The new orally active angiotensin II (A II) type-1 receptor antagonist olmesartan medoxomil is a prodrug, which is rapidly converted in vivo to the active ...
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 antagonist olmesartan medoxomil is a prodrug, which is rapidly converted in vivo to the active metabolite, olmesartan. The pharmacology, antihypertensive efficacy and safety of olmesartan medoxomil and/or the pharmacologically active metabolite, olmesartan, have been evaluated in both non-clinical and clinical models. Orally administered olmesartan medoxomil is rapidly absorbed from the gastrointestinal tract and converted during absorption to olmesartan, which is subsequently excreted without further metabolism. Peak plasma concentrations of olmesartan occur 1–3 h after administration, after which concentrations decrease with an elimination half-life of 10–15 h. The absolute bioavailability of olmesartan from olmesartan medoxomil tablets is 28.6%. In a single-dose crossover study in 16 patients with mild-to-moderate hypertension receiving a sodium-restricted diet, statistically significant lowering
of mean 24-h blood pressure was seen at doses of 10– 80 mg. Evaluation of 14 phase II/III studies has confirmed the antihypertensive efficacy of olmesartan medoxomil in over 3500 patients who received the drug for up to 2 years. Frequencies of adverse events during treatment with olmesartan medoxomil and placebo are similar, with no evidence of a dose response. There are no clinically significant effects on laboratory parameters, and the drug-interaction potential of olmesartan medoxomil is low. Current indications are that olmesartan medoxomil is a true once-daily, orally active A II antagonist with good antihypertensive efficacy and a favourable adverse-event profile. Clinical pharmacodynamic and efficacy studies support a usual dose of 20 mg once daily, increasing to 40 mg if needed. Journal of Human Hypertension (2002) 16 (Suppl 2), S13– S16. DOI: 10.1038/sj/jhh/1001391
Keywords: olmesartan medoxomil; pharmacokinetics; efficacy; safety; tolerability
Introduction
Pharmacology
The potentially harmful pressor effect of angiotensin II (A II) has long been recognized, and A II blockade, first using angiotensin-converting enzyme (ACE) inhibitors and more recently with A II type-1 receptor (AT1 receptor) antagonists, has been an exciting development that has completely changed the management of clinical hypertension and congestive heart failure.1 Orally active olmesartan medoxomil is among the latest A II antagonists to be developed. Olmesartan medoxomil is a prodrug that is rapidly converted in vivo to the pharmacologically active metabolite, olmesartan. The pharmacological properties and promising efficacy and safety profiles of olmesartan medoxomil are discussed in this overview.
Angiotensin II receptor antagonism
Correspondence: HR Brunner, Division of Hypertension and Vascular Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland. E-mail: hans-r.brunner얀chuv.hospvd.ch
Table 1 shows the wide range of inhibitory effects achieved in vitro by A II antagonists at bovine AT1 and AT2 receptors, expressed as the molar concentration displacing specific binding of 125I-labelled A II by 50% (IC50). At the adrenal cortical AT1 receptor, olmesartan inhibits the binding of 125I-labelled A II with an IC50 of 8.0 ± 0.8 nmol/l, but does not affect binding to the bovine cerebellar membrane AT2 receptor (IC50 ⬎ 100 000 nmol/l). The affinity of olmesartan for the AT1 receptor is higher than that of, for example, losartan (IC50 92 ± 5 nmol/l).2 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 with the medoxomil moiety. Following oral administration of olmesartan medoxomil in humans and animals, the intact parent ester has not been observed in
Olmesartan: angiotensin II antagonist HR Brunner
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Table 1 Comparison of inhibitory effects of angiotensin II (A II) antagonists on 125I-labelled A II binding to bovine adrenal cortical and cerebellar membranes in vitro A II antagonist
A II Olmesartan Olmesartan medoxomil Losartan Active metabolite of losartan (EXP 3174) Candesartan Saralasina PD-123177b
IC50 (nmol/l) AT1 receptor (adrenal cortex)
AT2 receptor (cerebellum)
± ± ± ± ±
0.57 ± 0.04 ⬎100 000 Not tested ⬎100 000 100 000
1.5 8.0 33 92 16
0.1 0.8 8 5 1
12 ± 1 5 ± 0.2 ⬎100 000
100 000 1.5 ± 0.1 150 ± 20
a AT1 and AT2 antagonist; bAT2 antagonist. IC50, concentration of antagonist displacing specific binding of 125I-labelled A II from bovine tissue receptors by 50% (mean ± s.e.). (Reproduced with permission from Reference 2.)
