Efficacy, safety, and pharmacokinetics of candesartan cilexetil in hypertensive children aged 6 to 17 years.

This 4-week randomized, double blind, placebo-controlled study (N=240), 1-year open label trial (N=233), and single-dose pharmacokinetic study (N=22) evaluated candesartan cilexetil (3 doses) in hypertensive children aged 6 to 17 years. Seventy-one percent were 12 years of age or older, 71% were male, and 47% were black. Systolic (SBP)/diastolic (DBP) blood pressure declined 8.6/4.8-11.2/8.0 mm Hg with candesartan and 3.7/1.8 mm Hg with placebo (P<.01 compared to placebo for SBP and for the mid and high doses for DBP; placebo-corrected 4.9/3.0-7.5/6.2 mm Hg). The slopes for dose were not, however, different from zero (P>.05). The response rate (SBP and DBP <95th percentile) after 1 year was 53%. The pharmacokinetic profiles in 6- to 12- and 12- to 17-year-olds were similar and were comparable to adults. Eight candesartan patients discontinued treatment because of an adverse event. Candesartan is an effective, well-tolerated antihypertensive agent for children aged 6 to 17 years and has a pharmacokinetic profile that is similar to that in adults.

Efficacy and safety of extended release metoprolol succinate in hypertensive children 6 to 16 years of age: a clinical trial experience.

OBJECTIVE: To evaluate the efficacy, tolerability, and blood pressure (BP) lowering effect of extended release metoprolol succinate (ER metoprolol) in children 6 to 16 years of age with established hypertension. STUDY DESIGN: Patients were randomized to one of four treatment arms: placebo or ER metoprolol (0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg). Data were analyzed on 140 intent-to-treat patients. RESULTS: Mean age (+/-SD) was 12.5 +/- 2.8 years and mean baseline BP was 132/78 +/- 9/9 mmHg. Following 4 weeks of treatment, mean changes in sitting BP were: placebo = -1.9/-2.1 mmHg; ER metoprolol 0.2 mg/kg = -5.2/-3.1 mmHg; 1.0 mg/kg = -7.7/-4.9 mmHg; 2.0 mg/kg = -6.3/-7.5 mmHg. Compared with placebo, ER metoprolol significantly reduced systolic blood pressure (SBP) at the 1.0 and 2.0 mg/kg dose (P = .027 and P = .049, respectively), reduced diastolic blood pressure (DBP) at the 2.0 mg/kg dose (P = .017), and showed a statistically significant dose response relationship for the placebo-corrected change in DBP from baseline. There were no serious adverse events or adverse events requiring study drug discontinuation among patients receiving active therapy. CONCLUSION: These data indicate that ER metoprolol is an effective and well-tolerated treatment for hypertension in children.

Metoprolol succinate extended release/hydrochlorothiazide combination tablets.

Lowering elevated blood pressure (BP) with drug therapy reduces the risk for catastrophic fatal and nonfatal cardiovascular events such as stroke and myocardial infarction. Given the heterogeneity of hypertension as a disease, the marked variability in an individual patient's BP response, and low response rates with monotherapy, expert groups such as the Joint National Committee (JNC) emphasize the value of combination antihypertensive regimens, noting that combinations, usually of different classes, have additive antihypertensive effects. Metoprolol succinate extended-release tablet is a beta-1 (cardio-selective) adrenoceptor-blocking agent formulated to provide controlled and predictable release of metoprolol. Hydrochlorothiazide (HCT) is a well-established diuretic and antihypertensive agent, which promotes natruresis by acting on the distal renal tubule. The pharmacokinetics, efficacy, and safety/tolerability of the antihypertensive combination tablet, metoprolol extended release hydrochlorothiazide, essentially reflect the well-described independent characteristics of each of the component agents. Not only is the combination product more effective than monotherapy with the individual components but the combination product allows a low-dose multidrug regimen as an alternative to high-dose monotherapy, thereby, minimizing the likelihood of dose-related side-effects.

Factorial antihypertensive study of an extended-release metoprolol and hydrochlorothiazide combination.

