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Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly
Original
articles
Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly Keith J. Simons, PhD,* Tara J. Martin, BScPharm,** Wade T. A. Watson, MD, FRCP(C),*** and F. Estelle R. Simons, MD, FRCP(C)*** Winnipeg, Manitoba,
Canada
In a double-blind, randomized, crossover study, the H,-receptor antagonists, terfenadine and chlorpheniramine, were investigated in eight healthy, fasting female subjects, aged 67.8 * SD 0.8 years, who ingested single doses of terfenadine, 1 mglkg (mean dose, 69.6 + II .2 mg), and chlorpheniramine, 0.12 mglkg (mean dose, 8.4 ‘- 1.3 mg). The mean serum-elimination half-life of terfenadine metabolite I was 8.7 + 3.7 hours. After tegenadine ingestion, signl$cant wheal suppression occurred from 2 to 24 hours compared to predose wheal size, with maximum wheal suppression, 42 2 13% to 60 + 16% from 2 to 12 hours. Significant flare suppression occurred from 2 to 24 hours, with maximum flare suppression, 75 ? 15% to 78 5 13% from 4 to 8 hours. The mean serum-elimination half-life of chlorpheniramine was 22.6 + 11 .O hours. After chlorpheniramine ingestion, significant wheal suppression occurred from 1 to 10 hours, inclusive, compared to predose wheal size, with maximum wheal suppression, 36 + 11% to 37 ? II % from 5 to 6 hours. Sign$cant jare suppression occurred from 1 to 12 hours, with maximumjare suppression of 43 + 14% to 46 * 19% at 2, 5, and 6 hours (p < 0.01). Adverse effects, chiefty sedation, occurred in five of eight patients after receiving terfenadine, and in all eight patients afier receiving chlorpheniramine; but, since no placebo control was administered, these adverse effects could not be definitely attributed to H,-receptor-antagonist ingestion. (J ALLERGY CLINIMMJNOL1990;85:540-7.)
There are few studies of the pharmacokinetics and pharmacodynamics of HI-receptor antagonists in the elderly; however, there is some evidence that the serum-elimination half-life values of these medications may he prolonged in this age group.’ The pharmacodynamics of H,-receptor antagonists in the elderly may he altered, also, with a single H,-receptorantagonist dose having a prolonged suppressive effect on the histamine-induced wheal and flare in older patients. ’
From the Health SciencesClinical ResearchCenter, *Faculties of Pharmacy, Medicine, and Science, **Faculty of Pharmacy, and ***Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. Supported by Merrell-Dow Pharmaceuticals(Canada)Inc. Received for publication Feb. 13, 1989. Revised Nov. 10, 1989. Accepted for publication Nov. 20, 1989. Reprint requests:F. E. R. Simons, MD, 840 Sherbrook St., Winnipeg, Manitoba, CanadaR3A 1Sl. **Mrs. Tara Martin was the recipient of a Medical ResearchCouncil of Canadaundergraduatesummer studentaward. ***Dr. Wade Watsonwas the recipient of a Sandoz Clinical ResearchFellowship. 111118480
540
Abbreviations used
HPLC: High-performance liquid chromatography E,: Maximum effect attributable to drug EC,,: Serumconcentrationproducing 50% of E,,
Chlorpheniramine and terfenadine are commonly used H,-receptor antagonists, available without prescription in many countries. Age-dependent changes in the pharmacokinetics of terfenadine2e6 and chlorpheniramine7*‘* have already heen demonstrated, since young adults eliminate these medications more slowly than children do. We hypothesized that pharmacokinetic and pharmacodynamic studies of terfenadine and chlorpheniramine in the elderly might reveal longer serum-elimination half-life values and longer duration of H,-receptor-antagonist action than found in younger patients. METHODS We performed a randomized, double-blind, crossover comparison of terfenadine and chloxpheniramine in which each patient received a single dose of either terfenadine or
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T’AEJtE I. Summary of pharmacokinetic and pharmacodynamic and chlorpheniramine in various age groups* Patient
population
Terfenadine metabolite I No. of subjects Age 64 Terfenadine dose (mg) Peakserum cone (rig/ml) Time of peak serum cone Half-life (hr) Wheal suppression(hr) Reference Chlorpheniramine No. of subjects Age W Chlorpheniramine dose (mg) Peak serum cone (rig/ml) Time of peak serum cone Half-life (hr) Wheal suppression(hr) Reference
Healthy
67.8 69.6 190 2.0 8.7
r +2 k 2
28.5 r 60 351 2 2.5 k 2.9 2
8 67.8 k 0.8 8.4 + 1.3 (0.12 mg/kg)
l-10 -
---._---. Children
13 6.2 41 0.5 0.5
at least I- 12t 5
-
3.0 + 1.6 22.6 f 11.0
~-.-__.
11
8 0.8 11.2 (1 mg/kg) 70 1.7 3.7 2-24
13.2 + 5.5
studies of terfenadine metaholite ! Healthy young adults
elderly
541
15 18-27
8 11.3 rt 2.9 3.8 k 2.7
17.3 2 4.4 I 10
7.45 38.1 242 2.3 2.0
” rt t I -+
0.54 3.6 (30 or 60 mg) 28 0.2 0.1
at least i 8’: 6 11 11.0 r 3.0 4.8 it: 1.1 (0.12 mgikg)
13.5 2 3.5 2.5 4 1.S 13.1 i 6.6 I-24 12 -w--e--
Cone,Concentration. *The studiesreportedin references 5, 6, and 12wereconductedin our laboratoryundersimilarconditionsto the presentstudy.Thestudy reportedin reference10wasselectedfrom the literatureon the basisof comparable studydesignto the presentstudy. ?Twenty-hourstudieswerenor conducted(references 5 and6) SWhealsuppression wasnot studied(references 7 to 11).
chlorpheniramine at least 4 weeks apart and was monitored for 72 hours after eachdose. The investigation protocol was approved by the Faculty Committee on the Use of Human Subjects in Researchof the University of Manitoba, and eachparticipant gave written, informed consentbefore taking part. Participants were required to be aged 65 years or older, in excellent health, not using any medication regularly, and within 10% of normal weight for height. They were excluded if they had any acute or chronic illness, if they had ever taken an H,-receptor antagonist regularly, if they had ever smoked, or if they ingested alcohol or xanthinecontaining beverages excessively. Each participant was healthy on physical examination and had a normal complete blood count and normal hepatic and renal function, as evidenced by normal direct and total-serum bilirubin, serum protein and albumin, alanine aminotransferase, aspartateaminotransferase,lactate dehydrogenase,yglutamyl transferase..serum creatinine, and blood urea nitrogen.
