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Telmisartan and Amlodipine (Telmisartan / Amlodipine Besylate) - Description and Clinical Pharmacology

 
 



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DESCRIPTION

Telmisartan and amlodipine tablet is a fixed dose combination of telmisartan and amlodipine.

Telmisartan and amlodipine tablets contain telmisartan, a non-peptide angiotensin II receptor (type AT1) antagonist. Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base. Telmisartan is chemically described as 4'-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid. Its empirical formula is C33H30N4O2 and its structural formula is:

Telmisartan and amlodipine tablets contain the besylate salt of amlodipine, a dihydropyridine calcium-channel blocker (CCB). Amlodipine besylate is a white to pale yellow crystalline der, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate’s chemical name is 3-Ethyl-5-methyl(4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate. Its empirical formula is C20H25ClN2O5•C6H6O3S and its structural formula is:

Telmisartan and amlodipine tablets are formulated in four strengths for oral administration with a combination of amlodipine besylate, equivalent to 5 mg or 10 mg of amlodipine free-base, with 40 mg, or 80 mg of telmisartan provided in the following four combinations: 40/5 mg, 40/10 mg, 80/5 mg, and 80/10 mg.

Telmisartan and amlodipine tablets also contain the following inactive ingredients: colloidal silicon dioxide, crosscarmellose sodium, ferric oxide red, ferric oxide yellow, mannitol, magnesium stearate, povidone, sodium hydroxide and sodium starch glycolate.

Telmisartan and amlodipine tablets are hygroscopic and require protection from moisture.

Telmisartan and amlodipine tablets require protection from light.

CLINICAL PHARMACOLOGY

Mechanism of Action

Telmisartan

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.

Amlodipine

Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

Pharmacodynamics

Telmisartan and Amlodipine Tablets

Telmisartan and amlodipine tablets have been shown to be effective in lowering blood pressure. Telmisartan and amlodipine tablet is a combination of two drugs with antihypertensive properties: a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II receptor blocker, telmisartan.

Both telmisartan and amlodipine, lower blood pressure by reducing peripheral resistance but through complementary mechanisms.

Telmisartan

In normal volunteers, a dose of telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours.

Plasma concentration of angiotensin II and plasma renin activity (PRA) increased in a dose-dependent manner after single administration of telmisartan to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg telmisartan to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significant changes in electrolytes (serum potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid).

In 30 hypertensive patients with normal renal function treated for 8 weeks with telmisartan 80 mg or telmisartan 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate, filtration fraction, renovascular resistance, or creatinine clearance.

Telmisartan has indications other than hypertension which can be found in the Micardis® (telmisartan) tablets package insert.

Amlodipine

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects of electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Amlodipine has indications other than hypertension which can be found in the Norvasc® package insert.

Pharmacokinetics

Telmisartan and Amlodipine Tablets  

The pharmacokinetics of amlodipine and telmisartan when combined are similar to the pharmacokinetics of amlodipine and telmisartan when administered separately.

After administering telmisartan and amlodipine tablets 80/10 mg with a high-fat meal, the total area under the plasma concentration-time curve (AUC) and Cmax for telmisartan decreased by about 24% and 60%, respectively. For amlodipine, AUC and Cmax were not altered [see DOSAGE AND ADMINISTRATION ].

Telmisartan

Following oral administration, peak concentrations (Cmax) of telmisartan are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration-time curve (AUC) of about 6% with the 40 mg tablet and about 20% after a 160 mg dose. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 20 to 160 mg, with greater than proportional increases of plasma concentrations (Cmax and AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half life of approximately 24 hours. Trough plasma concentrations of telmisartan with once daily dosing are about 10% to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.

Amlodipine

Peak plasma concentrations of amlodipine are reached 6 to 12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food.

Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Distribution

Telmisartan

Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α1 - acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters indicating additional tissue binding.

Amlodipine

The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.

Metabolism and Elimination

Telmisartan

Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).

Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.

Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.

