The New Oral Angiotensin II Antagonist Olmesartan Medoxomil: a Concise Overview

Home , Olmesartan

Journal of Human Hypertension (2002) 16 (Suppl 2), S13–S16  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview

HR Brunner Division of Hypertension and Vascular Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

The new orally active angiotensin II (A II) type-1 receptor of mean 24-h blood pressure was seen at doses of 10– antagonist olmesartan medoxomil is a prodrug, which 80 mg. Evaluation of 14 phase II/III studies has con- is rapidly converted in vivo to the active metabolite, firmed the antihypertensive efficacy of olmesartan olmesartan. The pharmacology, antihypertensive effi- medoxomil in over 3500 patients who received the drug cacy and safety of olmesartan medoxomil and/or the for up to 2 years. Frequencies of adverse events during pharmacologically active metabolite, olmesartan, have treatment with olmesartan medoxomil and placebo are been evaluated in both non-clinical and clinical models. similar, with no evidence of a dose response. There are Orally administered olmesartan medoxomil is rapidly no clinically significant effects on laboratory param- absorbed from the gastrointestinal tract and converted eters, and the drug-interaction potential of olmesartan during absorption to olmesartan, which is subsequently medoxomil is low. Current indications are that olmesar- excreted without further metabolism. Peak plasma con- tan medoxomil is a true once-daily, orally active A II centrations of olmesartan occur 1–3 h after adminis- antagonist with good antihypertensive efficacy and a tration, after which concentrations decrease with an favourable adverse-event profile. Clinical pharmaco- elimination half-life of 10–15 h. The absolute bioavail- dynamic and efficacy studies support a usual dose of ability of olmesartan from olmesartan medoxomil tab- 20 mg once daily, increasing to 40 mg if needed. lets is 28.6%. In a single-dose crossover study in 16 Journal of Human Hypertension (2002) 16 (Suppl 2), S13– patients with mild-to-moderate hypertension receiving a S16. DOI: 10.1038/sj/jhh/1001391 sodium-restricted diet, statistically significant lowering

Keywords: olmesartan medoxomil; pharmacokinetics; efﬁcacy; safety; tolerability

Introduction Pharmacology The potentially harmful pressor effect of angiotensin Angiotensin II receptor antagonism II (A II) has long been recognized, and A II blockade, Table 1 shows the wide range of inhibitory effects first using angiotensin-converting enzyme (ACE) achieved in vitro by A II antagonists at bovine AT inhibitors and more recently with A II type-1 recep- 1 and AT2 receptors, expressed as the molar concen- tor (AT1 receptor) antagonists, has been an exciting tration displacing specific binding of 125I-labelled A development that has completely changed the man- II by 50% (IC50). At the adrenal cortical AT1 recep- agement of clinical hypertension and congestive tor, olmesartan inhibits the binding of 125I-labelled heart failure.1 Orally active olmesartan medoxomil ± A II with an IC50 of 8.0 0.8 nmol/l, but does not is among the latest A II antagonists to be developed. affect binding to the bovine cerebellar membrane Olmesartan medoxomil is a prodrug that is rapidly AT receptor (IC Ͼ 100000 nmol/l). The affinity of converted in vivo to the pharmacologically active 2 50 olmesartan for the AT1 receptor is higher than that metabolite, olmesartan. The pharmacological of, for example, losartan (IC 92 ± 5 nmol/l).2 properties and promising efficacy and safety profiles 50 of olmesartan medoxomil are discussed in this overview. Pharmacokinetic parameters The medoxomil ester of olmesartan was developed in preference to the active compound olmesartan, because the oral bioavailability of the latter is low (4.5%) and is increased (to 28.6%)3 by esterification Correspondence: HR Brunner, Division of Hypertension and Vas- with the medoxomil moiety. Following oral adminis- cular Medicine, Centre Hospitalier Universitaire Vaudois, 1011 tration of olmesartan medoxomil in humans and ani- Lausanne, Switzerland. E-mail: hans-r.brunnerȰchuv.hospvd.ch mals, the intact parent ester has not been observed in Olmesartan: angiotensin II antagonist HR Brunner S14 Table 1 Comparison of inhibitory effects of angiotensin II (A II) washout 8 mg olmesartan medoxomil intra- 125 antagonists on I-labelled A II binding to bovine adrenal cortical venously over 5 min.4 and cerebellar membranes in vitro As shown in Table 2, Cmax and AUC at steady state