BACKGROUND: To attain goal blood pressure (BP), many hypertensive patients require combination antihypertensive therapy. Thiazide diuretic/beta-blocker regimens lower BP, and clinical studies indicate that they reduce the risk for cardiovascular consequences of hypertension. Fixed-dose combination tablets can simplify multidrug treatment regimens. METHODS: This multicenter, randomized, double-blind, placebo-controlled, unbalanced factorial study (N = 1571) was designed to determine whether hydrochlorothiazide (HCT) and extended release (ER) metoprolol both contribute to an antihypertensive effect. Hypertensive adults with sitting diastolic BP (SiDBP) 95 to 114 mm Hg and systolic BP (SiSBP) <180 mm Hg received one of three hydrochlorothiazide doses (6.25 mg, 12.5 mg, or 25 mg), one of four ER-metoprolol doses (25 mg, 50 mg, 100 mg, 200 mg), or one of nine of the combinations or placebo for 8 weeks. RESULTS: Blood pressure decreased with all combinations (P < .001 v placebo); reductions were dose related, ranging from 8.7 to 15.7 mm Hg (SiDBP) and 9.7 to 18.9 mm Hg (SiSBP) (model-derived values). Reductions with placebo were 5.3 (SiDBP) and 4.2 mm Hg (SiSBP). Both active agents contributed to the combination effect (P = .0015 for SiDBP; P = .0006 for SiSBP). Several low-dose combinations were approximately as effective as high doses of the individual agents (differences within 1 to 2.5 mm Hg). The adverse event discontinuation rate was 2.9%. Serum potassium decreased and uric acid increased with increasing doses of HCT. CONCLUSIONS: Extended-release metoprolol/hydrochlorothiazide is an effective antihypertensive combination that offers additive antihypertensive contributions from both components.

A factorial study of combination hypertension treatment with metoprolol succinate extended release and felodipine extended release results of the Metoprolol Succinate-Felodipine Antihypertension Combination Trial (M-FACT).

BACKGROUND: Many hypertensive patients require combination therapy to achieve target blood pressure (BP). beta-Blockers and dihydropyridine calcium channel blockers are effective as monotherapy in hypertensive patients and have complementary mechanisms for lowering BP. METHODS: This multicenter, randomized, placebo-controlled, unbalanced factorial study included a 4- to 5-week single-blind placebo, 9-week, double-blind treatment as well as a 2-week double-blind, down-titration period. Patients (N = 1092) were randomized to one of 16 treatment groups: extended-release (ER) metoprolol succinate (25, 100, or 400 mg), ER felodipine (2.5, 10, or 20 mg), ER felodipine/ER metoprolol succinate (2.5/25, 2.5/100, 2.5/400, 10/25, 10/100, 10/400, 20/25, 20/100, or 20/400 mg), or placebo. RESULTS: At baseline, treatment groups were well balanced; mean sitting BP was 152.6/99.9 mm Hg. Monotherapy with ER metoprolol succinate induced dose-related reductions in sitting systolic/diastolic BP (DBP) (mean 8.1/7.7 to 9.7/11.1 mm Hg) as did ER felodipine (mean 7.7/7.7 to 14.0/11.8) and the combinations reflected additive effects (mean 13.8/11.0 to 19.8/15.2). The decline in the placebo group was 2.1/4.0 mm Hg. All combinations were more effective than their components (P < .05 for all but ER metoprolol succinate 25/ER felodipine 20). When compared with the highest doses of the individual agents (ER metoprolol succinate 400 mg; ER felodipine 20 mg), the low-dose combination ER metoprolol succinate 25/ER felodipine 2.5 was approximately as effective (differences in DBP <1 mm Hg). The most common adverse events leading to discontinuation were peripheral edema (4%), headache (2%), and fatigue (1%). Higher rates of peripheral edema and flushing were associated with high-dose ER felodipine, either alone or in combination. CONCLUSIONS: The antihypertensive effects of ER metoprolol succinate and ER felodipine are dose-related, and when given in combination, their BP-lowering effects are additive over a wide dose range. Low-dose combination therapy is comparable in effectiveness to high-dose monotherapy but is better tolerated.

Characterization of renal biomarkers for use in clinical trials: effect of preanalytical processing and qualification using samples from subjects with diabetes.

