The Effects of Tegaserod (HTF 919) on the Pharmacokinetics and Pharmacodynamics of Digoxin in Healthy Subjects

Abstract

Tegaserod (HTF 919) is a highly specific 5-HT4 receptor partial agonist that exhibits promotile activity throughout the gastrointestinal tract and is under development for the treatment of functional gastrointestinal motility disorders. The present study was designed to assess the effect of multiple doses of tegaserod on the single-dose pharmacokinetics and pharmacodynamics of digoxin, a commonly prescribed agent for congestive heart failure. The study was an open-label, randomized, two-period crossover design of 12 healthy subjects. One treatment included digoxin treatment alone; the other treatment included a combined digoxin and tegaserod treatment. On day 1 of the digoxin treatment period, subjects received a single 1 mg oral dose of digoxin. In the combined tegaserod/digoxin treatment period, subjects received a single oral dose of 1 mg digoxin after 3 days of tegaserod (6 mg bid). After coadministration of tegaserod, systemic exposure to digoxin was decreased; mean AUC decreased by 11.9% (p < 0.05) relative to digoxin alone. Cmax was decreased by about 15% (p < 0.05). The 0.5-hour difference in the median tmax between the two treatments was not statistically significant. Because the steady-state trough concentration of digoxin (C(SS,min)) correlates with pharmacological effects, C(SS,min) for digoxin alone and in combination with tegaserod was simulated based on both parametric compartmental modeling and nonparametric superpositioning approaches. The predicted arithmetic mean C(SS,min) for combination therapy is 86% to 89% of that following digoxin alone. Likewise, the predicted arithmetic mean steady-state peak concentration (C(SS,min)) and AUC at steady state during a dosing interval (AUC(SS,tau)) have a similar decrease. This extent of decrease in systemic exposure of digoxin at steady state is unlikely to be clinically relevant. Administration of tegaserod (6 mg bid) was well tolerated, both alone and in combination with a single dose of digoxin. There were no pharmacodynamic changes in ventricular rate and QT interval following coadministration of tegaserod with digoxin. The 1.5-hour and 2-hour postdose plasma concentrations of tegaserod on days 3 and 4 confirmed adequate exposure. In conclusion, dose adjustment for digoxin is unlikely to be needed when tegaserod is coadministered.

Tegaserod in the treatment of irritable bowel syndrome (IBS) with constipation as the prime symptom

“…Tegaserod can be metabolized by hepatic cytochrome P450 isozymes (CYP P450) or excreted in urine and feces ( Appel-Dingemanse 2002 ). Other drugs are also metabolized by CYP P450, but there is no evidence of drug–drug interactions between tegaserod and such drugs, including theophylline ( Zhou, Khalilieh, et al 2001 ), dextromethorphan ( Kalbag et al 2000 ), digoxin ( Zhou, Horowitz, et al 2001 ), warfarin ( Ledford et al 2000 ), oral contraceptives ( Zhou et al 2000 ), or antidepressants ( Vickers et al 2001 ; Appel-Dingemanse 2002 ). These findings indicate that tegaserod can be safely administered alongside these commonly used drugs, with no need for dosage adjustments.…”

Tegaserod for Constipation‐Predominant Irritable Bowel Syndrome

“…1,24,42 No clinically significant interactions with digoxin, warfarin, or oral contraceptives have been reported. 1,43 The primary N-glucuronide metabolite produced in tegaserod metabolism has no inhibitory potential toward CYP enzymes in vitro. 24 Furthermore, in contrast to other promotility drugs, such as cisapride and erythromycin, tegaserod and its main metabolite did not prolong the QT interval in isolated rabbit hearts.…”

The rationale, efficacy and safety evidence for tegaserod in the treatment of irritable bowel syndrome

“…Therefore, there are no predictable interactions with the medications which most frequently lead to adverse consequences in this context (oral anticoagulants, oral contraceptives, digoxin, theophylline) [82,83]. A lack of effect on warfarin activity has also been presented in abstract form [84].…”