Low-dose famotidine and effervescent cimetidine in healthy subjects: a placebo-controlled overnight ph study

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1 Aliment Pharmacol Ther 1998; 12: 469±474. Low-dose famotidine and effervescent cimetidine in healthy subjects: a placebo-controlled overnight ph study T. G. REILLY*, C. E. GRIMLEY*, B. USSELMANN*, J. COTTRELL,S.G.MANN,S.RASKINà& C. U. NWOKOLO* *Department of Gastroenterology, Walsgrave Hospital, Coventry, UK; Johnson & Johnson Merck Sharp & Dohme, High Wycombe, UK; and àmerck Research Laboratories, USA Accepted for publication 29 December 1997 SUMMARY Background: Amongst the low-dose H 2 -receptor antagonists available for the self-medication of dyspepsia, both famotidine 10 mg and cimetidine 200 mg have been shown to raise intragastric ph, but there is a delay after ingestion before signi cant effects can be demonstrated. A new effervescent preparation of cimetidine 200 mg releases an acid buffer which has a more rapid effect on intragastric ph. Aim: To investigate the relative abilities of low-dose famotidine and effervescent cimetidine to raise intragastric ph after a single postprandial evening dose. Methods: Twenty-four healthy subjects (12 men, 12 women, median age 32 years) completed a three-period crossover trial of famotidine 10 mg, effervescent cimetidine 200 mg and placebo. After a standard meal was given at h to subjects fasted for 5.5 h, drug or placebo was given at h. Intragastric ph was recorded with combined glass electrodes from to h by digital recorders. Results: Over the 12 h post-dose period the mean area under the ph/time curve (AUC ) after famotidine 10 mg was 3.73, after cimetidine 200 mg effervescent 2.79, and after placebo Over the same period the median ph and percentage of time that recordings were above ph 3 were 3.45 and 52.5 after famotidine 10 mg, 2.40 and 33.8 after cimetidine 200 mg effervescent, and 1.68 and 15.9 after placebo. Both active treatments were signi cantly different from placebo by each measure (P < 0.001), and famotidine 10 mg was signi cantly more effective than cimetidine 200 mg effervescent by each measure over the 0±12 h period (P < 0.001). Comparisons of mean AUCs for each 15 min period after dosing showed that decrease in acidity was signi cantly greater after cimetidine 200 mg effervescent than after famotidine 10 mg for the rst 60 min. In the later post-dose period only famotidine 10 mg raised ph for all time points to 12 h, whilst the effect of effervescent cimetidine 200 mg was detectable to» 8h. Conclusions: Inhibition of gastric acidity over the 12 h post-dose period was signi cantly greater and endured longer after famotidine 10 mg than after effervescent cimetidine 200 mg, but for the 60 min period immediately after dosing the effect on intragastric ph was signi cant following effervescent cimetidine 200 mg but not famotidine 10 mg. This suggests effervescent formulations of H 2 -receptor antagonists with an acid buffer have a more rapid effect on intragastric ph than lm-coated tablets. INTRODUCTION Correspondence to: Dr C. U. Nwokolo, Department of Gastroenterology, Walsgrave Hospital, Clifford Bridge Road, Coventry CV2 2DX, UK. Since January 1994 those self-medicating for dyspepsia in the UK have been able to use low-dose H 2 -receptor antagonists. 1 In healthy subjects a single postprandial Ó 1998 Blackwell Science Ltd 469

