Famotidine Effects on Theophylline Pharmacokinetics in Subjects Affected by COPD

Famotidine Effects on Theophylline Pharmacokinetics in Subjects Affected by COPO* Comparison with Clmetldlne and Placebo E Verdiani, M.D.; S. Di Carlo, M.D.; and A Bartmti, M.D., F.C.C.E

The effect of a new H.-antagonist, famotidine, on theophylline pharmacokinetics was compared with placebo and cimetidine in 26 patients affected by COPD. Cimetidine, placebo, and famotidine were administered, four days each

drug at random, to all the subjects. Results suggest that famotidine, contrary to cimetidine, does not influence theophylline metabolism in man. (Chat 1988; 94:807-10)

Theophylline is still widely used in the treatment of asthma and COPD, in spite of a limited therapeutic ratio, dose-related toxicity and a marked interindividual variability of clearance.' Moreover, several frequently used drugs have been shown to influence metabolism of theophylline. 2 Theophylline-treated patients often need a concomitant intake of Hj-antagonfsts, and it is now well established that cimetidine reduces theophylline clearance. This effect is probably due to the binding of the imidazole ring of cimetidine to the heme moiety of hepatic cytocrome P450. 3 Recently a new potent H 2-antagonist, famotidine, has been introduced, with a chemical structure (it is a guanidinothyazole derivative) different from cimetidine." The purpose of this study was to investigate, in patients affected by COPD, the effects of famotidine on the pharmacokinetics of theophylline, in comparison with placebo and cimetidine.

laboratory evaluation, ECG, chest x-ray films, pulmonary function testing (PFf), and blood gas measurements (BGM~ Six subjects did not give sufficient cooperation to perform PIT Each patient was given a treatment which, according to circumstances, included one or more among these drugs or classes of drugs: antibiotics, digoxin, diuretics, Pragonists, corticosteroids, oxygen. The trial was started as soon as the patient was judged stable, on the basis of the following criteria: (1) stable PaO. and PaCO. at repeated BGM at rest in room air; (2) stable FEV1 at repeated PFT (variations not exceeding ± 10 percent); (3) resolution of radiological and clinical signs of heart failure (if present); and (4) resolution of fever and purulent sputum (if present) The 26 subjects were allocated, according to whether taking theophylline or not, to two groups as follows: Group A: 16 patients receiving theophylline (Theo-Dur), 300 mg twice a day (at 8 AM and at 8 PM), for at least seven days before the trial started. Group B: Ten patients not receiving theophylline. Each patient of group A received, in randomized sequence, cimetidine, 400 mg twice a day orally for four days, placebo for four days, famotidine (Famodil), 40 mg once a day orally for four days. On the fourth day of each treatment, blood samples were collected immediately and two, four, six, eight, ten, and 12 hours after administration of theophylline. Each patient of group B received cimetidine, placebo, and famotidine, in a random sequence, according to the same schedule as group A. On the fourth day of each treatment, theophylline, 200 mg, was infused into an arm vein, over 30 minutes, and blood samples were collected 15, 30, 45, 60. lBO, 300, 420, 540, and 660 minutes after theophylline infusion. Serum theophylline concentrations were measured using a homogenous enzyme immunoassay technique. Drugs known to in8uence theophylline metabolism were avoided, and methylxanthines were removed from the diet throughout the study

METHODS

Subjects Twenty-six patients participated in this stud); after giving informed consent Clinical data concerning these patients are shown in 'Iahle 1. They all were affected by COPD and were admitted to the deparbnent of pneumology because an exacerbation was clinically suspected. The diagnosis of right heart failure was made when enlargement of the right heart chambers was seen on chest x-ray films, possibly associated with dilatation of the vena cava and signs of pulmonary arterial hypertension. Other physical findings, such as congestive hepatomegaly positive hepatojugular reflux and ankle edema, were also present.

7Hal Protocol Each patient underwent complete physical examination, routine *From the Divisione di Pneumologia, Ospedale --G.A. Pizzetti," Grosseto, ltal}( *Presented in part at the sixth congress of the European Society of Pneumology Amsterdam, August 31, 1987. Manuscript received December 23; revision accepted March 28. Reprint requests: Dr. ~dianill Divi8ione di Pneumologia 1, Vaale Cifnabue 109, Grosset», lttdy 58100

Data Analysis and Statiatics For the patients of group A, the bioavailability was assumed to be uni~ The total body clearance of theophylline (Cl) for group A was calculated by the equation Cl=D/AUC AUC is the area under the curve during a dose interval. AUC was measured with a planimeter on the serum concentration against time curve; D is the single dose of theophylline in milligrams per kilogram. Plasma elimination half-life (tl/2) was calculated, for group B patients, as CHEST I 94 I 4 I OCTOBER. 1988