At the beginning of each 72-hour study, participants reported to the Health SciencesClinical ResearchCenter at 0800 hours after an g-hour fast and had an indwelling venous catheter with “heparin lock” inserted. Blood samplesof 5 ml for measurementof serum terfenadine metabolite I or chlorpheniramine concentrations were collected from the “heparin lock” before, and 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours, and then by venipuncture at 24, 48, and 72 hours
after administration of a single dose of terfenadine, 1.O mg/kg, or chIorpheniramine, 0.12 mgikg, as identical appearing and tasting white opaque suspensions.Before dose and from 1 to 12 hours after dose, the first I .O ml of each blood sample was discarded, and after each sample was obtained, the heparin lock was rinsed with I .O ml of 0.9% saline, followed by 0.5 ml of a sofution containing 10 U of heparin per milliliter of 0.9% saline. Xanthine-containing food and beverageswere restricted for 8 hours after dose, and alcohol ingestion was not permitted during the study. A standardizedlight snackwas served 2 hours a&x dosing, and standardized meals were served 4 and 8 hours after dosing. Blood sampIeswere centrifuged at 3700 rpm ( 1370 g), and serumwastransferredto glasstubesand stored, securely capped,at - 20” C. Serumchlozphenirarnineconcentrations were determined by HPLCiZ Serum samples were dkalinized and extracted with ether. C~~n~~e and the internal standard,tripekannamine,were back extractedfrom the ether into 100 ~1 of 1.7% phosphoric acid and injected into a modular HPLC system. On a @Bonded Cla column with a mobile phase of 20% ace&&rile in 0.75 mol/L of ammonium phosphate buffer, pH 2.7, at 2.3 mI/min, the chlorpheniramine and internal standard&ted at 7.2 and 5.2 minutes, respectively. The lower limit of sensitivity of the HPLC assay Forchlotpheniramine was 2 rig/ml, with a coefficient of variation of 6.6 :e 2.0% during 4 weeks.
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500 300 200 I Terfenadlne Metabolite I T CMorpheniramine
100
Mean
5 c 50 ,e k
+ SD.
n-8 T
Time (h)
FIG. 1. Serum concentration versus time plots of terfenadine metabolite I after ingestion of a single dose of terfenadine, 1.0 mg/kg, and serum concentration versus time plots of chlorpheniramine after ingestion of a single dose of chlorpheniramine, 0.12 mg/kg, by eight elderly subjects. The mean serum elimination half-life value of terfenadine metabolite I was 8.7 ? 3.7 hours and that of chlorpheniramine was 22.6 4 11 .O hours.
Serumterfenadinemetabolite I concentrationswere measuredat Fluka GmbH, New-Ulm, WestGermany, by HPLC with fluorescencedetection. This method has a lower limit of sensitivity of 20 nglml. Over the serum concentration range from 20 to 200 rig/ml, the mean coefficient of variation was 2.0 * 0.9%. Each time a blood sample was obtained, an intradermal test was performed with 0.01 ml of a solution containing histamine phosphate, 0.1 mg/ml (0.036 mg/ml of histamine). A different site on the volar surface of the forearm was used for each test, and the sequenceof sites chosen was identical in all participants. Wheal-and-flare circumferenceswere traced with a felt-tipped pen 10 minutes after histamine injection and transferredto transparentpaper. Injections and tracings of the wheal-and-flare circumferences were madeby the sameinvestigator. Wheal-and-flareareas were measuredwith an IBM-PC (IBM Instruments, Inc., Danbury, Conn.) and digitizer with stereometricmeasurement software.13During the time this study was performed, the coefficient of variation, with one observertracing areas, was 7.8% for areasof 0.4 cm2,representativeof the smallest wheal areas traced, and 1.9% for areas of approximately 4.0 cm2,representativeof an averageflare area. Each time the blood testsand skin tests were performed, participants were questionedabout adverseeffects, such as sedation,light-headedness,feelings of disorientation or diz-
CLIN. IMMUNOL. MARCH 1990
ziness, dry mouth, visual changes,or difficulty in urinating. If participantsfell asleep,the duration of sleepwas recorded. Serum concentration versus time data from all subjects were analyzed individually, as reported previously,‘, ‘. 6.” with standardequations for model-independentanalysis,‘” and the PKCALC interactive computer program” on an IBM-PC. The results were comparedto results found previously in terfenadine and chlorpheniramine studies in children and in healthy young adults.‘-‘* The histamine-induced wheal-and-flare areas were analyzed as absolute values and as percent reduction of predose terfenadine or chlorpheniramine control values. Pharmacodynamic analysis was performed by plotting mean percent suppression of histamine-inducedwheals and flares versusmeanserumH,receptor-antagonistconcentrationsand fitting the datato the E,, model.I6 For all statistical comparisons, the two-way analysis of variance with participant and sample time, or participant and age-relatedstudy as the criteria of classification, and the Tukey and Bonferroni multiple-range tests were used. Differences were considered significant at p < 0.05.l’ In all analyses,the standarddeviation was used to indicate the extent of variance; however, wheal-and-flare data were graphed with the standarderror of the mean.
RESULTS Eight alert, active, healthy ladies, mean age 67.8 + 0.8 years, completed the study. After a mean terfenadine dose of 69.6 ? 11.2 mg, the mean peak serum terfenadine metabolite I concentration of 190 + 70 rig/ml occurred at a mean peak time of 2.0 ? 1.7 hours. The serum elimination half-life of terfenadine metabolite I was 8.7 + 3.7 hours (Table I; Fig. 1). After a single terfenadine dose, significant wheal suppressionoccurred from 2 to 24 hours, inclusive, comparedto the meanpredosewheal area. Maximum wheal suppressionoccurred from 2 to 12 hours, compared to wheal size at all other times (p < 0.01). Significant flare suppressionoccurred from 2 to 24 hours, inclusive, comparedto the mean predoseflare size (p < 0.01). Maximum flare suppressionoccurred from 4 to 8 hours, inclusive, after terfenadine ingestion (p < 0.01) (Fig. 2). Terfenadine produced >50% suppression of the histamine-induced wheal from 3 to 8 hours, inclusive, after the dose, and >50% suppressionof the flare from 3 to 24 hours, inclusive, after the dose.Flare suppression>70% occurredfrom 4 to 10 hours, inclusive, with peak suppression of 78% at 6 hours (Fig. 3). After a mean chlorpheniramine dose of 8.4 & 1.3 mg, the elderly patients had a mean peak serum chlorpheniramine concentrationof 13.2 + 5.5 ng / ml at a mean time of 3.O t 1.6 hours. The mean serum elimination half-life of chlqpheniramine was 22.6 -+ ll.Ohours,witharangeof9.2to41.0hours (Table I; Fig. 1).
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Q B 2 0 ii ,\E
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suppression
lo 8-
6-
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0
10
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48
72
Time (h) FIG. 2. Mean wheal-and-flare areas after intradermal injection of 0.01 ml of histamine phosphate lo.1 mg/ml) before and 1 to 72 hours after a single dose of terfenadine, 1.0 mg/kg, in eight elderly subjects. Significant wheal suppression occurred from 2 to 24 hours, inclusive, compared to mean predose wheal size, and maximum wheal suppression occurred from 2 to 12 hours, compared to mean wheal size at all other times. Significant ffare suppression occurred from 2 to 24 hours, inclusive, compared to the mean predose flare size, and maximum flare suppression occurred from 4 to 8 hours, inclusive, compared to flare size at all other times (p < 0.01).