2 470 T. G. REILLY et al. dose of famotidine 10 mg in the early evening was found to decrease gastric acidity over the next 12 h to a greater degree than cimetidine 200 mg, 2 which over this period was no different from placebo. In fed subjects the effect of famotidine 10 mg on intragastric ph does not become signi cant until after 90 min, 3 while 1000 mg calcium carbonate antacid tablets raise ph immediately but the effect only lasts for 60 min. The effect of a preparation of an H 2 -receptor antagonist which releases sodium citrate has not previously been compared with that of a lm-coated tablet. The aim of the study was to compare the ability of famotidine 10 mg (Pepcid AC, Johnson & Johnson MSD Ltd, UK) and effervescent cimetidine 200 mg (StomeÂdine; Smith Kline Beecham Lab. Pharm., France) to raise intragastric ph in healthy fed subjects. The primary hypothesis was that during the post-dose period, inhibition of gastric acidity would be signi cantly greater after dosing with either active treatment than with placebo. Additionally it was hypothesized that famotidine 10 mg would be signi cantly more effective than effervescent cimetidine 200 mg in reducing gastric acidity over the post-dose period as a whole and over the predetermined intervals of 0±6 and 6±12 h after dosing. A further aim was to compare the effect on intragastric ph of famotidine 10 mg and effervescent cimetidine 200 mg in the early post-dose period (0± 3 h), to determine whether an effect of the effervescent citrate buffer could be observed. METHODS Subjects Twenty-four healthy subjects were invited to participate in the study, which was approved by the Coventry Research Ethics Committee. Each subject gave informed consent to the study. Study design Each subject was entered into a three-period crossover trial, and randomly assigned to one of six sequences of the three drugs (two three-period Latin squares, balanced for carry-over effect) with a wash-out period of 7 days between dosings. The study was an open label design in which one of the investigators remained blinded to the drugs until all data was gathered. On each of 6 study days, 12 subjects who had fasted for 5.5 h participated. In the Gastroenterology Research Unit each subject was intubated with a exible bipolar glass electrode (Ingold M440) which had been prepared by calibration on a Digitrapper electronic ph recorder (Synectics Ltd) to standard buffers of ph 7.0 and The probes were passed by the nasogastric route and their entry into the stomach determined by a drop in the ph to expected intragastric levels of < ph 3. They were then advanced a further 8 cm from that point to be in the most dependent part of the stomach. Each subject used the same electrode and Digitrapper on each occasion. Recordings were started at h. At h a standard meal was given: this consisted of a supermarket-purchased ready meal of lasagne and peas, followed by a chocolate-coated ice cream and two chocolate mints to give a total of 700 kcal, provided by 22 g protein, 70 g carbohydrate and 37 g fat; 250 ml of mineral water was given with the meal. At h the test medication was given. This was either a placebo tablet, a famotidine 10 mg tablet or effervescent cimetidine 200 mg which was dissolved in 50 ml of water, and followed by a further 50 ml water. All other medications were accompanied by 100 ml of water. At h all subjects received a further 250 ml of water. Free ambulation around the unit was permitted but nothing further to eat or drink until the end of the study. At h subjects retired to bed on the unit under the supervision of one of the investigators (TGR or CG) and at h the electrodes were removed. Each electrode underwent a post-study calibration to check for electrode drift ( ph 0.1 being the limit of acceptability) before the recorder was stopped and the electrode disconnected. Drug preparations. The preparation of famotidine 10 mg used was the standard lm-coated tablet. That of cimetidine 200 mg was an effervescent tablet which on immersion in water yields trisodium citrate with a buffering capacity of 14.8 mmol/l at ph 3.5. It also contains inactive ingredients including aspartame and sodium benzoate. Analysis of data The studies were recorded by Digitrapper III recorders (Synectics Ltd, Sweden). These are compact boxes worn on a belt which sample and record the reading of the attached electrode, and in this study were set to store a median gure every 4 s in random access memory units. Data are transferred via an interface cable to the