BACKGROUND: Identifying the potential for drug-induced kidney injury is essential for the successful research and development of new drugs. Newer and more sensitive preclinical drug-induced kidney injury biomarkers are now qualified for use in rat toxicology studies, but biomarkers for clinical studies are still undergoing qualification. The current studies investigated biomarkers in healthy volunteer (HV) urine samples with and without the addition of stabilizer as well as in urine from patients with normoalbuminuric diabetes mellitus (P-DM). METHODS: Urine samples from 20 male HV with stabilizer, 69 male HV without stabilizer, and 95 male DM without stabilizer (39 type 1 and 56 type 2) were analyzed for the following bio-markers using multiplex assays: α-1-microglobulin (A1M), ß-2-microglobulin, calbindin, clusterin, connective tissue growth factor (CTGF), creatinine, cystatin-C, glutathione S-transferase α (GSTα), kidney injury marker-1 (KIM-1), microalbumin, neutrophil gelatinase-associated lipocalin, osteopontin, Tamm-Horsfall urinary glycoprotein (THP), tissue inhibitor of metalloproteinase 1, trefoil factor 3 (TFF3), and vascular endothelial growth factor. RESULTS: CTGF and GSTα assays on nonstabilized urine were deemed nonoptimal (>50% of values below assay lower limits of quantification). "Expected values" were determined for HV with stabilizer, HV without stabilizer, and P-DM without stabilizer. There was a statistically significant difference between HV with stabilizer compared to HV without stabilizer for A1M, CTGF, GSTα, and THP. DM urine samples differed from HV (without stabilizer) for A1M CTGF, GSTα, KIM-1, microalbumin, osteopontin, and TFF3. A1M also correctly identified HV and DM with an accuracy of 89.0%. SUMMARY: These studies: 1) determined that nonstabilized urine can be used for assays under qualification; and 2) documented that A1M, CTGF, GSTα, KIM-1, microalbumin, osteopontin, and TFF3 were significantly increased in urine from P-DM. In addition, the 89.0% accuracy of A1M in distinguishing P-DM from HV may allow this biomarker to be used to monitor efficacy of potential renal protective agents.

Dosing in heavy-weight/obese patients with the LMWH, tinzaparin: a pharmacodynamic study.

This pharmacodynamic study examined weight-based dosing of the low molecular weight heparin (LMWH), tinzaparin, in heavyweight/obese subjects. Single doses (175 and 75 IU/kg) were administered subcutaneously (SC) to 37 healthy heavy-weight subjects (101-165 kg; 26-61 kg/m2). AUA and Amax values of anti-Xa and anti-IIa activities were consistent over these body weight and body mass index (BMI) ranges, indicating that tinzaparin pharmacodynamics are not influenced by body weight or BMI. The range of AUA and Amax values in the study population overlapped that of historical control normal-weight subjects (<100 kg), indicating that weight-adjusted tinzaparin dosing yields a predictable response regardless of body weight or BMI. Tinzaparin was well tolerated, although injection site bruising was commonly reported. SC tinzaparin dosing in heavy or obese patients is appropriate based on body weight alone; the dose need not be capped at a maximal absolute dose.

Intravenous and subcutaneous weight-based dosing of the low molecular weight heparin tinzaparin (Innohep) in end-stage renal disease patients undergoing chronic hemodialysis.