After a single chlorpheniramine dose, significant wheal suppressionoccurred from 1 to 10 hours, inclusive, compared to the mean predose wheal area (p < 0.01). Maximum wheal suppressionoccurred at 5 and 6 hours compared to wheal size at all other times. Significant flare suppressionoccurred from 1 to 12 hours, inclusive (p < O.Ol), compared to the mean predoseflare area. Maximum flare suppression occurred at 2, 5, and 6 hours, inclusive, after chlorpheniramine ingestion (p < 0.01) (Fig. 4). Maximum wheal suppression for chlorpheniramine was 37% and maximum flare suppression was 46% (Fig. 5). After terfenadine ingestion, four of eight elderly patients slept for 1.7 k 1.4 hours (range, 0.5 to 4.5 hours), and one patient complained of dizziness and light-headedness. After chlorpheniramine ingestion, six of eight patients slept for 1.8 t 1.3 hours (range, 1.O to 3.5 hours); one patient complained of lightheadednessand headache,and one patient complained of dry mouth. One patient became sleepy after ingesting terfenadine, but not after ingesting chlorpheniramine. No subject was entirely free from adverse effects in this study. The adverse effects appeared to be maximal when serum HI-receptorantagonist concentrations were highest. In the ab-
senceof a placebo control, however, the adverseeffects noted could not be definitively athibuted to H,receptor-antagonistingestion. DISCUSSKIN In this study, we measured tetfenadine metabolite 1 rather than terfenadine itself, becauseafter conventional single dosesof terfenadine, extremely low serum terfenadine concentrations, difficult to quantitate accurately by HPLC, are obtained.‘. ’ From studies of ‘4C-labeledterfenadine in healthy young adults, there is evidence that terfenadine is extensively converted to terfenadine metabolite 1, the active carboxylic acid metabolite of terfenadine (4-11-hydroxy4-[4-{hydroxydiphenyImethyl-1-piperidinyl)butyi]-aa-dimethylbenzene acetic acid hydrochloride) and terfenadine metabolite II (a-a-diphenyl-4-piperidinemethanol).‘. 4 Based on the rapid appearanceof terfenadine metabolite 1 in serum (Fig. I), terfknadine appearsto be readily absorbed in the elderly (Table I). Peakserumterfenadinemetabolite I concentrations and the time at which these concentrations occurred were similar in all age groups studied to date (Table I).5. ’ The absolute bioavailability of terfenadine is unknown. however, since there is no intmvenous formulation,
snd serum terfenadine
metabolite
1 concen-
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100 90
El Flare hwtleal WUl+SEM
b = 40 % 30 !#
-s it ’
20 10 0
-il 0
1
The (h) FIG. 3. Percent suooression of the histamine-induced .. of tetfenadine, 1 mg/kg, in elderly subjects.
nations after intravenous administration are not available for comparison to serum terfenadine metabolite I concentrations achieved after oral administration.x The serumelimination half-life value of terfenadine metabolite I was 8.7 + 3.7 hours in healthy elderly people, significantly longer (p < 0.05) than the mean elimination half-life values of 2.9 2 0.5 and 4.5 hours found in healthy young adults4+’ and the mean elimination half-life value of 2.0 + 0.1 hours found in children6 (Table I). The absorption of chlorpheniramine also appeared to be as rapid and complete in the elderly as it was in younger patients; peak serum chlorpheniramine concentrations and the times at which peak chlorpheniramine concentrationswere achieved were similar to data obtained previously (Table I).‘. 9*lo,‘* In the elderly, there was great interindividual variation in the serum-elimination half-life values for chlorpheniramine; the mean serum-elimination halflife value of 22.6 + 11.4 hours was not significantly different from the mean serum-elimination half-life values of 17.3 + 4.4 to 27.9 + 8.7 hours found in young adults’-I0 but was significantly longer (p < 0.05) than the mean serum-elimination halflife values of 13.1 f 6.6 hours and 9.6 +- 3.6 hours, found after chlorpheniramine administration to children”~ I2 (Table I).
wheal-and-flare
areas after a single dose
Age-dependent changes in the pharmacokinetics of H,-receptor antagonists metabolized by the hepatic cytochrome P450 system might be expected in the elderly because of an age-related decrease in liver blood flow and smaller liver size, diminished number and function of hepatocytes, and reduced metabolizing capacity for medications with advancing age.18-22 The wheal-and-flare response to histamine is an objective, well-standardized bioassay that is valid in elderly patients.23 We have found that, in the elderly, as in younger patients, a single dose of terfenadine5~ 6 or of chlorpheniramine’* significantly suppressedthe wheal and flare for many hours. The mean peak serum concentrations of H,-receptor antagonists preceded the maximum suppressive effect on the wheals and flares by several hours, and the wheals and flares remained significantly suppressed, even when serum H,-receptor-antagonist concentrations were low, as found in previous studies.‘*6,I2H,receptor antagonistsand their active metabolites may be extensively bound to tissues, accounting for clinically and statistically significant antihistaminic effects even after serum concentrationshave declined. In this terfenadine/chlorpheniramine study in the elderly, adverse effects were reported by 62.5% of elderly patients ingesting the second-generationH,-
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flare
hvheal Mean+SEM
145
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‘O
ii h
8-
E
6-
T
** p< 0.01 from 0 , ‘P
-T
T
4-
3
4
5
l6
8
The (h) FIG. 4. Mean wheal-and-flare areas after intradermal injection of 0.01 ml of histamine phosphate (0.1 mg/ml) before and from 1 to 72 hours after a single dose of chlorpheniramine, 0.12 mg/kg by mouth, in eight elderly subjects. Significant wheal suppression occurred from 1 to 10 hours, inclusive, compared to mean predose wheal size, and maximum wheat suppression occurred at 5 and 6 hours, compared to mean wheal size at all other times. Significant flare suppression occurred from 1 to 12 hours, inclusive, compared to the mean predose flare size, and maximum flare suppression occurred at 2, 5, and 6 hours, inclusive, compared to flare size at all other times (p cl 0.01).
receptor antagonist, terfenadine, and were universal after administration of the first-generationH,-receptor antagonist, chlorpheniramine. The apparentincreased incidence of sedation in elderly patients after H,receptor-antagonist ingestion requires further investigation in noninvasive, placebo-controlled studies with more sophisticated techniques of monitoring sleep and sleep latency.% In the pharmacodynamicanalysis of the terfenadine data, we assumedthat serum terfenadine metabolite I concentrations represented the active compound. The values obtained for the wheal data were E,,,,, 62.9%, and EC&, 13.7 rig/ml. The values obtained for the flare data were E,,,,, 84.3%, and E&, 12.0 nglml. The results from the terfenadine studies in young adultssand in children6 could not be fitted precisely to the model, since the duration of sampling times in these studies was only 12 hours and 8 hours, respectively, resulting in insufficient data in the range where serum concentrations were declining and the histamine responsewas returning to baseline. However, the data available up to 12 hours’ and 8 hours6 in these younger subjectscould be superimposedexactly on the data from the elderly subjects.
In the terfenadine study in young adults,’ a 60 mg dose was administered every 12 hours for 56 days. There was no evidence of drug accumulation, since serum terfenadine metabolite I concentrations obtained before the dose on days 28 and 56 were not significantly higher than on day 1 and the suppression of histamine-induced wheals and flares on days 28 and 56 was not significantly greater than on day 1. If, however, elderly subjectsreceived terfenadine, 60 mg every 12 hours, three times the amount of terfenadine metabolite I should accumulate at steady state, compared to the amount that accumulates in young adults, since the half-life value of terfenadine metabolite I in the elderly is three times longer than it is in young adults. A more rational terfenadinedosageregimen in the elderly might be 60 mg every 24 hours, with the dose being administered at bedtime. This would still result in 50% more accumulation than occurs in young adults at steady state, but potential for sedation and other adverse effects would be reduced. Predictedsuppressionof the histamine-induced wheals and flares would be approximately 60% and 80%. respectively. When the chlorpheniramine data were analyxd
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100,
90% 80. f e!