A II antagonist IC50 (nmol/l) were greater than controls for all patient groups except for those with mild hepatic impairment. In AT1 receptor AT2 receptor patients with severe renal impairment, in whom (adrenal cortex) (cerebellum) exposure is increased 2.79-fold compared with ± ± healthy subjects, caution is required when starting A II 1.5 0.1 0.57 0.04 therapy, and the daily dose of olmesartan medox- Olmesartan 8.0 ± 0.8 Ͼ100 000 Olmesartan medoxomil 33 ± 8 Not tested omil should not exceed 20 mg. The results of this Losartan 92 ± 5 Ͼ100 000 study suggest that dosage adjustments in the popu- Active metabolite of 16 ± 1 100 000 lations tested may not be needed except for patients losartan (EXP 3174) with severe renal impairment. The increased plasma Candesartan 12 ± 1 100 000 Saralasina 5 ± 0.2 1.5 ± 0.1 concentrations of olmesartan in elderly and very PD-123177b Ͼ100 000 150 ± 20 elderly patients, and in patients with mild and moderate renal and hepatic impairment, were still sev- a b AT1 and AT2 antagonist; AT2 antagonist. IC50, concentration of eral-fold lower than those observed in other studies, antagonist displacing specific binding of 125I-labelled A II from where concentrations achieved after 80 mg olmesar- bovine tissue receptors by 50% (mean ± s.e.). (Reproduced with tan medoxomil daily were well tolerated.4 permission from Reference 2.) Drug interactions measurable amounts in plasma or excreta. Absorption The potential for drug interactions with olmesartan of olmesartan in humans following oral dosing with medoxomil has been evaluated using in vitro and in the medoxomil ester is rapid (t 1–3 h). Systemic max vivo studies. This drug has no or minimal inhibitory availability (measured as olmesartan maximum con- effects on human cytochrome P-450 activities at thera- centration (C ) and area under the curve (AUC) max peutic concentrations in vitro. A recent review con- values) increases linearly, or nearly so, over the thera- cludes that interactions between olmesartan medox- peutic dose range, although the increases are slightly omil and co-administered warfarin, digoxin or the less than dose-proportional at higher doses. antacid aluminium magnesium hydroxide are not The mean plasma elimination half-life of olmesartan clinically significant, and that olmesartan medoxomil in humans ranges from 10 to 15 h after multiple oral appears to have a low interactive potential.3 doses. The major route of excretion of olmesartan is in the faeces. Urinary excretion accounts for 10–16% of the administered dose. However, only a fraction (26%) Clinical antihypertensive efficacy of of the administered dose is available systemically and, olmesartan medoxomil of this, up to half is excreted in the urine and the The blood pressure (BP)-lowering effects of olmesar- 3,4 remainder in the faeces with unabsorbed drug. tan medoxomil have been confirmed in a model

Table 2 Pharmacokinetics of olmesartan medoxomil in elderly Effect of potential risk-group status on hypertensive, very elderly hypertensive, renally impaired and pharmacokinetics hepatically impaired patients In four studies, the inﬂuence of hypertensive Population n Deﬁnition Percentage patients’ risk status on pharmacokinetic parameters increase vs 4 of olmesartan medoxomil was investigated. The controls parameters in elderly, very elderly, renally impaired SS SS and hepatically impaired patients were compared C max AUC ␶ with appropriate controls as follows: у р • = Elderly hypertensive 12 65 75 years 9 33** elderly patients (65–75 years) (n 12) vs 12 Very elderly 17 у75 years 14* 44*** younger patients (18–45 years); 80 mg/day for 10 hypertensive days; Renally impaired a a • у = Mild 8 CLCR 40–50 ml/min 27 62 very elderly patients ( 75 years) (n 17) vs 16 a a Moderate 9 CLCR 20–39 ml/min 39 82 younger patients (18–45 years); 10 mg/day for 14 Ͻ a a Severe 9 CLCR 20 ml/min 56 179 days; Hepatically impaired • renally impaired patients (65–75 years) (eight Mild 4 Child-Pugh score р60b 30c mild, nine moderate, nine severe) vs eight healthy Moderate 8 Child-Pugh score 7–96b 48c* controls (41–47 years); 10 mg/day for 7 days; • *P Ͻ 0.05, **P Ͻ 0.01, ***P Ͻ 0.005. aNot statistically analysed. (in the USA only) hepatically impaired patients b c Cmax (maximum plasma concentration) after single dose. AUC␶ (26–72 years) (four mild, eight moderate) vs 12 (area under the plasma concentration/time curve) after single SS healthy controls (45–59 years); single oral dose of dose. CLCR, creatinine clearance; C max, Cmax at steady state; SS 10 mg olmesartan medoxomil and after 10 days AUC␶ , AUC at steady state. (Data from Reference 4.)