BACKGROUND: Patients with end-stage renal disease are subject to a broad range of thrombotic complications. Low molecular weight heparins (LMWHs) are effective antithrombotic agents; however, they are cleared largely by renal mechanisms, raising uncertainty about their use in renally impaired patients. METHODS: Twelve chronic hemodialysis subjects were administered two single doses of the LMWH tinzaparin, 75 IU/kg, 2 weeks apart: subcutaneously (SC) on an off-dialysis day and intravenously (IV) just before dialysis. RESULTS: Mean maximal anti-factor Xa (anti-Xa) activity was 0.33 IU/mL 4.0 hours after SC administration and 1.33 IU/mL 0.25 hours after IV administration. Anti-Xa half-lives were 3.89 and 2.31 hours, respectively. Anti-Xa activity returned to baseline within 24 hours of administration by either route. Consistent with population pharmacokinetic analyses of clinical study subjects with severe renal impairment, anti-Xa clearance after tinzaparin administration was reduced 28% relative to subjects with normal renal function. All 12 study subjects completed hemodialysis without requiring additional anticoagulation. One subject had minimal clotting in the dialyzer drip chamber, and one subject had mild prolonged bleeding at the vascular access site after dialysis needle removal. No major bleeding events occurred. CONCLUSION: Tinzaparin, 75 IU/kg, SC on an off-dialysis day and IV just before dialysis is well tolerated in chronic hemodialysis patients. The weight-based regimen of 75 IU/kg IV just before dialysis provides adequate anticoagulation. SC weight-based dosing on off-dialysis days is a feasible regimen for further clinical thromboprophylaxis efficacy studies in hemodialysis patients. The risk for clinical overdose in severely renally impaired patients using this weight-based regimen of tinzaparin is unlikely.

Antihypertensive efficacy of candesartan-lisinopril in combination vs. up-titration of lisinopril: the AMAZE trials.

The AMAZE (A Multicenter Trial Using Atacand and Zestril vs. Zestril to Evaluate the Effects on Lowering Blood Pressure) program included two identical studies sponsored by AstraZeneca LP. The oral form of candesartan is candesartan cilexetil; for simplicity, the term "candesartan" is used throughout this manuscript. Two identical multicenter, randomized, double-blind studies were performed to determine if addition of the angiotensin receptor blocker candesartan was more effective in lowering blood pressure than up-titration of lisinopril. Hypertensive patients (N=1,096) who were uncontrolled on lisinopril 20 mg daily were randomized (1:1) to receive either 8 weeks of high-dose lisinopril (40 mg) or the addition of candesartan (16 mg) for 2 weeks followed by 32 mg for 6 weeks. Study 1 (n=538) demonstrated decreases in trough sitting systolic/diastolic blood pressures at Week 8 by 6.2/5.9 mm Hg, respectively, for the lisinopril up-titration treatment group and by 11.6/8.3 mm Hg, respectively, for the lisinopril plus candesartan treatment group (p<0.01 in comparing both blood pressures reductions between the two treatment groups). Corresponding results for Study 2 (n=558) are reductions of 8.7/6.2 mm Hg and 9.5/7.4 mm Hg, respectively, for each of the two treatment groups. For Study 2, comparisons of systolic/diastolic blood pressures between the two treatment groups were not statistically significantly different (p=0.51/p=0.08, respectively). Post hoc pooled analysis (N=1,096) demonstrated a slightly greater blood pressure reduction with lisinopril plus candesartan compared with lisinopril (3.1/1.7 mm Hg). A 95% confidence interval limit for the difference in least squares mean change from baseline in systolic blood pressure between the two treatment groups is -4.8 to -1.5 and is -2.8 to -0.7 in mm Hg for diastolic blood pressure. The blood pressure control rates (<140/<90 mm Hg) were 42.7% and 36.9%, respectively. Both treatment regimens were well tolerated in all groups. In conclusion, for hypertensive patients not controlled by lisinopril 20 mg once daily, addition of candesartan (32 mg once daily) or doubling the dose of lisinopril provides safe, additional reduction of blood pressure.

Efficacy, safety and pharmacokinetics of candesartan cilexetil in hypertensive children from 1 to less than 6 years of age.