70.
6 Rare dl wheal
i
60,
Mean+SEM
E 3 ifi
50 40. 30,
i 20, I
10,
0,
4 0
12
1
The
40
72
(h)
FIG. 5. Percent suppression of the histamine-induced wheal-and-flare single dose of chlorpheniramine, 0.12 mg/kg, by elderly subjects.
with the E, model, the values obtained for the wheal data were E,, 70.8%, and E&, 10.2 rig/ml, and for the flare data, E,, 117.6%) and E&,, 12.0 rig/ml. No comparison between the data from this study in the elderly and the data obtained in studies of young adults could be made becausewheal-andflare suppressionor other pharmacodynamic studies of chlorpheniramine were not included in any of the chlorphenimmine pharmacokinetic studies in young adults.‘-lo In our study of chlorpheniramine in children,‘* limited pharmacodynamicdata were obtained, but the histamine-induced wheals and flares were analyzed with maximum diameter, not area, and times of blood sampling and measurementof the whealand-flare suppression were too infrequent to permit comparative analysis with the data obtained in the elderly subjects. If chlorpheniramine is administered in a dose of 4 to 8 mg every 4 to 6 hours, steady-stateserum chlorpheniramine concentrationswill be approximately five times the serum chlorpheniramine concentrationsobtained after a single dose. These elevatedsteady-state serum concentrationswould likely be associatedwith considerable sedation. In the elderly, based on predictions from pharmacodynamicand pharmacokinetic data, a more rational dosageregimen might be chlorpheniramine, 8 mg every 24 hours administered at bedtime. With this dosageregimen, chlorpheniramine
24
areas after ingestion
of a
accumulation of approximately 1.3 times the single dose values might occur at steady state; peak serum chlorpheniramine concentrations and peak sedation would occm during the night when the patient presumably would be sleeping anyway. Predicted suppression of the histamine-induced wheals and flares would be approximately 40% and 60%, respectively. Further investigation of the pharmacokinetics and pharmacodynamics of the HI-receptor antagonists, terfenadine and chlorpheniramine, should be performed at steady-state serum concentrations in the elderly, becausein this population these medications may be commonly prescribedfor long-term treatment of rhinitis, pruritus, or urticaria. If the presently recommended manufacturers’ dosageregimens are followed, that is, terfenadine, 60 mg twice daily in adults,*’ and chlorpheniramine, 4 mg every 4 to 6 hours in adults,” considerableH,-receptor-antagonist accumulation in serum, with concomitant adverseeffects, is likely to occur in older patients. Although no special dosage recommendationsregarding terfenadine or chlorpheniramine are available for the elderly, the results of this study suggestthat current treatment regimens with terfenadine and chlorpheniramine require modification in these patients. We acknowledge the assistanceof Dr. Anders Lundell and Dr. Z. B. Salama.
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1. Simons KJ, Watson WTA, Chen XY, Simons FER. Pharmacokinetic and pharmacodynamic studies of the H, receptor antagonist of hydroxyzine in the elderly. Clin Pharmacol Ther 1989;45:9-14. 2. Cook CE, Williams DL, Myers M. et al. Radioimmunoassay for terfenadine in human plasma. J Pharm Sci 1980;69: 14192:1. 3. Okerholm RA, Weiner DL, Hook RH, et al. Bioavailability of terfenadine in man. Biopharm Drug Dispos 1981;2:185-90. 4. Garteiz DA. Hook RH, Walker BJ, Okerholm RA. Pharmacokinetics and biotransformation studies of terfenadine in man. Arzneimittelforschung 1982;32: 1185-90. 5. Simons FER, Watson WTA, Simons KJ. Lack of subsensitivity to terfenadine during long-term terfenadine treatment. J AL-
LERGYCLIN IMMIJNOL1988;82:1068-75. 6. Simons FER. Watson WTA, Simons KJ. The pharmacokinetics and pharmacodynamics of terfenadine in children. J ALLERGY CLIN
IMMUNOL1987;80:884-90.
7. Vallner JJ, Needham TE, Chan W, Viswanathan CT. Intravenous administration of chlorpheniramine to seven subjects. Curr Ther Res 1979;26:449-53. 8. Yacobi A, Stoll RG, Chao GC, et al. Evaluation of sustainedaction chlorpheniramine-pseudoephedrine dosage forms in humans. J Pharm Sci 1980;69: 1077-81. 9. Huang S-M, Athanikar NK, Sridhar K, Huang YC, Chiou WL. Pharmacokinetics of chlorpheniramine after intravenous and oral administration in normal adults. Eur J Clin Pharrnacol 1982;22:359-65. 10. Kotzan JA, Vallner JJ, Stewart JT, et al. Bioavailability of regular and controlled-release chlorpheniramine products. J Pharm SCI 1982;71:919-23. 11. Thompson IA, Bloedow DC, Leffert FH. Pharmacokinetics of intravenous chlorpheniramine in children. J Pharm Sci 1981; 70: 1284-6. 12. Simons FER, Luciuk GH, Simons KJ. Pharmacokinetics and efficacy of chlorpheniramine in children. J ALLERGY CLINIM-
MUNOL1982;69:376-81.
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13. Gendrcau-Reid L, Simons KJ, Simons FER. Comparison of the suppressive effect of astemizole, terfenadinc. and hydroxyzine on histamine-induced wheals and Bares in humans f 41
LERGYCLIN IMMUNOL1986;77:335-40. 14. Gibaldi M, Perrier D. Pharmacokinetics New Y~)rk: Marcel Dekker, 1982. 15. Shumaker RC. PKCALC: a BASIC interactive computer pro. gram for statistical and pharmacokinetic analyn~s of data Drug Metab Rev 1986;17:331-48. 16. Holford NHG, Sheiner LB. Understanding the tloseeffect relationship: clinical application of pharmacokineticpharmaccdynamic models. Clin Pbarmacokinet I98 l&429-53. 17. Steele RGD, Torrie JH. Principles and pmcedurt:s of statistics: a biometrical approach. New York: McGraw-Iii Il. 1980: 172. 94. 18. Montamat SC, Cusack BJ, Vestal RE. Management of drug therapy in the elderly. N Engl J Med 1989;321:303-9. 19. Eve&t DE, Avom I. Drug prescribing for the elderly Arch Intern Med 1986; 146:2393-6. 20. Loi C-M, Vestal RE. Drug metabolism in the elderly. Pharmacol Ther 1988;36:13 l-49. 21. Goldberg PB, Roberts J. Pharmacologic basis for developing rational drug regimens for elderly patients. Med Clin North Am 1983;67:315-3 1. 22. Shepherd AMM. Physiological changes with aging: relevance to drug study design. In: Cutler NR, Narang PK. eds. DN~ studies in the elderly-methodological concerns. New York: Plenum Medical Books, 1986:49-67. 23. Skassa-Bmciek W, Manderscheid J-C. Michel F-B, Bousquet J. Skin test reactivity to histamine from infancy to old age. J ALLERGYCLIN IMMUNOL1987:80:711-6. 24. Roehrs TA. Tietz EI, Zorick FJ, Roth T. Daytime sleepiness and antihistamines. Sleep 1984;7:137-41. 25. McEvoy GK. American Hospital Form&try Servtce Drug Information. Bethesda American Society of Hospital Pharmacy. 1989:2-29.