807

Table l-ClinicGl ChartlCteriatica ofltJIienta Subjects* 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

22

23 24

25 26

Sex M M M M M M M M

M

M M F M M M M M

M

M

M M

M M

M

M M

Age (yr)

Weight, kg

Height, cm

Smoker

PaOI,t mmHg

69 72 65 70 76 63 64 76 67 63 77 68 57 56 65 59 66 79 70 61 66 59 79 69 73 64

71 64 84 59 56 63 74 69 63 70 57 56 71 64 75 85 60 80 55 79 71 68 47 73 48 74

167 175 164 163 152 165 165 160 155 160 171 160 165 186 164 174 160 175 168 173 168 170 170 160 160 165

No Ex No Ex No Yes Yes No Ex Ex No No Ex Ex Yes Ex Ex Ex Ex Ex No Ex No No Yes Yes

72 49 84 67 47 79 56 68 44 94 48 74 71 91 57 84 77 87 80 71 58 45 69 80 59 62

PaCOI,t mmHg

FEV.,t

33

34.9 39.6 36.8 38.8 43.9 45 43 58.6 38.2 45.6 37.9 46.8 36.7 42.7 35.6 33.6 43.7 41.9 41.3 39.2 41.9 34.9 36.9 43.3 43.5

L

RHFi

1.475 1.999 2.635 1.505 0.814 1.286 0.792 0.540

No No No No Yes No No Yes No No No No No No Yes No No No Yes No No Yes No No No No

2.363 1.601 1.247 1.762 1.493 2.170 1.010 1.940 1.546 1.190 0.892 0.695

*Subjects 1 to 16 received theophylline orally; 17 to 26, intravenously tValues taken when patient was stable and in the study *RHF indicates right heart failure (see text),

t1/2 = O. 693/~ was obtained, by linear regression analysis, as the slope of the plot of log plasma theophylline concentration against time, in the elimination phase. Analysis of measurements during cimetidine, famotidine, or placebo administration was performed by means of ANOVA for repeated measures. Comparison between mean results after placebo and after active treatments were performed by means of the Dunnett test. ~

RESULTS

Group A

Table 2 shows the values of clearance (CI) during famotidine (0.64 ± 0.27 ml-min-kg -1), placebo (0.64±0.28 ml-min-1-kg- 1), and cimetidine (0.55±0.23 ml-min-1-kg- 1). There is no statistically significant difference between famotidine and placebo, while the values of Cl during cimetidine are significantly lower than those during placebo (p<0.05). GroupB

The values of tI/2 observed during cimetidine, famotidine, and placebo are shown in Table 3. Cimetidine lengthened the elimination half-life of theophylline, 10.76 ± 3.48 hours, in comparison with both placebo, 8.52 ± 3.27 hours, and famotidine, 7.54 ± 2.84 hours, (p<0.05). Figure 1 shows the three elimination curves, obtained by plotting the mean theophylline serum con808

centrations, in the elimination phase, against time. The mean theophylline serum concentrations at five, seven, nine, and 11 hours are significantly higher Table 2-TottJl Body Clearance oj TheophylUne in 16 ltJIienta ofGroup A· Clearance (ml'min-1'Kg-l) Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

X

SD

F

P

C

0.48 0.72 1.10 1.21 0.38 0.40 0.63 0.30 0.59 0.66 0.48 0.61 0.56 0.58 0.50 1.11 0.64 0.27

0.44 0.59 0.99 1.34 0.45 0.41 0.93 0.39 0.70 0.59 0.52 0.70 0.34 0.40 0.58 0.93 0.64 0.28

0.46 0.51 0.82 1.21 0.34 0.43 0.62 0.36 0.61 0.47 0.41 0.70 0.32 0.36 0.48 0.70 0.55 0.23

NS ANOVA: F=5.875 (p
p<.OS

Famotidine Effectson Theophylline PharrnacoIdnetI (Verdlanl, Di ClIrIo, BatontJ)