Amlodipine

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Special Populations

Renal  Insufficiency

Telmisartan: No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration [see WARNINGS AND PRECAUTIONS ].

Amlodipine: The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

Hepatic  Insufficiency

Telmisartan: In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see WARNINGS AND PRECAUTIONS and USE IN SPECIFIC POPULATIONS ].

Amlodipine: Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Therefore, start with a low initial dose of amlodipine.

Gender

Plasma concentrations of telmisartan are generally 2 to 3 times higher in females than in males. In clinical trials, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary.

Geriatric  Patients

Telmisartan: The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years [see DOSAGE AND ADMINISTRATION ].

Amlodipine: Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Therefore, start with a low initial dose of amlodipine [see DOSAGE AND ADMINISTRATION ].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Telmisartan

There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day).

Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.

No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day).

Amlodipine

Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m2 basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m2 basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m2 basis).

Developmental Toxicity

Telmisartan

No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day).

Amlodipine

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the maximum recommended human dose [MRHD] of 10 mg amlodipine on a mg/m2 basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

CLINICAL STUDIES

Telmisartan and Amlodipine Tablets

The efficacy of telmisartan and amlodipine tablets for treatment of hypertension was studied in 1 placebo-controlled and 2 active-controlled trials.

An 8-week multicenter, randomized, double-blind, placebo-controlled, parallel group factorial study in patients with mild to severe hypertension was conducted to determine if treatment with telmisartan and amlodipine tablet was more effective in reducing blood pressure compared to the respective monotherapies. The study randomized 1461 patients with baseline systolic blood pressure between 117 and 179 mmHg (mean 153 mmHg) and a baseline diastolic blood pressure between 90 and 119 (mean 102 mmHg) to one of the 16 treatment arms. Patients assigned to receive amlodipine 10 mg started on amlodipine 5 mg or combinations thereof for the first two weeks. The four key treatment combinations (including combinations of telmisartan 40 or 80 mg and amlodipine 5 or 10 mg) had statistically significant reduction in in-clinic seated trough cuff systolic and diastolic blood pressure compared to the respective individual monotherapies (Table 5).

Table 5: Placebo-Subtracted Mean Change from Baseline in Seated Systolic/Diastolic Blood Pressure (mmHg): Combination Therapy vs Monotherapy Components
Amlodipine, mg
Telmisartan, mg

0
40
80
0

-12.1/-7.2
-11.8/-7.8
5
-12.9/-7.2
-19.3/-10.3
-19.6/-12.0
10
-18.2/-10.9
-22.2/-14.0
-23.9/-13.9

The majority of the antihypertensive effect of the telmisartan/amlodipine combination was attained within 2 weeks after initiation of therapy. In patients receiving a telmisartan/amlodipine combination significantly larger reductions in seated diastolic and systolic blood pressure compared to patients treated with the respective monotherapies were observed at every assessment (Week 2, 4, 6, and 8).

The antihypertensive effect of telmisartan and amlodipine tablets was similar in patients ≥65 years than below 65 years of age, in male and female patients, and in patients with and without diabetes.

The magnitude of blood pressure lowering in black patients approached that observed in non-black patients but the number of black patients was limited (237 of 1461 patients).

Automated ambulatory blood pressure monitoring (ABPM) performed in a subset of 562 patients confirmed the results seen with in-clinic systolic and diastolic blood pressure reductions over the entire 24-hour dosing period.

In a double-blind, active-controlled study, a total of 1097 patients with mild to severe hypertension (mean baseline systolic/diastolic BP 149.5/96.6 mmHg) who were not adequately controlled on amlodipine 5 mg received telmisartan and amlodipine (40/5 mg or 80/5 mg) or amlodipine alone (5 mg or 10 mg). After 8 weeks administration, each of the combination treatments was statistically significantly superior to both amlodipine monotherapy doses in reducing diastolic and systolic blood pressures. Edema related events (peripheral edema, generalized edema, and edema) in patients who received telmisartan and amlodipine (40/5 mg or 80/5 mg) were significantly lower as compared to patients who received amlodipine 10 mg (4.3% vs 27.2%, respectively).