articles
Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly Keith J. Simons, PhD,* Tara J. Martin, BScPharm,** Wade T. A. Watson, MD, FRCP(C),*** and F. Estelle R. Simons, MD, FRCP(C)*** Winnipeg, Manitoba,
Canada
In a double-blind, randomized, crossover study, the H,-receptor antagonists, terfenadine and chlorpheniramine, were investigated in eight healthy, fasting female subjects, aged 67.8 * SD 0.8 years, who ingested single doses of terfenadine, 1 mglkg (mean dose, 69.6 + II .2 mg), and chlorpheniramine, 0.12 mglkg (mean dose, 8.4 ‘- 1.3 mg). The mean serum-elimination half-life of terfenadine metabolite I was 8.7 + 3.7 hours. After tegenadine ingestion, signl$cant wheal suppression occurred from 2 to 24 hours compared to predose wheal size, with maximum wheal suppression, 42 2 13% to 60 + 16% from 2 to 12 hours. Significant flare suppression occurred from 2 to 24 hours, with maximum flare suppression, 75 ? 15% to 78 5 13% from 4 to 8 hours. The mean serum-elimination half-life of chlorpheniramine was 22.6 + 11 .O hours. After chlorpheniramine ingestion, significant wheal suppression occurred from 1 to 10 hours, inclusive, compared to predose wheal size, with maximum wheal suppression, 36 + 11% to 37 ? II % from 5 to 6 hours. Sign$cant jare suppression occurred from 1 to 12 hours, with maximumjare suppression of 43 + 14% to 46 * 19% at 2, 5, and 6 hours (p < 0.01). Adverse effects, chiefty sedation, occurred in five of eight patients after receiving terfenadine, and in all eight patients afier receiving chlorpheniramine; but, since no placebo control was administered, these adverse effects could not be definitely attributed to H,-receptor-antagonist ingestion. (J ALLERGY CLINIMMJNOL1990;85:540-7.)
There are few studies of the pharmacokinetics and pharmacodynamics of HI-receptor antagonists in the elderly; however, there is some evidence that the serum-elimination half-life values of these medications may he prolonged in this age group.’ The pharmacodynamics of H,-receptor antagonists in the elderly may he altered, also, with a single H,-receptorantagonist dose having a prolonged suppressive effect on the histamine-induced wheal and flare in older patients. ’
From the Health SciencesClinical ResearchCenter, *Faculties of Pharmacy, Medicine, and Science, **Faculty of Pharmacy, and ***Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. Supported by Merrell-Dow Pharmaceuticals(Canada)Inc. Received for publication Feb. 13, 1989. Revised Nov. 10, 1989. Accepted for publication Nov. 20, 1989. Reprint requests:F. E. R. Simons, MD, 840 Sherbrook St., Winnipeg, Manitoba, CanadaR3A 1Sl. **Mrs. Tara Martin was the recipient of a Medical ResearchCouncil of Canadaundergraduatesummer studentaward. ***Dr. Wade Watsonwas the recipient of a Sandoz Clinical ResearchFellowship. 111118480
540
Abbreviations used
HPLC: High-performance liquid chromatography E,: Maximum effect attributable to drug EC,,: Serumconcentrationproducing 50% of E,,
Chlorpheniramine and terfenadine are commonly used H,-receptor antagonists, available without prescription in many countries. Age-dependent changes in the pharmacokinetics of terfenadine2e6 and chlorpheniramine7*‘* have already heen demonstrated, since young adults eliminate these medications more slowly than children do. We hypothesized that pharmacokinetic and pharmacodynamic studies of terfenadine and chlorpheniramine in the elderly might reveal longer serum-elimination half-life values and longer duration of H,-receptor-antagonist action than found in younger patients. METHODS We performed a randomized, double-blind, crossover comparison of terfenadine and chloxpheniramine in which each patient received a single dose of either terfenadine or
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T’AEJtE I. Summary of pharmacokinetic and pharmacodynamic and chlorpheniramine in various age groups* Patient
population
Terfenadine metabolite I No. of subjects Age 64 Terfenadine dose (mg) Peakserum cone (rig/ml) Time of peak serum cone Half-life (hr) Wheal suppression(hr) Reference Chlorpheniramine No. of subjects Age W Chlorpheniramine dose (mg) Peak serum cone (rig/ml) Time of peak serum cone Half-life (hr) Wheal suppression(hr) Reference
Healthy
67.8 69.6 190 2.0 8.7
r +2 k 2
28.5 r 60 351 2 2.5 k 2.9 2
8 67.8 k 0.8 8.4 + 1.3 (0.12 mg/kg)
l-10 -
---._---. Children
13 6.2 41 0.5 0.5
at least I- 12t 5
-
3.0 + 1.6 22.6 f 11.0
~-.-__.
11
8 0.8 11.2 (1 mg/kg) 70 1.7 3.7 2-24
13.2 + 5.5
studies of terfenadine metaholite ! Healthy young adults
elderly
541
15 18-27
8 11.3 rt 2.9 3.8 k 2.7
17.3 2 4.4 I 10
7.45 38.1 242 2.3 2.0
” rt t I -+
0.54 3.6 (30 or 60 mg) 28 0.2 0.1
at least i 8’: 6 11 11.0 r 3.0 4.8 it: 1.1 (0.12 mgikg)
13.5 2 3.5 2.5 4 1.S 13.1 i 6.6 I-24 12 -w--e--
Cone,Concentration. *The studiesreportedin references 5, 6, and 12wereconductedin our laboratoryundersimilarconditionsto the presentstudy.Thestudy reportedin reference10wasselectedfrom the literatureon the basisof comparable studydesignto the presentstudy. ?Twenty-hourstudieswerenor conducted(references 5 and6) SWhealsuppression wasnot studied(references 7 to 11).
chlorpheniramine at least 4 weeks apart and was monitored for 72 hours after eachdose. The investigation protocol was approved by the Faculty Committee on the Use of Human Subjects in Researchof the University of Manitoba, and eachparticipant gave written, informed consentbefore taking part. Participants were required to be aged 65 years or older, in excellent health, not using any medication regularly, and within 10% of normal weight for height. They were excluded if they had any acute or chronic illness, if they had ever taken an H,-receptor antagonist regularly, if they had ever smoked, or if they ingested alcohol or xanthinecontaining beverages excessively. Each participant was healthy on physical examination and had a normal complete blood count and normal hepatic and renal function, as evidenced by normal direct and total-serum bilirubin, serum protein and albumin, alanine aminotransferase, aspartateaminotransferase,lactate dehydrogenase,yglutamyl transferase..serum creatinine, and blood urea nitrogen.
