Controlled Study of the Putative Interaction Between Famotidine and Theophylline in Patients with Chronic Obstructive Pulmonary Disease

Abstract

The effects of famotidine (80 mg per day), cimetidine (1600 mg per day), and placebo on theophylline pharmacokinetic parameters in chronic obstructive pulmonary disease (COPD) patients were compared. This was an open-label, randomized, three-period cross-over study, in which each subject first underwent a seven-day theophylline washout period, and thereafter received three single intravenous doses of theophylline (5 mg/kg infused over 30 minutes) during the study. Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days (19 doses). Theophylline was infused after the 17th dose of each treatment. Fourteen serial blood samples were collected before the start of each infusion, and for 30 hours after the end of each infusion. Plasma samples were assayed for theophylline, pharmacokinetic parameters were estimated, and treatment effects on each parameter were compared. Fourteen COPD patients completed all three periods of the investigation. Famotidine treatment had virtually no effect on any of theophylline's pharmacokinetic parameters. In contrast, cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows: Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h (P < .001), and prolonged theophylline harmonic mean half-life from 6.6 to 9.6 hours (P < .001) and mean residence time from 10.8 to 15.0 hours (P < .001). Cimetidine treatment slightly increased theophylline volume of distribution by approximately 10%, and that change also was statistically significant (P = .032). The authors conclude that the treatment effects of cimetidine on theophylline pharmacokinetic parameters were in accord with those reported by others, and that famotidine treatment had no effect on any of theophylline's pharmacokinetic parameters in COPD patients.

Volume of Distribution is Unaffected by Metabolic Drug–Drug Interactions

“…Relevant information on the specificity of all substrates analyzed are outlined in Table 1 and the inhibitory specificities of the perpetrator drugs included in this analysis are listed in Table 2. The comprehensive literature search identified DDI studies for the following index substrates where V ss measurements were available: caffeine [14], metoprolol [15], midazolam [16][17][18][19][20][21][22][23][24][25], theophylline [26][27][28][29][30][31][32][33][34][35][36][37][38], and tolbutamide [39] ( Table 3). Any additional victim-perpetrator combinations (with non-index substrates) investigated in these studies where V ss measurements were available were also analyzed, including alfentanil [20], antipyrine [27], and lidocaine [19] ( Table 4).…”

“… Pharmacokinetic values reported in the table are based on published average values, unless otherwise noted AUC area under the curve, BID twice daily, CL clearance, Con control, MATE1 Multidrug and Toxic Extrusion 1, MRT mean residence time, NAT N-acetyl transferase, NR not reported, OCT organic cation transporter, P-gp P-glycoprotein, QD once daily, QID four times a day, t 1/2,z terminal half-life, Refs reference, TID three times a day, V ss volume of distribution at steady state, XO xanthine oxidase a Ratios are calculated by digitization of published average plasma concentration–time profiles and performing a non-compartmental analysis b Ratios are calculated for each individual using published individual pharmacokinetic data; the reported value reflects the average of each individual ratio c AUC was calculated with the equation AUC = dose/CL using known dose and reported average values of CL d AUC was calculated for each individual with the equation AUC = dose/CL using known dose and reported individual values of CL; the reported value reflects the average of each individual ratio e MRT was calculated with the equation V ss = CL·MRT using reported average values of CL and V ss f MRT was calculated for each individual with the equation V ss = CL·MRT using reported individual values of CL and V ss ; the reported value reflects the average of each individual ratio g Ratios are calculated by digitization of a published plasma concentration–time profile of a single representative subject, which may not be reflective of all subjects in the study h Ratios are calculated by digitization of individual published plasma concentration–time profiles and performing a non-compartmental analysis; the reported value reflects the average of each individual ratio i Midazolam was dosed intravenously at the same time as an oral probe cocktail of tolbutamide, dextromethorphan, and caffeine j Interaction arm included n = 7 subjects; however, the control arm is only n = 6 as one subject dropped out of the study k A list of additional drugs being taken by these subjects with chronic obstructive pulmonary disease can be found in the original article by Bachmann et al [ 32 ] …”

“…Further, the variability associated with V ss values was much greater in extensive metabolizers than poor metabolizers, with CV values of 44% and 22%, respectively. The issue of variability between individuals is further Interaction arm included n = 7 subjects; however, the control arm is only n = 6 as one subject dropped out of the study k A list of additional drugs being taken by these subjects with chronic obstructive pulmonary disease can be found in the original article by Bachmann et al [32] 28%/23% a [19] + Midazolam (0.075 mg/kg; single dose) Unknown [44] compounded in pharmacogenomic studies where often only a very small number of individuals can be recruited for the less frequently occurring genotypes.…”

Extraneuronal Monoamine Transporter Mediates the Permissive Action of Cortisol in the Guinea Pig Trachea: Possible Involvement of Tracheal Chondrocytes

“…Most of the studies ascribed the amelioration of airway hyper-responsiveness to the anti-reflux effect of H2R antagonists on gastroesophageal tract, although some studies mentioned that the blockade of weak H2R signaling in airway tissue may also work in part. However, we noticed that several reports emphasized the influence of H2R antagonists on the disposition of theophylline in both healthy volunteers [31] and patients with airway disorders [32]. Although these results were thought to be related to CYP450-mediated metabolism, it could also be explained as impact on the xenobiotic transporter, such as EMT.…”

Introduction to Biostatistics

“…Note that the patients who received streptomycin fared better in general than the controls. The interactions between theophylline and two other drugs (famotidine and cimetidine) were studied in fourteen patients with chronic obstructive pulmonary disease (Bachmann, et al, 1995). Of particular interest were the pharmacokinetics of theophylline when it was being taken simultaneously with each drug.…”