Table 6: Effect on Seated Systolic/Diastolic Blood Pressure: Combination Therapy vs Monotherapy
Treatment Group
Mean Change 1
Difference from amlodipine 5 mg
Difference from amlodipine 10 mg
Telmisartan and amlodipine 40/5 mg; n=270
-13.6 / -9.4
-7.4*  -3.6*
-2.4 2  / -1.4
Telmisartan and amlodipine 80/5 mg; n=271
-15.0 / -10.6

-8.8* / -4.9*

-3.9 / -2.7

Amlodipine 5 mg; n=255
-6.2 / -5.7
----
----
Amlodipine 10 mg; n=261
-11.1 / -8.0
----
----

1 Mean change from baseline at Week 8 in seated systolic/diastolic blood pressure
2 p<0.05

In a second double-blind, active-controlled study, a total of 947 patients with mild to severe hypertension (mean baseline systolic/diastolic BP 147.5/95.6 mmHg) who were not adequately controlled on amlodipine 10 mg received telmisartan and amlodipine (40/10 mg or 80/10 mg) or amlodipine alone (10 mg). After 8 weeks, each of the combination treatments was statistically significantly superior to amlodipine monotherapy in reducing diastolic and systolic blood pressures.

Table 7: Effect on Seated Systolic/Diastolic Blood Pressure: Combination Therapy vs Monotherapy
Treatment Group
Mean Change 1
Difference from amlodipine 10 mg
Telmisartan and amlodipine 
40/10 mg; n=306
-11.1 / -9.2
-3.7 2  / -2.8
Telmisartan and amlodipine 
80/10 mg; n=310
-11.3 / -9.3
-3.9 / -2.8
Amlodipine 10 mg; n=305
-7.4 / -6.5
----

1 Mean change from baseline at Week 8 in seated systolic/diastolic blood pressure
2 p<0.05

There are no trials of telmisartan and amlodipine demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

Telmisartan

The antihypertensive effects of telmisartan have been demonstrated in six principal placebo-controlled clinical trials, studying a range of 20 to 160 mg; one of these examined the antihypertensive effects of telmisartan and hydrochlorothiazide in combination. The studies involved a total of 1773 patients with mild to moderate hypertension (diastolic blood pressure of 95 to 114 mmHg), 1031 of whom were treated with telmisartan. Following once daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure.

Upon initiation of antihypertensive treatment with telmisartan, blood pressure was reduced after the first dose, with a maximal reduction by about 4 weeks. With cessation of treatment with telmisartan tablets, blood pressure gradually returned to baseline values over a period of several days to one week. During long term studies (without placebo control) the effect of telmisartan appeared to be maintained for up to at least one year. The antihypertensive effect of telmisartan is not influenced by patient age, gender, weight, or body mass index. Blood pressure response in black patients (usually a low-renin population) is noticeably less than that in Caucasian patients. This has been true for most, but not all, angiotensin II antagonists and ACE inhibitors.

In a controlled study, the addition of telmisartan to hydrochlorothiazide produced an additional dose-related reduction in blood pressure that was similar in magnitude to the reduction achieved with telmisartan monotherapy. Hydrochlorothiazide also had an added blood pressure effect when added to telmisartan.

The onset of antihypertensive activity occurs within 3 hours after administration of a single oral dose. At doses of 20, 40, and 80 mg, the antihypertensive effect of once daily administration of telmisartan is maintained for the full 24-hour dose interval. With automated ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24-hour trough-to-peak ratio for 40 to 80 mg doses of telmisartan was 70% to 100% for both systolic and diastolic blood pressure. The incidence of symptomatic orthostasis after the first dose in all controlled trials was low (0.04%).

There were no changes in the heart rate of patients treated with telmisartan in controlled trials.

Amlodipine

The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours post-dose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect.

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