At the beginning of each 72-hour study, participants reported to the Health SciencesClinical ResearchCenter at 0800 hours after an g-hour fast and had an indwelling venous catheter with “heparin lock” inserted. Blood samplesof 5 ml for measurementof serum terfenadine metabolite I or chlorpheniramine concentrations were collected from the “heparin lock” before, and 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours, and then by venipuncture at 24, 48, and 72 hours
after administration of a single dose of terfenadine, 1.O mg/kg, or chIorpheniramine, 0.12 mgikg, as identical appearing and tasting white opaque suspensions.Before dose and from 1 to 12 hours after dose, the first I .O ml of each blood sample was discarded, and after each sample was obtained, the heparin lock was rinsed with I .O ml of 0.9% saline, followed by 0.5 ml of a sofution containing 10 U of heparin per milliliter of 0.9% saline. Xanthine-containing food and beverageswere restricted for 8 hours after dose, and alcohol ingestion was not permitted during the study. A standardizedlight snackwas served 2 hours a&x dosing, and standardized meals were served 4 and 8 hours after dosing. Blood sampIeswere centrifuged at 3700 rpm ( 1370 g), and serumwastransferredto glasstubesand stored, securely capped,at - 20” C. Serumchlozphenirarnineconcentrations were determined by HPLCiZ Serum samples were dkalinized and extracted with ether. C~~n~~e and the internal standard,tripekannamine,were back extractedfrom the ether into 100 ~1 of 1.7% phosphoric acid and injected into a modular HPLC system. On a @Bonded Cla column with a mobile phase of 20% ace&&rile in 0.75 mol/L of ammonium phosphate buffer, pH 2.7, at 2.3 mI/min, the chlorpheniramine and internal standard&ted at 7.2 and 5.2 minutes, respectively. The lower limit of sensitivity of the HPLC assay Forchlotpheniramine was 2 rig/ml, with a coefficient of variation of 6.6 :e 2.0% during 4 weeks.
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500 300 200 I Terfenadlne Metabolite I T CMorpheniramine
100
Mean
5 c 50 ,e k
+ SD.
n-8 T
Time (h)
FIG. 1. Serum concentration versus time plots of terfenadine metabolite I after ingestion of a single dose of terfenadine, 1.0 mg/kg, and serum concentration versus time plots of chlorpheniramine after ingestion of a single dose of chlorpheniramine, 0.12 mg/kg, by eight elderly subjects. The mean serum elimination half-life value of terfenadine metabolite I was 8.7 ? 3.7 hours and that of chlorpheniramine was 22.6 4 11 .O hours.
Serumterfenadinemetabolite I concentrationswere measuredat Fluka GmbH, New-Ulm, WestGermany, by HPLC with fluorescencedetection. This method has a lower limit of sensitivity of 20 nglml. Over the serum concentration range from 20 to 200 rig/ml, the mean coefficient of variation was 2.0 * 0.9%. Each time a blood sample was obtained, an intradermal test was performed with 0.01 ml of a solution containing histamine phosphate, 0.1 mg/ml (0.036 mg/ml of histamine). A different site on the volar surface of the forearm was used for each test, and the sequenceof sites chosen was identical in all participants. Wheal-and-flare circumferenceswere traced with a felt-tipped pen 10 minutes after histamine injection and transferredto transparentpaper. Injections and tracings of the wheal-and-flare circumferences were madeby the sameinvestigator. Wheal-and-flareareas were measuredwith an IBM-PC (IBM Instruments, Inc., Danbury, Conn.) and digitizer with stereometricmeasurement software.13During the time this study was performed, the coefficient of variation, with one observertracing areas, was 7.8% for areasof 0.4 cm2,representativeof the smallest wheal areas traced, and 1.9% for areas of approximately 4.0 cm2,representativeof an averageflare area. Each time the blood testsand skin tests were performed, participants were questionedabout adverseeffects, such as sedation,light-headedness,feelings of disorientation or diz-
CLIN. IMMUNOL. MARCH 1990
ziness, dry mouth, visual changes,or difficulty in urinating. If participantsfell asleep,the duration of sleepwas recorded. Serum concentration versus time data from all subjects were analyzed individually, as reported previously,‘, ‘. 6.” with standardequations for model-independentanalysis,‘” and the PKCALC interactive computer program” on an IBM-PC. The results were comparedto results found previously in terfenadine and chlorpheniramine studies in children and in healthy young adults.‘-‘* The histamine-induced wheal-and-flare areas were analyzed as absolute values and as percent reduction of predose terfenadine or chlorpheniramine control values. Pharmacodynamic analysis was performed by plotting mean percent suppression of histamine-inducedwheals and flares versusmeanserumH,receptor-antagonistconcentrationsand fitting the datato the E,, model.I6 For all statistical comparisons, the two-way analysis of variance with participant and sample time, or participant and age-relatedstudy as the criteria of classification, and the Tukey and Bonferroni multiple-range tests were used. Differences were considered significant at p < 0.05.l’ In all analyses,the standarddeviation was used to indicate the extent of variance; however, wheal-and-flare data were graphed with the standarderror of the mean.
RESULTS Eight alert, active, healthy ladies, mean age 67.8 + 0.8 years, completed the study. After a mean terfenadine dose of 69.6 ? 11.2 mg, the mean peak serum terfenadine metabolite I concentration of 190 + 70 rig/ml occurred at a mean peak time of 2.0 ? 1.7 hours. The serum elimination half-life of terfenadine metabolite I was 8.7 + 3.7 hours (Table I; Fig. 1). After a single terfenadine dose, significant wheal suppressionoccurred from 2 to 24 hours, inclusive, comparedto the meanpredosewheal area. Maximum wheal suppressionoccurred from 2 to 12 hours, compared to wheal size at all other times (p < 0.01). Significant flare suppressionoccurred from 2 to 24 hours, inclusive, comparedto the mean predoseflare size (p < 0.01). Maximum flare suppressionoccurred from 4 to 8 hours, inclusive, after terfenadine ingestion (p < 0.01) (Fig. 2). Terfenadine produced >50% suppression of the histamine-induced wheal from 3 to 8 hours, inclusive, after the dose, and >50% suppressionof the flare from 3 to 24 hours, inclusive, after the dose.Flare suppression>70% occurredfrom 4 to 10 hours, inclusive, with peak suppression of 78% at 6 hours (Fig. 3). After a mean chlorpheniramine dose of 8.4 & 1.3 mg, the elderly patients had a mean peak serum chlorpheniramine concentrationof 13.2 + 5.5 ng / ml at a mean time of 3.O t 1.6 hours. The mean serum elimination half-life of chlqpheniramine was 22.6 -+ ll.Ohours,witharangeof9.2to41.0hours (Table I; Fig. 1).
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16-
N” E L?
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I5
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Mean+SEM *f p< 0.01 from 0 * p < 0.01
Q B 2 0 ii ,\E
maximum
suppression
lo 8-
6-
4
5
6
0
10
12
24
48
72
Time (h) FIG. 2. Mean wheal-and-flare areas after intradermal injection of 0.01 ml of histamine phosphate lo.1 mg/ml) before and 1 to 72 hours after a single dose of terfenadine, 1.0 mg/kg, in eight elderly subjects. Significant wheal suppression occurred from 2 to 24 hours, inclusive, compared to mean predose wheal size, and maximum wheal suppression occurred from 2 to 12 hours, compared to mean wheal size at all other times. Significant ffare suppression occurred from 2 to 24 hours, inclusive, compared to the mean predose flare size, and maximum flare suppression occurred from 4 to 8 hours, inclusive, compared to flare size at all other times (p < 0.01).