Journal of Human Hypertension Olmesartan: angiotensin II antagonist HR Brunner S15 Table 3 Measurement of 24-h diastolic blood pressure (DBP) in week 8 from another study.8 In the study with 12 a single-dose pharmacodynamic study of olmesartan medoxomil weeks follow-up, all doses of olmesartan medoxomil in sodium-restricted hypertensive patients from 10 mg/day to 80 mg/day were superior to placebo in respect of the primary efficacy measure, Treatment 24-h DBP DBP AUC0–24 h (mm Hg) (mm Hg × hour) mean decrease in sitting diastolic BP (DBP) between baseline and final visit, and in response rates. In the Group 1 (n = 8) study with 8 weeks’ follow-up, doses of 2.5–40 mg Placebo 88.2 ± 5.3 2089 ± 76.2 caused significant mean decreases in sitting dia- Olmesartan medoxomil (mg) stolic and systolic BP (SBP). 2.5 84.3 ± 5.5 2002 ± 87.5 10 81.3 ± 5.6* 1926 ± 71.3* As indicated in Table 5, the 20 mg and 40 mg 40 81.8 ± 5.3* 1934 ± 83.9* doses of olmesartan medoxomil were significantly superior to the 5 mg dose at all time points, and the Group 2 (n = 8) Placebo 79.1 ± 4.9 1881 ± 93.2 40 mg dose was superior to the 10 mg dose at weeks Olmesartan medoxomil (mg) 4, 8 and 12. In the integrated efficacy analysis, as in 5 76.5 ± 5.5 1814 ± 102.0* individual studies, the 40 mg dose was numerically 20 70.7 ± 5.3* 1694 ± 104.3* ± ± superior to the 20 mg dose in reducing SBP. In the 80 70.2 5.5* 1668 111.7* key dose-ranging study,6 the 40 mg dose was also numerically superior to the 20 mg dose in reducing *P Ͻ 0.05 vs placebo; pairwise comparison based on ranks. Data ± DBP and in responder rate. A dose of 40 mg may be are means s.e. AUC0–24 h, area under the curve for 24-h DBP profiles. (Reproduced with permission from Reference 6.) beneficial in patients who do not respond adequately to a 20 mg dose. Of special interest is an 8-week study that was pharmacodynamic study in hypertensive patients in conducted to evaluate the efficacy of olmesartan whom the renin-angiotensin system was stimulated medoxomil dosing regimens of 5, 20 and 80 mg once by a low-sodium diet for 3 days and a single 40 mg or twice daily in 289 patients (DBP 100–115 dose of oral furosemide.5 In this pharmacodynamic mm Hg). In addition to conventional (cuff) BP model, two groups of eight patients each received measurement, 24-h ambulatory BP monitoring was three single olmesartan medoxomil doses and pla- used. Both methods showed that there were no sig- cebo using a crossover method. Blood pressures nificant differences between once- and twice-daily were recorded by ambulatory monitoring. The study dosing regimens (Figure 1). showed that doses of olmesartan medoxomil in the range 10–80 mg are more effective than placebo in Clinical safety and tolerability lowering BP (Table 3).6 A clinical programme comprising 14 phase II and Table 6 shows the incidence of treatment-emergent phase III studies confirmed the BP-lowering effect of adverse events (AEs), serious adverse events (SAEs) olmesartan medoxomil. In these studies over 5000 overall, and those judged to be even remotely related patients were randomized, and more than 3500 were to treatment, in patients receiving olmesartan treated with olmesartan medoxomil. About half of medoxomil in the placebo-controlled studies. Over- these patients received long-term olmesartan all and treatment-related incidences of AEs and medoxomil, including over 800 for at least 6 SAEs are similar for the olmesartan medoxomil and months, over 500 for at least 1 year, and over 360 placebo groups of patients. patients who took olmesartan medoxomil for 2 years There were no dose relationships for incidences (including more than 60 patients aged у75 years).7 of overall or related AEs.7,9 The most frequently Table 4 shows the mean efficacy data at week 12, reported AE was headache (Table 7). The most from a pivotal phase II dose-ranging study,6 and at notable difference between olmesartan medoxomil

Table 4 Antihypertensive activity of olmesartan medoxomil compared with placebo in two studies

Parameter Week Placebo Olmesartan medoxomil dose (mg/day)

2.55 10204080

⌬DBP 8 4.10 8.40* 8.25* 12.81* 11.83* 12.56* ND (mm Hg) 12 9.5 11.8 11.2 12.9* 14.1* 15.5* 15.8* ⌬SBP 8 2.06 8.95* 10.12* 14.57* 13.12* 17.29* ND (mm Hg) 12a 9.1 14.3 14.5 17.1 18.4 20.6 20.7 Responder rate 8 34.6 49.4 47.4 63.0* 67.5* 63.3* ND (%) 12 45.5 59.5 50.4 66.4** 72.1** 73.8** 77.8**

*P Ͻ 0.05, **P Ͻ 0.0085 vs placebo. aNot statistically analysed. ⌬DBP, ⌬SBP, decrease from baseline in sitting diastolic or systolic blood pressure; ND, not done. Week 8, n = 80–91; week 12, n = 107–117. (Data from References 6 and 8.)

