Pharmacokinetics of Orally and Intravenously Administered Telmisartan in Healthy Young and Elderly Volunteers and in Hypertensive Patients

Abstract

A series of studies was conducted in healthy young males and healthy elderly males or females to evaluate the pharmacokinetic profile of telmisartan. In addition, two phase-II clinical trials assessed the pharmacokinetics and the safety of telmisartan in mild-to-moderate hypertensive patients. Telmisartan was given as a single oral (1-160 mg) or intravenous (10-160 mg) dose to young males. In another multiple-dose study, telmisartan 320 mg was administered orally once daily for 7 days to healthy young male subjects. Elderly subjects received oral telmisartan (20 and 120 mg) once daily for 7 days. Telmisartan doses of 10, 20, 40, 80, 120 and 160 mg were taken once daily by mild-to-moderate hypertensive patients for 7 days. Additionally, oral telmisartan (40, 80 or 120 mg) was administered once daily for 28 days to hypertensive subjects. Following oral dosing, median time to maximum plasma telmisartan concentration was 0.5 - 2 h, with maximum plasma concentrations increasing disproportionately with dose. By contrast, plasma concentrations were directly related to the intravenous dose. Steady state was observed after 5-7 days of once-daily administration, and there was no clinically relevant accumulation at 28 days. The plasma concentration-time profiles were similar in all study groups and were characterized by fast absorption and a rapid biexponential decline after the peak plasma concentration, with a prolonged terminal elimination phase (> 20 h in healthy and hypertensive subjects). Telmisartan was well tolerated, with a low incidence of drug-related adverse events. The most frequent event was headache, which also occurred in placebo-treated control subjects. No changes in heart rate, electrocardiograms or clinical chemistry were detected following receipt of telmisartan. The study thus shows that high systemic levels of telmisartan, which are well tolerated, can be attained in healthy adults of any age and in hypertensive subjects. The long terminal elimination half-life makes telmisartan suitable for once-daily dosing and contributes to the sustained efficacy over the full 24-h dosing interval.

Antihypertensive efficacy of telmisartan vs ramipril over the 24-h dosing period, including the critical early morning hours: a pooled analysis of the PRISMA I and II randomized trials

“…The superiority of telmisartan over ramipril in this time period is consistent with the established pharmacokinetic profiles of these agents. [21][22][23] It is also consistent with the results of other trials using 24-h ABPM that have shown superior efficacy of telmisartan compared with antihypertensives from a range of classes, including losartan, 24,25 valsartan, 15,16 amlodipine 26 and perindopril. 27 Evidence that reduction of morning BP provides clinical benefit comes from a study of patients with type II diabetes, hypertension and nephropathy, in whom a reduction of morning SBP in response to antihypertensive treatment was shown to correlate significantly with a slowing of the progression of renal damage.…”

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

“…The HLM CL int, u, met values for these compounds are 22, 29, 76, and 128 ml/min per milligram, respectively , smaller than the value for telmisartan [395 ml/min per milligram microsomal protein with bovine serum albumin (Gill et al, 2012), 1212 ml/min per milligram microsomal protein with bovine serum albumin (this study)]. However, their mean half-lives (3.4, 1.78, 1, and 1.2 hours, respectively) are much shorter than that of telmisartan (20 hours) (Lindahl et al, 1996;Weber et al, 1996;Muck et al, 1997;Stangier et al, 2000b;Niemi et al, 2005). To address the inconsistency between in vitro and in vivo observations, we hypothesize that telmisartan glucuronide is converted by intestinal microflora into telmisartan, and telmisartan experiences enterohepatic recirculation.…”

Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist With Selective PPARγ–Modulating Activity

“…Moreover, telmisartan was the only ARB that activated PPAR␥ when tested at lower concentrations (1 to 5 mol/L) that can be achieved in plasma with conventional oral dosing (data not shown). 39 Telmisartan concentrations of Ͻ10 mol/L did not significantly affect the activity of PPAR␣ or PPAR␦, although 25 mol/L telmisartan appeared to cause a modest activation (4-fold) of PPAR␣ (data not shown).…”