After a single chlorpheniramine dose, significant wheal suppressionoccurred from 1 to 10 hours, inclusive, compared to the mean predose wheal area (p < 0.01). Maximum wheal suppressionoccurred at 5 and 6 hours compared to wheal size at all other times. Significant flare suppressionoccurred from 1 to 12 hours, inclusive (p < O.Ol), compared to the mean predoseflare area. Maximum flare suppression occurred at 2, 5, and 6 hours, inclusive, after chlorpheniramine ingestion (p < 0.01) (Fig. 4). Maximum wheal suppression for chlorpheniramine was 37% and maximum flare suppression was 46% (Fig. 5). After terfenadine ingestion, four of eight elderly patients slept for 1.7 k 1.4 hours (range, 0.5 to 4.5 hours), and one patient complained of dizziness and light-headedness. After chlorpheniramine ingestion, six of eight patients slept for 1.8 t 1.3 hours (range, 1.O to 3.5 hours); one patient complained of lightheadednessand headache,and one patient complained of dry mouth. One patient became sleepy after ingesting terfenadine, but not after ingesting chlorpheniramine. No subject was entirely free from adverse effects in this study. The adverse effects appeared to be maximal when serum HI-receptorantagonist concentrations were highest. In the ab-
senceof a placebo control, however, the adverseeffects noted could not be definitively athibuted to H,receptor-antagonistingestion. DISCUSSKIN In this study, we measured tetfenadine metabolite 1 rather than terfenadine itself, becauseafter conventional single dosesof terfenadine, extremely low serum terfenadine concentrations, difficult to quantitate accurately by HPLC, are obtained.‘. ’ From studies of ‘4C-labeledterfenadine in healthy young adults, there is evidence that terfenadine is extensively converted to terfenadine metabolite 1, the active carboxylic acid metabolite of terfenadine (4-11-hydroxy4-[4-{hydroxydiphenyImethyl-1-piperidinyl)butyi]-aa-dimethylbenzene acetic acid hydrochloride) and terfenadine metabolite II (a-a-diphenyl-4-piperidinemethanol).‘. 4 Based on the rapid appearanceof terfenadine metabolite 1 in serum (Fig. I), terfknadine appearsto be readily absorbed in the elderly (Table I). Peakserumterfenadinemetabolite I concentrations and the time at which these concentrations occurred were similar in all age groups studied to date (Table I).5. ’ The absolute bioavailability of terfenadine is unknown. however, since there is no intmvenous formulation,
snd serum terfenadine
metabolite
1 concen-
544
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et al.
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100 90
El Flare hwtleal WUl+SEM
b = 40 % 30 !#
-s it ’
20 10 0
-il 0
1
The (h) FIG. 3. Percent suooression of the histamine-induced .. of tetfenadine, 1 mg/kg, in elderly subjects.
nations after intravenous administration are not available for comparison to serum terfenadine metabolite I concentrations achieved after oral administration.x The serumelimination half-life value of terfenadine metabolite I was 8.7 + 3.7 hours in healthy elderly people, significantly longer (p < 0.05) than the mean elimination half-life values of 2.9 2 0.5 and 4.5 hours found in healthy young adults4+’ and the mean elimination half-life value of 2.0 + 0.1 hours found in children6 (Table I). The absorption of chlorpheniramine also appeared to be as rapid and complete in the elderly as it was in younger patients; peak serum chlorpheniramine concentrations and the times at which peak chlorpheniramine concentrationswere achieved were similar to data obtained previously (Table I).‘. 9*lo,‘* In the elderly, there was great interindividual variation in the serum-elimination half-life values for chlorpheniramine; the mean serum-elimination halflife value of 22.6 + 11.4 hours was not significantly different from the mean serum-elimination half-life values of 17.3 + 4.4 to 27.9 + 8.7 hours found in young adults’-I0 but was significantly longer (p < 0.05) than the mean serum-elimination halflife values of 13.1 f 6.6 hours and 9.6 +- 3.6 hours, found after chlorpheniramine administration to children”~ I2 (Table I).
wheal-and-flare
areas after a single dose
Age-dependent changes in the pharmacokinetics of H,-receptor antagonists metabolized by the hepatic cytochrome P450 system might be expected in the elderly because of an age-related decrease in liver blood flow and smaller liver size, diminished number and function of hepatocytes, and reduced metabolizing capacity for medications with advancing age.18-22 The wheal-and-flare response to histamine is an objective, well-standardized bioassay that is valid in elderly patients.23 We have found that, in the elderly, as in younger patients, a single dose of terfenadine5~ 6 or of chlorpheniramine’* significantly suppressedthe wheal and flare for many hours. The mean peak serum concentrations of H,-receptor antagonists preceded the maximum suppressive effect on the wheals and flares by several hours, and the wheals and flares remained significantly suppressed, even when serum H,-receptor-antagonist concentrations were low, as found in previous studies.‘*6,I2H,receptor antagonistsand their active metabolites may be extensively bound to tissues, accounting for clinically and statistically significant antihistaminic effects even after serum concentrationshave declined. In this terfenadine/chlorpheniramine study in the elderly, adverse effects were reported by 62.5% of elderly patients ingesting the second-generationH,-
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flare
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145
12-
P a
‘O
ii h
8-
E
6-
T
** p< 0.01 from 0 , ‘P
-T
T
4-
3
4
5
l6
8
The (h) FIG. 4. Mean wheal-and-flare areas after intradermal injection of 0.01 ml of histamine phosphate (0.1 mg/ml) before and from 1 to 72 hours after a single dose of chlorpheniramine, 0.12 mg/kg by mouth, in eight elderly subjects. Significant wheal suppression occurred from 1 to 10 hours, inclusive, compared to mean predose wheal size, and maximum wheat suppression occurred at 5 and 6 hours, compared to mean wheal size at all other times. Significant flare suppression occurred from 1 to 12 hours, inclusive, compared to the mean predose flare size, and maximum flare suppression occurred at 2, 5, and 6 hours, inclusive, compared to flare size at all other times (p cl 0.01).
receptor antagonist, terfenadine, and were universal after administration of the first-generationH,-receptor antagonist, chlorpheniramine. The apparentincreased incidence of sedation in elderly patients after H,receptor-antagonist ingestion requires further investigation in noninvasive, placebo-controlled studies with more sophisticated techniques of monitoring sleep and sleep latency.% In the pharmacodynamicanalysis of the terfenadine data, we assumedthat serum terfenadine metabolite I concentrations represented the active compound. The values obtained for the wheal data were E,,,,, 62.9%, and EC&, 13.7 rig/ml. The values obtained for the flare data were E,,,,, 84.3%, and E&, 12.0 nglml. The results from the terfenadine studies in young adultssand in children6 could not be fitted precisely to the model, since the duration of sampling times in these studies was only 12 hours and 8 hours, respectively, resulting in insufficient data in the range where serum concentrations were declining and the histamine responsewas returning to baseline. However, the data available up to 12 hours’ and 8 hours6 in these younger subjectscould be superimposedexactly on the data from the elderly subjects.
In the terfenadine study in young adults,’ a 60 mg dose was administered every 12 hours for 56 days. There was no evidence of drug accumulation, since serum terfenadine metabolite I concentrations obtained before the dose on days 28 and 56 were not significantly higher than on day 1 and the suppression of histamine-induced wheals and flares on days 28 and 56 was not significantly greater than on day 1. If, however, elderly subjectsreceived terfenadine, 60 mg every 12 hours, three times the amount of terfenadine metabolite I should accumulate at steady state, compared to the amount that accumulates in young adults, since the half-life value of terfenadine metabolite I in the elderly is three times longer than it is in young adults. A more rational terfenadinedosageregimen in the elderly might be 60 mg every 24 hours, with the dose being administered at bedtime. This would still result in 50% more accumulation than occurs in young adults at steady state, but potential for sedation and other adverse effects would be reduced. Predictedsuppressionof the histamine-induced wheals and flares would be approximately 60% and 80%. respectively. When the chlorpheniramine data were analyxd
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100,
90% 80. f e!