3 LOW- DOSE FAMOTIDINE OR EFFERVESCENT CIMETIDINE ON INTRAGASTRIC ph 471 hard disk of a personal computer, one le per study, and can be loaded into a dedicated software program which displays the raw data numerically and graphically. Each study comes across as a block of data with each row representing the data for 1 min ( fteen 4 s readings). These studies continued for 13.5 h and thus consisted of stored readings. The les were downloaded from the PC in ASCII format for further importing into another software package (SAS/STAT; SAS Institute, Cary, NC) for statistical analysis. The area under the ph/time curve (AUC ) was calculated for each 15 min period from dosing to 3 h, and for each hour from 3 to 12 h. The median values for the 0±12 h, 0±6 h and 6±12 h post-dose periods were compared. To obtain these values for each drug, the median of the fteen 4 s ph readings in each minute was taken for each subject, and after grouping subjects by drug, group median values were derived for each minute. Medians were used because of the large variability typically seen as a result of the measuring technique used in this study. Pairwise comparisons were made between either drug and placebo, and between the two drugs, and the signi cance of these was tested. The proportion of ph readings above 3.0 was calculated for each drug and these were compared. All statistical comparisons were performed by analysis of variance. Prede ned periods of interest The primary analysis period was prede ned as that from 0 to 12 h after the drug being given, and the measure of central tendency employed to test the primary hypothesis was the AUC. Comparison of medians and percentage time above ph 3 over this period, and of AUC over periods from 0 to 6 h and 6±12 h made up a secondary analysis. Exploratory analyses were made using 15 min AUC values for the period of onset from 0 to 3 h, and to look at duration of effect hourly AUCs from 3 to 12 h. RESULTS Twenty-four subjects were recruited and completed the study per protocol. Twelve of the subjects were male, 12 female, and their median age was 32 years (range 20± 51 years). All studies were well tolerated and no signi cant side-effects or adverse events were reported during or after any study. Analysis for period and carryover effects was negative. Primary analysis Comparison of mean areas under the ph/time curve (AUCs) for the period 0±12 h post-dose shows signi cant differences between both drugs and placebo, and also that famotidine 10 mg raised intragastric ph to a signi cantly greater degree than effervescent cimetidine 200 mg. Secondary analyses Median ph values for the period 0±12 h post-dose are given in Table 1, and show signi cant differences both between the two active drugs and placebo, and between the two drugs in favour of famotidine 10 mg. AUC comparisons for the periods 0±6 h and 6±12 h likewise show signi cant superiority for famotidine 10 mg, Table 1. Mean area under the ph vs. time curve, median ph values and percentage of time above ph 3 for three prede ned periods of enquiry for two drugs and placebo Mean AUC (ratio to placebo) Median ph (ratio to placebo) Percentage time above ph 3* 0±12 h 0±6 h 6±12 h 0±12 h 0±6 h 6±12 h 0±12 h 0±6 h 6±12 h Placebo Famotidine 10 mg (1.81, (1.68, (1.94, (2.05, (1.72, (2.24, (P < 0.001) (P < 0.001) (P < 0.001) P < 0.001) P < 0.001) P < 0.001) P < 0.001) P < 0.001) P < 0.001) Cimetidine 200 mg effervescent (1.35, (1.41, (1.30, (1.43, (1.37, (1.42, (P < 0.001) (P < 0.001) (P ˆ 0.01) P < 0.001) P < 0.001) P ˆ 0.003) P < 0.001) P ˆ 0.001) P ˆ 0.003) Famotidine/cimetidine P < P ˆ P < P < P < P < P < P ˆ P < Signi cance testing by Hochberg's modi ed Bonferroni procedure.

