Telmisartan/Amlodipine: Single-pill combination in hypertension.. - (Page 657)

Telmisartan: A Review 657 interval (CI) for the between-group difference in GFR (-7.1 mL/min/1.73 m2) was greater than the predefined noninferiority margin (-10 mL/min/ 1.73 m2).[54] In 12-month comparisons with other ARBs, telmisartan 40–80 mg once daily reduced the adjusted mean UACR to a greater extent than losartan 50–100 mg once daily (29.8% vs 21.4%; p = 0.03) in a study that randomized 860 patients with type 2 diabetes, hypertension and a UACR ‡700 mg/g at baseline (AMADEO study),[55] while telmisartan 80 mg once daily decreased geometric mean 24-hour proteinuria to the same extent as valsartan 160 mg once daily (33% vs 33%) in a trial that randomized 885 patients with type 2 diabetes, hypertension and a 24-hour proteinuria of ‡900 mg (VIVALDI trial).[56] Based on the dosages administered in these studies, the BP-lowering effect of telmisartan was not significantly different from that of losartan[55] and valsartan.[56] The effects of telmisartan on GFR and UACR in key CVD prevention trials (ONTARGET[68,69] and TRANSCEND[70,71]) are discussed in section 4. 2.6 Cerebrovascular Effects ANG II has been implicated in the pathogenesis of stroke;[5] studies in animal models suggest that telmisartan may have a beneficial effect on cerebrovascular disease.[67] In spontaneously hypertensive rats, for example, telmisartan delayed the onset of stroke in stroke-prone animals[72] and reversed the remodelling of cerebral arterioles (both as monotherapy[73] and in combination with ramipril[74]). The effect of telmisartan on stroke incidence in key CVD prevention trials (ONTARGET,[68,69] TRANSCEND[70,71] and PRoFESS[75]) is discussed in section 4. 3. Pharmacokinetic Properties Orally administered telmisartan is rapidly absorbed, with peak plasma concentrations (Cmax) of the drug achieved in 0.5–1 hour in healthy volunteers and patients with mild to moderate hypertension.[8] The mean absolute bioavailability of telmisartan is »50%; coadministration ª 2011 Adis Data Information BV. All rights reserved. with food results in a clinically insignificant reduction in the bioavailability of the drug.[8] Steady-state plasma concentrations are reached after 5–7 days of repeated administration of telmisartan; drug accumulation after prolonged administration appears unlikely.[8] Mean Cmax and area under the plasma concentration-time curve from time zero to infinity values at steady state were 465 ng/mL and 2651 ng h/mL in 41 patients with mild to moderate hypertension who received oral telmisartan 80 mg once daily for 28 days.[8] Telmisartan is highly bound (>99%) to plasma proteins, mainly albumin and a1-acid glycoprotein. However, the highly lipophilic nature of the drug facilitates tissue penetration; this is reflected in its high volume of distribution (»500 L), which exceeds that of losartan, valsartan, candesartan cilexetil and eprosartan.[8,15] Although telmisartan undergoes hepatic glucuronidation (to form the inactive metabolite telmisartan-1-O-acylglucuronide), it is eliminated largely unchanged and almost entirely in the faeces, via biliary excretion.[8] Mean total body clearance and terminal elimination half-life (t½) values at steady state were 30 L/h and 19.6 h in patients with mild to moderate hypertension who received telmisartan 80 mg/day,[8] which is the recommended dosage for CVD prevention (section 6). Telmisartan has the longest t½ among ARBs.[15,76] The pharmacokinetics of telmisartan are not influenced to a clinically relevant extent by age, sex or degree of renal impairment, nor is the drug removed by haemodialysis.[8] A lower starting dose is recommended in patients with severe renal impairment and those with endstage renal failure requiring haemodialysis (see section 6). Plasma concentrations of telmisartan were higher in patients with hepatic insufficiency than those without liver impairment; the absolute bioavailability of the drug increased to almost 100% in the former, albeit the t½ was unchanged. The maximum recommended dosage of telmisartan in patients with mild to moderate hepatic impairment is 40 mg once daily; the drug is contraindicated in patients with severe hepatic impairment (see section 6).[8,10] Cytochrome P450 (CYP) isoenzymes are not involved in the metabolism of telmisartan, indicating Á Drugs 2011; 71 (6)

Table of Contents for the Digital Edition of Telmisartan/Amlodipine: Single-pill combination in hypertension..

Telmisartan/Amlodipine: Single-pill combination in hypertension..
Contents
Abstract
Introduction
Pharmacodynamic Properties
Anti-Inflammatory Effects
Endothelial Effects
Metabolic Effects
Cardiovascular Effects
Renal Effects
Cerebrovascular Effects
Pharmacokinetic Properties
Drug Interactions
Therapeutic Efficacy
ONTARGET
TRANSCEND
PRoFESS
Pooled Analyses of the TRANSCEND and PRoFESS studies
Tolerability
Comparisons with Placebo

Telmisartan/Amlodipine: Single-pill combination in hypertension..