70.
6 Rare dl wheal
i
60,
Mean+SEM
E 3 ifi
50 40. 30,
i 20, I
10,
0,
4 0
12
1
The
40
72
(h)
FIG. 5. Percent suppression of the histamine-induced wheal-and-flare single dose of chlorpheniramine, 0.12 mg/kg, by elderly subjects.
with the E, model, the values obtained for the wheal data were E,, 70.8%, and E&, 10.2 rig/ml, and for the flare data, E,, 117.6%) and E&,, 12.0 rig/ml. No comparison between the data from this study in the elderly and the data obtained in studies of young adults could be made becausewheal-andflare suppressionor other pharmacodynamic studies of chlorpheniramine were not included in any of the chlorphenimmine pharmacokinetic studies in young adults.‘-lo In our study of chlorpheniramine in children,‘* limited pharmacodynamicdata were obtained, but the histamine-induced wheals and flares were analyzed with maximum diameter, not area, and times of blood sampling and measurementof the whealand-flare suppression were too infrequent to permit comparative analysis with the data obtained in the elderly subjects. If chlorpheniramine is administered in a dose of 4 to 8 mg every 4 to 6 hours, steady-stateserum chlorpheniramine concentrationswill be approximately five times the serum chlorpheniramine concentrationsobtained after a single dose. These elevatedsteady-state serum concentrationswould likely be associatedwith considerable sedation. In the elderly, based on predictions from pharmacodynamicand pharmacokinetic data, a more rational dosageregimen might be chlorpheniramine, 8 mg every 24 hours administered at bedtime. With this dosageregimen, chlorpheniramine
24
areas after ingestion
of a
accumulation of approximately 1.3 times the single dose values might occur at steady state; peak serum chlorpheniramine concentrations and peak sedation would occm during the night when the patient presumably would be sleeping anyway. Predicted suppression of the histamine-induced wheals and flares would be approximately 40% and 60%, respectively. Further investigation of the pharmacokinetics and pharmacodynamics of the HI-receptor antagonists, terfenadine and chlorpheniramine, should be performed at steady-state serum concentrations in the elderly, becausein this population these medications may be commonly prescribedfor long-term treatment of rhinitis, pruritus, or urticaria. If the presently recommended manufacturers’ dosageregimens are followed, that is, terfenadine, 60 mg twice daily in adults,*’ and chlorpheniramine, 4 mg every 4 to 6 hours in adults,” considerableH,-receptor-antagonist accumulation in serum, with concomitant adverseeffects, is likely to occur in older patients. Although no special dosage recommendationsregarding terfenadine or chlorpheniramine are available for the elderly, the results of this study suggestthat current treatment regimens with terfenadine and chlorpheniramine require modification in these patients. We acknowledge the assistanceof Dr. Anders Lundell and Dr. Z. B. Salama.
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1. Simons KJ, Watson WTA, Chen XY, Simons FER. Pharmacokinetic and pharmacodynamic studies of the H, receptor antagonist of hydroxyzine in the elderly. Clin Pharmacol Ther 1989;45:9-14. 2. Cook CE, Williams DL, Myers M. et al. Radioimmunoassay for terfenadine in human plasma. J Pharm Sci 1980;69: 14192:1. 3. Okerholm RA, Weiner DL, Hook RH, et al. Bioavailability of terfenadine in man. Biopharm Drug Dispos 1981;2:185-90. 4. Garteiz DA. Hook RH, Walker BJ, Okerholm RA. Pharmacokinetics and biotransformation studies of terfenadine in man. Arzneimittelforschung 1982;32: 1185-90. 5. Simons FER, Watson WTA, Simons KJ. Lack of subsensitivity to terfenadine during long-term terfenadine treatment. J AL-
LERGYCLIN IMMIJNOL1988;82:1068-75. 6. Simons FER. Watson WTA, Simons KJ. The pharmacokinetics and pharmacodynamics of terfenadine in children. J ALLERGY CLIN
IMMUNOL1987;80:884-90.
7. Vallner JJ, Needham TE, Chan W, Viswanathan CT. Intravenous administration of chlorpheniramine to seven subjects. Curr Ther Res 1979;26:449-53. 8. Yacobi A, Stoll RG, Chao GC, et al. Evaluation of sustainedaction chlorpheniramine-pseudoephedrine dosage forms in humans. J Pharm Sci 1980;69: 1077-81. 9. Huang S-M, Athanikar NK, Sridhar K, Huang YC, Chiou WL. Pharmacokinetics of chlorpheniramine after intravenous and oral administration in normal adults. Eur J Clin Pharrnacol 1982;22:359-65. 10. Kotzan JA, Vallner JJ, Stewart JT, et al. Bioavailability of regular and controlled-release chlorpheniramine products. J Pharm SCI 1982;71:919-23. 11. Thompson IA, Bloedow DC, Leffert FH. Pharmacokinetics of intravenous chlorpheniramine in children. J Pharm Sci 1981; 70: 1284-6. 12. Simons FER, Luciuk GH, Simons KJ. Pharmacokinetics and efficacy of chlorpheniramine in children. J ALLERGY CLINIM-
MUNOL1982;69:376-81.
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13. Gendrcau-Reid L, Simons KJ, Simons FER. Comparison of the suppressive effect of astemizole, terfenadinc. and hydroxyzine on histamine-induced wheals and Bares in humans f 41
LERGYCLIN IMMUNOL1986;77:335-40. 14. Gibaldi M, Perrier D. Pharmacokinetics New Y~)rk: Marcel Dekker, 1982. 15. Shumaker RC. PKCALC: a BASIC interactive computer pro. gram for statistical and pharmacokinetic analyn~s of data Drug Metab Rev 1986;17:331-48. 16. Holford NHG, Sheiner LB. Understanding the tloseeffect relationship: clinical application of pharmacokineticpharmaccdynamic models. Clin Pbarmacokinet I98 l&429-53. 17. Steele RGD, Torrie JH. Principles and pmcedurt:s of statistics: a biometrical approach. New York: McGraw-Iii Il. 1980: 172. 94. 18. Montamat SC, Cusack BJ, Vestal RE. Management of drug therapy in the elderly. N Engl J Med 1989;321:303-9. 19. Eve&t DE, Avom I. Drug prescribing for the elderly Arch Intern Med 1986; 146:2393-6. 20. Loi C-M, Vestal RE. Drug metabolism in the elderly. Pharmacol Ther 1988;36:13 l-49. 21. Goldberg PB, Roberts J. Pharmacologic basis for developing rational drug regimens for elderly patients. Med Clin North Am 1983;67:315-3 1. 22. Shepherd AMM. Physiological changes with aging: relevance to drug study design. In: Cutler NR, Narang PK. eds. DN~ studies in the elderly-methodological concerns. New York: Plenum Medical Books, 1986:49-67. 23. Skassa-Bmciek W, Manderscheid J-C. Michel F-B, Bousquet J. Skin test reactivity to histamine from infancy to old age. J ALLERGYCLIN IMMUNOL1987:80:711-6. 24. Roehrs TA. Tietz EI, Zorick FJ, Roth T. Daytime sleepiness and antihistamines. Sleep 1984;7:137-41. 25. McEvoy GK. American Hospital Form&try Servtce Drug Information. Bethesda American Society of Hospital Pharmacy. 1989:2-29.