washout 8 mg olmesartan venously over 5 min.4
medoxomil
intra-
As shown in Table 2, Cmax and AUC at steady state were greater than controls for all patient groups except for those with mild hepatic impairment. In patients with severe renal impairment, in whom exposure is increased 2.79-fold compared with healthy subjects, caution is required when starting therapy, and the daily dose of olmesartan medoxomil should not exceed 20 mg. The results of this study suggest that dosage adjustments in the populations tested may not be needed except for patients with severe renal impairment. The increased plasma concentrations of olmesartan in elderly and very elderly patients, and in patients with mild and moderate renal and hepatic impairment, were still several-fold lower than those observed in other studies, where concentrations achieved after 80 mg olmesartan medoxomil daily were well tolerated.4 Drug interactions
measurable amounts in plasma or excreta. Absorption of olmesartan in humans following oral dosing with the medoxomil ester is rapid (tmax 1–3 h). Systemic availability (measured as olmesartan maximum concentration (Cmax) and area under the curve (AUC) values) increases linearly, or nearly so, over the therapeutic dose range, although the increases are slightly less than dose-proportional at higher doses. The mean plasma elimination half-life of olmesartan in humans ranges from 10 to 15 h after multiple oral 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%) of the administered dose is available systemically and, of this, up to half is excreted in the urine and the remainder in the faeces with unabsorbed drug.3,4 Effect of potential risk-group status on pharmacokinetics In four studies, the influence of hypertensive patients’ risk status on pharmacokinetic parameters of olmesartan medoxomil was investigated.4 The parameters in elderly, very elderly, renally impaired and hepatically impaired patients were compared with appropriate controls as follows: • elderly patients (65–75 years) (n = 12) vs 12 younger patients (18– 45 years); 80 mg/day for 10 days; • very elderly patients (⭓75 years) (n = 17) vs 16 younger patients (18– 45 years); 10 mg/day for 14 days; • renally impaired patients (65–75 years) (eight mild, nine moderate, nine severe) vs eight healthy controls (41– 47 years); 10 mg/day for 7 days; • (in the USA only) hepatically impaired patients (26–72 years) (four mild, eight moderate) vs 12 healthy controls (45–59 years); single oral dose of 10 mg olmesartan medoxomil and after 10 days Journal of Human Hypertension
The potential for drug interactions with olmesartan medoxomil has been evaluated using in vitro and in vivo studies. This drug has no or minimal inhibitory effects on human cytochrome P-450 activities at therapeutic concentrations in vitro. A recent review concludes that interactions between olmesartan medoxomil and co-administered warfarin, digoxin or the antacid aluminium magnesium hydroxide are not clinically significant, and that olmesartan medoxomil appears to have a low interactive potential.3
Clinical antihypertensive efficacy of olmesartan medoxomil The blood pressure (BP)-lowering effects of olmesartan medoxomil have been confirmed in a model Table 2 Pharmacokinetics of olmesartan medoxomil in elderly hypertensive, very elderly hypertensive, renally impaired and hepatically impaired patients Population
n
Definition
Percentage increase vs controls SS C SS max AUC
Elderly hypertensive 12 ⭓65 ⭐75 years Very elderly 17 ⭓75 years hypertensive Renally impaired Mild 8 CLCR 40–50 ml/min Moderate 9 CLCR 20–39 ml/min Severe 9 CLCR ⬍20 ml/min Hepatically impaired Mild 4 Child-Pugh score ⭐6 Moderate 8 Child-Pugh score 7–9
9 14*
33** 44***
27a 39a 56a
62a 82a 179a
0b 6b
30c 48c*
*P ⬍ 0.05, **P ⬍ 0.01, ***P ⬍ 0.005. aNot statistically analysed. b Cmax (maximum plasma concentration) after single dose. cAUC (area under the plasma concentration/time curve) after single dose. CLCR, creatinine clearance; C SS max, Cmax at steady state; AUCSS , AUC at steady state. (Data from Reference 4.)