Journal of Human Hypertension Olmesartan: angiotensin II antagonist HR Brunner S16 Table 5 Integrated efﬁcacy analysis of mean placebo-corrected Table 7 Treatment-emergent adverse events in at least 1% of decrease in trough sitting systolic blood pressure (mm Hg) for a patients receiving olmesartan medoxomil in placebo-controlled range of olmesartan medoxomil doses parallel-group studies

Week Olmesartan medoxomil dose (mg/day) Event No. (%) of patients with adverse events 2.55 10204080 Olmesartan Placebo medoxomil (n = 451) 2 5.32 4.95 6.54 7.93 7.98 11.43 = 4 5.45 5.85 6.68 8.32 9.09 12.18 (n 2259) 8 4.20 6.64 7.35 9.77 11.35 12.98 12 5.65 5.11 7.22 8.37 11.51 11.09 Headache 105 (4.7) 25 (5.5) No. of 222–281 377–866 393–507 312–516 156–194 113–234 Dizziness 51 (2.3) 2 (0.4) patients ␥-GT increased 39 (1.7) 3 (0.7) Hypertriglyceridaemia 39 (1.7) 2 (0.4) (Data from Reference 7.) Inﬂuenza-like symptoms 38 (1.8) 10 (2.2) Bronchitis 26 (1.2) 4 (0.9) Haematuria 24 (1.1) 3 (0.7)

␥-GT, ␥-glutamyltransferase. (Data from Reference 9.)

Conclusions Current indications are that olmesartan medoxomil is a true once-daily, orally active A II antagonist with good antihypertensive efficacy and a favourable AE profile. Clinical pharmacodynamic and efficacy studies support a usual dose of 20 mg once daily, increasing to 40 mg if needed.

Figure 1 Clinical efficacy of olmesartan medoxomil as assessed References by mean changes in diastolic blood pressure (DBP) from baseline during 23 hours after treatment at a 20 mg dose. Mean changes 1 Brunner HR. Olmesartan medoxomil: a new AT1 recep- in DBP from baseline to week 8 remained similar for 20 mg o.d. tor antagonist for the treatment of hypertension. Intro- and 10 mg b.i.d. (᭺) placebo; (̅) 10 mg b.i.d.; (࡯) 20 mg o.d. duction. J Hypertens 2001; 19 (Suppl): S1–S2. 2 Koike H, Sada T, Mizuno M. In vitro and in vivo pharmacology of olmesartan medoxomil, an angiotensin II type AT receptor antagonist. J Hypertens 2001; 19 Table 6 Treatment-emergent total adverse events (AEs) and seri- 1 ous adverse events (SAEs) overall and judged to be at least (Suppl): S3–S14. remotely treatment-related in hypertensive patients 3 Laeis P, Pu¨ chler K, Kirch W. The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the Treatment n Percentage of Percentage of risk of clinically relevant drug interaction. J Hypertens group patients with AEs patients with SAEs 2001; 19 (Suppl): S21–S32. 4 von Bergmann K et al. Olmesartan medoxomil: influ- Overall Related Overall Related ence of age, renal and hepatic function on the pharmacokinetics of olmesartan medoxomil. J Hypertens 2001; 19 (Suppl): S33–S40. Olmesartan 3190 50.9 26.9 2.0 0.5 medoxomil 5Pu¨ chler K, Nussberger J, Laeis P, Witte P-U. Blood Placebo 582 45.9 21.8 1.4 0.5 pressure and endocrine effects of single doses of CS- 866, a novel angiotensin II antagonist in salt-restricted (Data on file.) hypertensive patients. J Hypertens 1997; 15: 1809– 1812. 6 Brunner HR, Nussberger J. Relevance of clinical pharmacological models for the evaluation of the thera- and placebo was in dizziness (2.3% vs 0.4% of peutic dose range of an AT1 receptor antagonist. patients), which may be related to the pharmaco- J Hypertens 2001; 19 (Suppl): S15–S20. 9 7Pu¨ chler K, Laeis P, Stumpe KO. Blood pressure dynamic effect of the active drug. response, but not adverse event incidence, correlates There were no clinically significant differences in with dose of angiotensin II antagonist. J Hypertens the effects of olmesartan medoxomil and placebo on 2001; 19 (Suppl): S41–S48. liver enzymes (alanine and aspartate aminotransfer- 8 Data on file, Sankyo. Study 866–305. ases, alkaline phosphatase and ␥-glutamyltrans- 9Pu¨ chler K, Laeis P, Stumpe KO. Dose related differ- ferase) or total bilirubin, and there was no evidence ences in blood pressure response are not related to of any AEs on liver function. There were no clini- adverse event incidence [poster]. ESH 11th European cally significant changes in other laboratory test meeting on Hypertension, Milan, Italy, June 2001. parameters.7

Journal of Human Hypertension