ANOVA: F=7.I43 p
p<.05

by starting the study only when patients have reached stable conditions. The effects of a possible unexpected further improvement are counterbalanced by randomization of treatments. The variability among patients, due to the smoking habit, to different therapy regimens and to different clinical and functional conditions, is not relevant in the evaluation of our results because each patient is his own control. A time course of longer than four days of administration for each drug would have extended the length of the hospitalization too much. However, Mojaverian and eo-workers' also showed that a single dose of cimetidine is able to affect theophylline metabolism. The time to reach the new steady state is dependent on the new half-life of theophylline. In a study of adults, Vestal et al? showed that the new steady state concentrations required four days to reach maximum. Nell" says that in her experience, four days of therapy with cimetidine are enough to produce a 30 percent increase in theophylline levels. We cannot exclude that prolonged treatment with famotidine might produce effects different from those we have observed. All patients treated orally received slow-release theophylline twice a day for at least one week before entering the study This is adequate time for theophylline serum concentration to reach the steady-state at the start of the trial. In our patients, cimetidine reduced theophylline elimination: it produced a significant reduction of the clearance in the group of patients taking theophylline orally and a significant prolongation of the elimination half-life in the patients who were given a single intravenous dose of theophylline. Our results are of practical relevance because it is possible that theophylline is often prescribed in pa- . tients being treated with Ht-antagonists and viceversa. Moreover, in some patients, it may be necessary to use theophylline also in the presence of a history of peptic ulcer or gastritis. On the other hand, curing gastroesophageal reflux,

NS

(p<0.05) for cimetidine (4.9 ± 1.4; 4.3 ± 1.3; 3.9 ± 1.3 and 3.4±1.3) than for placebo (4.2±0.8; 3.7±1.0; 3.0 ± 0.8 and 2.5 ± 0.9) and famotidine (4.3 ± 0.8; 3.5±0.8; 2.8±0.8 and 2.5±0.9). There is no significant difference between famotidine and placebo at any sampling time. DISCUSSION

Mojaverian and eo-workers' have examined the effects of cimetidine and famotidine on the single dose pharmacokinetics of theophylline in rats. These authors suggest that famotidine, in contrast with cimetidine, does not interfere with theophylline metabolism in rats. The results we have obtained in our patients are consistent with those of Mojaverian and coworkers' and confirm a study done in normal volunteers by Chremos and co-workers. 5 Because theophylline clearance is influenced by several factors, including hypoxemia, airway obstruction, fever, heart failure, and liver disfunction," possible biases may be introduced into our study by an improvement which could have occurred in blood gases, lung, heart, or liver function during the trial. However, we think that these biases have been avoided 10

-.- Cimetidine

mg/1

-0-

Placebo

-. Famotidine

1+----+---t-----+------l~-_+_-~

o

2

4

6

hours

8

10

12

FIGURE 1. Semilogarithmic elimination curves in the group 8 patients after administration of theophylline, 200 mg mtravenouslj; Famotidine vs placebo: not significant at all sampling times. Cimetidine vs placebo: p
801

a classic indication for Hi-antagonists, may often induce a significant improvement in respiratory conditions of some patients affected by COPD (and often already being treated with theophylline). 9 In conclusion, famotidine, contrary to cimetidine, does not seem to affect theophylline metabolism when the two drugs are used in human subjects according to the commonly advised dosage schedules. Our results suggest that, in the above mentioned circumstances, theophylline and famotidine may be concomitantly administered without adjustments in the dosage of theophylline. ACKNOWLEDGMENTS: Dr. Fabrizio Martelli provided technical assistance, and Professor Sebastiano Bianco reviewed the manuscript

REFERENCES 1 Weinberger M, Hendeles L. Theophylline use: an overview J Allergy Clin Immunol 1985; 76:277-84 2 Jonkman JHG. Therapeutic consequences of drug interactions with theophylline pharmacokinetics. J Allergy Clin Immunol

810

1986; 78:736-42 3 Knodell RG, Holtzman JL, Cranksham DL, Steele NM, Stanley LN. Drug metabolism by rat and human hepatic microsomes in response to interaction with H-receptor antagonists. Gastroenterology 1982; 82:84-88 4 Mojaverian I: Bocci ML Jr, Saccar CL, Vlasses PH, Ferguson RK. Cimetidine vs famotidine: the effect on the pharmacokinetics of theophylline in rats. Eur J Drug Metabol Pharmacokin 1985; 10:155-59 5 Chremos AH, Lin JH, Yeh KC, Chiou R, Bayne WF, Lipschutz K, et ale Famotidine does not interfere with the disposition of theophylline in man: Comparison to cimetidine (abstract) Clio Pharmacal Ther 1987; 39:187 6 Hendeles L, Massanari M, Weinberger M. Update on the pharmacodynamics and pharmacokinetics of theophylline. Chest 1985; 88(suppI2):103-11 7 Vestal RE, Thummel KE, Musser B. Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonary disease: a study using stable isotope methodology during oral dose administration. Br J Clin Pharmacoll983; 15:411-18 8 Nell PAt Letter to the editor. Ann Allergy 1986; 57:442 9 Allen cj Newhouse Ml: Clinical commentary: gastroesophageal reflux and chronic respiratory disease. Am Rev Respir Dis 1984; 129:645-47

Famotldlne Effectson Theophylline Pharmacokinetics (Verdlanl, DI cano, Batonti)