Olmesartan: angiotensin II antagonist HR Brunner
Table 3 Measurement of 24-h diastolic blood pressure (DBP) in a single-dose pharmacodynamic study of olmesartan medoxomil in sodium-restricted hypertensive patients Treatment
Group 1 (n = 8) Placebo Olmesartan medoxomil (mg) 2.5 10 40 Group 2 (n = 8) Placebo Olmesartan medoxomil (mg) 5 20 80
24-h DBP (mm Hg)
DBP AUC0–24 h (mm Hg × hour)
88.2 ± 5.3
2089 ± 76.2
84.3 ± 5.5 81.3 ± 5.6* 81.8 ± 5.3*
2002 ± 87.5 1926 ± 71.3* 1934 ± 83.9*
79.1 ± 4.9
1881 ± 93.2
76.5 ± 5.5 70.7 ± 5.3* 70.2 ± 5.5*
1814 ± 102.0* 1694 ± 104.3* 1668 ± 111.7*
week 8 from another study.8 In the study with 12 weeks follow-up, all doses of olmesartan medoxomil from 10 mg/day to 80 mg/day were superior to placebo in respect of the primary efficacy measure, mean decrease in sitting diastolic BP (DBP) between baseline and final visit, and in response rates. In the study with 8 weeks’ follow-up, doses of 2.5– 40 mg caused significant mean decreases in sitting diastolic and systolic BP (SBP). As indicated in Table 5, the 20 mg and 40 mg doses of olmesartan medoxomil were significantly superior to the 5 mg dose at all time points, and the 40 mg dose was superior to the 10 mg dose at weeks 4, 8 and 12. In the integrated efficacy analysis, as in individual studies, the 40 mg dose was numerically superior to the 20 mg dose in reducing SBP. In the key dose-ranging study,6 the 40 mg dose was also numerically superior to the 20 mg dose in reducing DBP and in responder rate. A dose of 40 mg may be beneficial in patients who do not respond adequately to a 20 mg dose. Of special interest is an 8-week study that was conducted to evaluate the efficacy of olmesartan medoxomil dosing regimens of 5, 20 and 80 mg once or twice daily in 289 patients (DBP 100–115 mm Hg). In addition to conventional (cuff) BP measurement, 24-h ambulatory BP monitoring was used. Both methods showed that there were no significant differences between once- and twice-daily dosing regimens (Figure 1).
*P ⬍ 0.05 vs placebo; pairwise comparison based on ranks. Data are means ± s.e. AUC0–24 h, area under the curve for 24-h DBP profiles. (Reproduced with permission from Reference 6.)