4 472 T. G. REILLY et al. Figure 1. Mean area under the ph/time curve: 15 min intervals relative to dose. This plot shows the geometric means of the AUC for each 15 min interval over the rst 180 min after dosing. The asterisks denote signi cant (P < 0.05) comparisons between famotidine 10 mg and effervescent cimetidine 200 mg. although the difference between it and effervescent cimetidine 200 mg is less marked in the earlier period. The proportions of time spent above ph 3 for the 0± 12 h period were approximately one-half for famotidine 10 mg, one-third for effervescent cimetidine 200 mg, and one-sixth for placebo. Exploratory analyses The 15 min AUCs for the period 0±3 h and 1 h AUCs for the period 3±12 h were analysed. The results, shown in Figure 1 and Table 2, show that for the period from dosing to 60 min effervescent cimetidine 200 mg raised intragastric ph signi cantly higher than famotidine 10 mg, while after this time only famotidine 10 mg raised intragastric ph signi cantly for each hour up to the end of the study at 12 h. The effect of effervescent cimetidine 200 mg differs signi cantly from placebo up to the 8 h point but not thereafter. Figure 2 shows the ph medians for each 5 min interval by drug. To obtain these values median ph was found for each 5 min interval by subject and the median of these values were taken by drug. Inspection of this gure indicates that the median ph was greatest following famotidine 10 mg over the whole study period, but that there was a period of 60 min immediately following dosing when cimetidine 200 mg effervescent increased intragastric ph to a greater degree than famotidine 10 mg. It also shows that both active drugs can be clearly distinguished from placebo for the greater part of the study but that during the early period the traces for placebo and famotidine 10 mg were close. DISCUSSION Famotidine was released from prescription control in January 1994 and a low-dose preparation made available for the short-term treatment of dyspepsia. The duration of action of famotidine 10 mg has previously been studied. A postprandial dose of famotidine 10 mg 4 inhibited meal-stimulated acid secretion within 90 min and a signi cant effect was still noted at 8.7 h after the dose when recording ceased. A signi cant difference from placebo up to 9 h post-dose 2 has Table 2. Mean AUCs for hourly intervals from 3 h post-dose to the end of the study period Time interval (hours) after dosing 3±4 4±5 5±6 6±7 7±8 8±9 9±10 10±11 11±12 Famotidine 10 mg (placebo comparison) (1.72, (2.20, (2.53, (2.72, (2.49, (1.88, (1.82, (1.62, (1.42, P < 0.001) P < 0.001) P < 0.001) P < 0.001) P < 0.001) P < 0.001) P < 0.001) P < 0.001) P ˆ 0.005) Cimetidine (placebo comparison) (1.31, (1.32, (1.63, (1.60, (1.52, (1.27, (1.21, (1.25, (1.09, P ˆ 0.005) P ˆ 0.045) P ˆ 0.004) P < 0.001) P ˆ 0.003) P ˆ 0.053) P ˆ 0.11) P ˆ 0.046) P ˆ 0.47) Placebo

5 LOW- DOSE FAMOTIDINE OR EFFERVESCENT CIMETIDINE ON INTRAGASTRIC ph 473 Figure 2. Group median intragastric ph after dosing with three drugs, displaying ph medians for each 5 min interval by drug (n ˆ 24). been shown for famotidine 10 mg. However, studies in fed subjects suggest that the onset of action on intragastric acidity for famotidine 10 mg is not much before 90 min. If the use of these drugs is to prevent nocturnal symptoms after dosing in the early evening plainly this should be soon enough. However, if the users of the drug require immediate symptomatic relief then more rapid acid-neutralizing capability might be an advantage. A comparison of famotidine 10 mg and calcium carbonate antacid tablets measured acid inhibition and acid neutralizing capability by the intragastric titration technique 3 which has been shown to be an accurate way of measuring secretion of acid. 5 Famotidine 10 mg could not be shown to act before 90 min after dosing but a dose of 1000 mg calcium carbonate neutralized acid rapidly after dosing (6.7 mmol in the rst 30 min), although its duration of action was only 60 min. After feeding, although gastric acidity initially decreases due to the buffering capacity of food, secretion of gastric acid rapidly increases. 