Objective: To evaluate the steady-state pharmacokinetics (PK) and dose proportionality of the selective 5-HT4 receptor partial agonist tegaserod (HTF 919) in healthy subjects.
Methods: Eighteen subjects were given 2, 6, or 12-mg doses of tegaserod twice daily (b.i.d.) for 5 days, with PK and safety assessments made during the 12 h or 24 h following first administration, and 12 h after the final dose.
Results: Tegaserod was rapidly absorbed [time to reach measured maximum plasma concentration after multiple administrations (tmax,ss) 1 h]. Steady-state PK were consistent with single-dose PK characteristics supporting that there was no accumulation of tegaserod in plasma based on systemic exposure. Mean measured maximum plasma concentration after multiple administrations (Cmax,ss) and area under the plasma concentration-time curve over one dosing interval (tau, 0-12 h after drug administration, AUC tau) were between 0.7 +/- 0.3 ng/ml and 5.6 +/- 2.9 ng/ml and 2.4 +/- 1.3 h.ng/ml and 20.4 +/- 14.0 h.ng/ml, respectively, indicating dose-proportional PK of tegaserod in the range 2-12 mg b.i.d. Tegaserod was safe and well tolerated. No serious adverse events were reported.
Conclusion: Tegaserod exhibits no accumulation and dose-proportional PK after multiple doses.