pharmacodynamic study in hypertensive patients in whom the renin-angiotensin system was stimulated by a low-sodium diet for 3 days and a single 40 mg dose of oral furosemide.5 In this pharmacodynamic model, two groups of eight patients each received three single olmesartan medoxomil doses and placebo using a crossover method. Blood pressures were recorded by ambulatory monitoring. The study showed that doses of olmesartan medoxomil in the range 10–80 mg are more effective than placebo in lowering BP (Table 3).6 A clinical programme comprising 14 phase II and phase III studies confirmed the BP-lowering effect of olmesartan medoxomil. In these studies over 5000 patients were randomized, and more than 3500 were treated with olmesartan medoxomil. About half of these patients received long-term olmesartan medoxomil, including over 800 for at least 6 months, over 500 for at least 1 year, and over 360 patients who took olmesartan medoxomil for 2 years (including more than 60 patients aged ⭓75 years).7 Table 4 shows the mean efficacy data at week 12, from a pivotal phase II dose-ranging study,6 and at
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Clinical safety and tolerability Table 6 shows the incidence of treatment-emergent adverse events (AEs), serious adverse events (SAEs) overall, and those judged to be even remotely related to treatment, in patients receiving olmesartan medoxomil in the placebo-controlled studies. Overall and treatment-related incidences of AEs and SAEs are similar for the olmesartan medoxomil and placebo groups of patients. There were no dose relationships for incidences of overall or related AEs.7,9 The most frequently reported AE was headache (Table 7). The most 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) 2.5
5
10
20
40
80
⌬DBP (mm Hg)
8 12
4.10 9.5
8.40* 11.8
8.25* 11.2
12.81* 12.9*
11.83* 14.1*
12.56* 15.5*
ND 15.8*
⌬SBP (mm Hg)
8 12a
2.06 9.1
8.95* 14.3
10.12* 14.5
14.57* 17.1
13.12* 18.4
17.29* 20.6
ND 20.7
Responder rate (%)
8 12
49.4 59.5
47.4 50.4
63.0* 66.4**
67.5* 72.1**
63.3* 73.8**
ND 77.8**
34.6 45.5
*P ⬍ 0.05, **P ⬍ 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
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Table 5 Integrated efficacy analysis of mean placebo-corrected decrease in trough sitting systolic blood pressure (mm Hg) for a range of olmesartan medoxomil doses
Table 7 Treatment-emergent adverse events in at least 1% of patients receiving olmesartan medoxomil in placebo-controlled parallel-group studies
Week
Event
Olmesartan medoxomil dose (mg/day) 2.5
5
10
20
40
No. (%) of patients with adverse events
80
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 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 No. of 222–281 377–866 393–507 312–516 156–194 113–234 patients (Data from Reference 7.)
Olmesartan medoxomil (n = 2259) Headache Dizziness ␥-GT increased Hypertriglyceridaemia Influenza-like symptoms Bronchitis Haematuria
105 51 39 39 38 26 24
(4.7) (2.3) (1.7) (1.7) (1.8) (1.2) (1.1)
Placebo (n = 451)
25 2 3 2 10 4 3
(5.5) (0.4) (0.7) (0.4) (2.2) (0.9) (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 by mean changes in diastolic blood pressure (DBP) from baseline during 23 hours after treatment at a 20 mg dose. Mean changes in DBP from baseline to week 8 remained similar for 20 mg o.d. and 10 mg b.i.d. (䊊) placebo; (왕) 10 mg b.i.d.; (쮿) 20 mg o.d.
Table 6 Treatment-emergent total adverse events (AEs) and serious adverse events (SAEs) overall and judged to be at least remotely treatment-related in hypertensive patients Treatment group
Olmesartan medoxomil Placebo
n
Percentage of patients with AEs
Percentage of patients with SAEs
Overall
Related
Overall
Related
3190
50.9
26.9
2.0
0.5
582
45.9
21.8
1.4
0.5
(Data on file.)
and placebo was in dizziness (2.3% vs 0.4% of patients), which may be related to the pharmacodynamic effect of the active drug.9 There were no clinically significant differences in the effects of olmesartan medoxomil and placebo on liver enzymes (alanine and aspartate aminotransferases, alkaline phosphatase and ␥-glutamyltransferase) or total bilirubin, and there was no evidence of any AEs on liver function. There were no clinically significant changes in other laboratory test parameters.7 Journal of Human Hypertension
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