadine on histamine-induced skin wheals in man. Eur J Clin Pharmacol 1977;12:195.

ta terfenacline

‘to75

15. Reinberg A, Levi F, Guillet P, Burke JT. Nicoiai .A. t’hnnopharmacological study of antihistamines in man with special references to terfenadine. Eur J Clin Pharmacol 197X;14:245. 16. Bantz EW, Dolen WK, Nelson HS. A double-blmd evaluation of skin test suppression produced by two doses oi terfenadine. J ALLERGY CLIN IMMUNOL 1987;80:99. 17. Garteiz DA. Hook RH, Walker BJ, Okerhoim KA. Pharmacokinetics and biotransformation studies of terfenddine in man. Arzneimittelforschung 1982;32: I 185. 18. Pang KS. A review of metabolite kinetics. 1 Pharrnacokinet Biopharm 1985; 13:633. 19. Simons KJ, Simons FER. The effect of chrome administration of hydroxyzine on hydroxyzine pharmacokineiics in dogs. J ALLERGY CLIN IMMUNOL

1987;79:928.

20. Roman IJ, Kassem N, Gural RP, Herron J. Suppression of histamine-induced wheal response by loratadine (SCH 298511 over 28 days in man. Ann Allergy 1986:57:X3 21. Richards DM, Brogden RN, Heel RC, Speight TM, Avery GS. Astemizole: a review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1984;28:38. 22. Bateman DN, Chapman PH, Rawlins MD. The effects of astemizole on histamine-induced weal and flare. Eur J CLin Pharmacol 1983;25?47.

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