BACKGROUND: Few antihypertensive drugs are available in appropriate formulations for infants. METHOD: We investigated candesartan cilexetil liquid suspension in a 4-week, randomized double-blind dose-ranging study followed by a 1-year open-label treatment phase (NCT00244621). The drug was administered at 0.05, 0.2 or 0.4 mg/kg per day in 93 hypertensive children aged 1-5 years, of whom 74 had underlying renal disorders. RESULTS: A single-dose pharmacokinetic profile was obtained in 10 patients. At 4 weeks, SBP declined dose dependently by 6, 9 and 12 mmHg in the three dose groups (P = 0.01), and DBP by 5, 8 and 11 mmHg (P = 0.03). During the 1-year follow-up, responder rates (both SBP and DBP < 95th percentile) ranged from 48.2 to 54.1%. Candesartan lowered the blood pressure regardless of age, sex, BMI or cause of hypertension. The pharmacokinetic profile was independent of age, sex and weight, and was similar to that in older children and adults. In participants with proteinuric renal disease (urinary albumin/creatinine ratio >30 mg/g), a 57% median decline in albumin/creatinine ratio was observed at 4 weeks, which was dose related (P = 0.007) and persisted with long-term administration. There were no notable electrocardiographic or laboratory abnormalities. A mild decline in estimated glomerular filtration rate observed at 4 weeks was not progressive with long-term dosing. Candesartan was generally well tolerated; two patients withdrew for adverse events (fatigue and worsening glomerulopathy). One patient died, probably from acute-on-chronic renal failure. CONCLUSION: Candesartan cilexetil dose-dependently decreases blood pressure and albuminuria in hypertensive infants and is generally well tolerated.

Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program.

OBJECTIVES: We explored the incidence and predictors of hyperkalemia in a broad population of heart failure patients. BACKGROUND: When used in optimal doses to treat patients with heart failure, renin-angiotensin-aldosterone system (RAAS) inhibitors improve clinical outcomes but can cause hyperkalemia. METHODS: Participants in the CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) (n = 7,599) Program were randomized to standard heart failure therapy plus candesartan or placebo, titrated as tolerated to a target of 32 mg once daily with recommended monitoring of serum potassium and creatinine. We assessed the incidence and predictors of hyperkalemia associated with dose reduction, study drug discontinuation, hospitalization, or death over the median 3.2 years of follow-up. RESULTS: Independent of treatment assignment, the risk of hyperkalemia increased with age > or =75 years, male gender, diabetes, creatinine > or =2.0 mg/dl, K+ > or =5.0 mmol/l, and background use of angiotensin-converting enzyme inhibitors or spironolactone. Candesartan increased the rate of aggregate hyperkalemia from 1.8% to 5.2% (difference 3.4%, p < 0.0001) and serious hyperkalemia (associated with death or hospitalization) from 1.1% to 1.8% (difference 0.7%, p < 0.001), with hyperkalemia associated with death reported in 2 (0.05%) candesartan patients and 1 (0.03%) placebo patient. The benefit of candesartan in reducing cardiovascular death or heart failure hospitalization (relative risk reduction 16%, p < 0.0001) was uniform in these subgroups, as was the incremental risk of hyperkalemia. CONCLUSIONS: The risk of hyperkalemia is increased in symptomatic heart failure patients with advanced age, male gender, baseline hyperkalemia, renal failure, diabetes, or combined RAAS blockade. Although these groups derive incremental clinical benefit from candesartan, careful surveillance of serum potassium and creatinine is particularly important.

Extending the role of antithrombotic agents: an example based on the low-molecular-weight heparin, tinzaparin.

We illustrate a strategy for developing an antithrombotic agent based on the low-molecular-weight heparin (LMWH) tinzaparin experience. After anti-factor Xa and IIa activity pharmacokinetic characterization in healthy volunteers, clinical studies first explored the doses and then confirmed thrombosis prevention effects in postoperative (general and hip or knee replacement surgery) settings as compared with placebo and active treatments. This experience and additional dose-finding assessments led to large clinical studies verifying the effectiveness of tinzaparin in the treatment of deep vein thrombosis and acute pulmonary embolism. Subgroup analyses from these studies and preclinical experiments suggested a role for tinzaparin in patients with malignancy who are at high risk for thromboembolic complications. Challenging patient populations and other thrombotic disorders spawned interest in tinzaparin studies in the obese, the hemodialysis, the stroke, peripheral angioplasty, and the pregnant patient as well as in children with thromboembolic disorders. New therapeutic challenges were addressed with a bridging study for patients requiring interruption of oral anticoagulant therapy, a study of patients undergoing cardioversion for atrial fibrillation, and outpatient venous thromboembolism treatment studies. Efficient antithrombotic development programs not only build on traditional indications but elaborate on new therapeutic hypotheses generated from clinical studies, new therapeutic areas, and on-going basic science research programs.