6 Intragastric titration has shown that the amount of acid secreted after feeding is between 15 and 25 meq in the rst hour. 6 A typical antacid may contain an in vitro buffering capacity of 25±30 meq in a dose of 10 ml, though this will vary widely in vivo depending on the protein content of the meal, the bioavailability of different antacids, and various in vivo events. The acid neutralizing capacity of the trisodium citrate buffer in the effervescent cimetidine we studied was 14.8 mmol. This makes it plausible that the effect we noted after effervescent cimetidine 200 mg was due solely to acid buffering, and suggests that the buffering is of an order of magnitude which might be clinically relevant. The technique we used is well established 7, 8 and provides a measure of intragastric acidity rather than acid secretion. The results of the primary analysis indicate that both drugs signi cantly decrease intragastric acidity when taken postprandially and that over the entire post-dose period there is a signi cant difference between the drugs, with famotidine 10 mg being the more effective. The rst 60 min after dosing however, show clearly that the preparation with citrate buffer has an earlier onset of action. A previous comparison of famotidine 10 mg and cimetidine 200 mg using the same technique 2 did not show either this early difference in favour of cimetidine, nor a signi cant difference from placebo for cimetidine 200 mg over the entire post-dose period. Comparison of the ph/time curves of the two studies emphasizes the similarity of the postdose periods, and the difference in statistical signi cance may be accounted for by a different number of subjects (16 not 24) and the presence in the earlier study of a non-responder to H 2 -receptor antagonists. This does not explain the rise in ph in the rst hour seen in the present study, and it seems reasonable to account for it by the acid buffering capacity of the effervescent formulation. Direct comparison of cimetidine 800 mg in effervescent and standard preparations, which showed an immediate rise in ph after the former but not the latter tends to bear out this assumption. 9 That this effect occurs with other H 2 -receptor antagonists than cimetidine is shown by a comparison of ranitidine and cimetidine in effervescent and standard formulations which demonstrated the same immediate rise in ph following both effervescent drugs. 10 This pharmacodynamic study gives no information about clinical ef cacy, and it is not certain whether the

6 474 T. G. REILLY et al. statistical difference in the early period between the two preparations tested here would translate into a clinical difference. Nevertheless, our results suggest that the addition of acid-buffering capacity to the formulation of famotidine 10 mg, the more successful drug overall, should allow early period acid-neutralizing capability to merge into drug-induced acid suppression after the rst 90 min. This might result in a novel preparation more effective than either of those we studied. ACKNOWLEDGEMENTS This study was funded by a grant from Merck Research Laboratories. The authors thank Sister Jean West and the staff of the Gastroenterology Investigation Unit, Walsgrave Hospital, Coventry, for their support. REFERENCES 1 Committee on the Safety of Medicines London. Medicines newly released for self-medication. Current Problems in Pharmacovigilance (MCA) 1994; 20: 4. 2 Reilly TG, Panos MZ, Mann SG, Walt RP. Low-dose H 2 - receptor antagonists as single post-prandial doses: a placebocontrolled comparative study of overnight ph. Gut 1995; 37: 325±8. 3 Feldman M. Comparison of the effects of over-the-counter famotidine and calcium carbonate antacid on postprandial gastric acid. A randomized controlled trial. J Am Med Assoc 1996; 275: 1428±31. 4 Laskin OL, Patterson P, Shingo S, Lasseter KC, Shamblen EC. Pharmacodynamics and dose±response relationship of famotidine: a double-blind randomised placebo-controlled trial. J Clin Pharmacol 1993; 33: 636±9. 5 Fordtran JS, Walsh JH. Gastric acid secretion rate and buffer content of the stomach after eating. Results in normal subjects and in patients with duodenal ulcer. J Clin Invest 1973; 52: 645±57. 6 Merki HS, Walt RP. Gastric secretion. In: Misiewicz JJ, Pounder RE, Venables CW, eds. Diseases of the Gut and Pancreas, 2nd edn, Vol. 1. Oxford: Blackwell Science, 1994: 209±20. 7 Merki HS, Witzel L, Walt RP, et al. Day to day variation of twenty four hour intragastric acidity. Gastroenterology 1988; 94: 887±91. 8 Walt RP, Male PJ, Rawlings J, Hunt RH, Milton-Thompson GJ, Misiewicz JJ. Comparison of the effects of ranitidine, cimetidine and placebo on the 24 hour intragastric acidity and nocturnal acid secretion in patients with duodenal ulcer. Gut 1981; 22: 49±54. 9 StroÈm M, Jonkman JHG, Peeters PAM, De Bruin H. Intragastric ph rise with effervescent citrate-cimetidine. Lancet 1991; 337: Smout AJPM, Jonkman JHG, Peeters PAM, De Bruin H. Effect of an evening dose of regular and effervescent formulations of ranitidine or cimetidine on intragastric ph in healthy volunteers. Alimentary Pharmacol Ther 1995; 9: 51.