Acute and longer-term safety results from a pooled analysis of duloxetine studies for the treatment of children and adolescents with major depressive disorder.

OBJECTIVE: To assess acute and longer-term safety of duloxetine in the treatment of children and adolescents with major depressive disorder (MDD), a pooled analysis of data from two completed randomized, double-blind, multicenter, phase 3, placebo- and active-controlled trials was undertaken. In these studies, neither duloxetine (investigational drug) nor fluoxetine (active control) demonstrated a statistically significant improvement compared with placebo on the primary efficacy measure. METHODS: Patients ages 7-17 years with MDD as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) received duloxetine (n=341), fluoxetine (n=234), or placebo (n=225) for 10 week acute and 26 week extended (duloxetine or fluoxetine only) treatments. Safety measures included treatment-emergent adverse events (TEAEs), the Columbia-Suicide Severity Rating Scale, vital signs, electrocardiograms, laboratory samples, and growth (height and weight) assessments. RESULTS: Significantly more patients discontinued because of adverse events during duloxetine (8.2%) treatment than during placebo (3.1%) treatment (p≤0.05). TEAEs in >10% of duloxetine-treated patients were headache and nausea. No completed suicides or deaths occurred. During acute treatment, 6.6% of duloxetine-, 8.0% of fluoxetine-, and 8.2% of placebo-treated patients had worsening suicidal ideation from baseline. Among patients initially randomized to duloxetine or fluoxetine who had suicidal ideation at study baseline, 81% of duloxetine- and 77% of fluoxetine-treated patients had improvements in suicidal ideation at end-point in the 36-week studies. Suicidal behavior occurred in two fluoxetine-treated patients and one placebo-treated patient during acute treatment, and in seven duloxetine-treated patients and one fluoxetine-treated patient during extended treatment. Duloxetine-treated patients had a mean pulse increase of ∼3 beats per minute, and mean blood pressure (both systolic and diastolic) increases of <2.0 mm Hg at week 36. Weight decrease (≥3.5%) during acute treatment occurred with statistically (p≤0.05) greater frequency for both the duloxetine (11.4%) and fluoxetine (11.5%) groups versus the placebo (5.5%) group; however, mean weight increase occurred for both duloxetine and fluoxetine groups during extended treatment. CONCLUSION: Results from this pooled analysis of two studies were consistent with the known safety and tolerability profile of duloxetine. Clinical Trial Registry Numbers: NCT00849901 and NCT00849693.

A randomized, open-label, dose-response study of losartan in hypertensive children.

BACKGROUND AND OBJECTIVES: Once-daily losartan reduces BP in a dose-dependent manner and is well tolerated in hypertensive children aged 6-16 years. This study assessed the dose-response relationship, safety, and tolerability of losartan in hypertensive children aged 6 months to 6 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a 12-week, randomized, open-label, dose-ranging study, with a 2-year extension. Patients were randomized to losartan at the following dosages: 0.1 mg/kg per day (low), 0.3 mg/kg per day (medium), or 0.7 mg/kg per day (high). Losartan was titrated to the next dose level (to a 1.4 mg/kg per day maximum dosage, not exceeding 100 mg/d, which was not one of the three original doses offered at randomization) at weeks 3, 6, and 9 for patients who did not attain their goal BP and were not taking the highest dose. Dose response was evaluated by analyzing the slope of change in sitting systolic BP (SBP; primary end point) and diastolic BP (DBP; secondary end point) after 3 weeks compared with baseline. Adverse events (AEs) were recorded throughout. RESULTS: Of the 101 patients randomized, 99 were included in the analysis (low dose, n=32; medium dose, n=34; and high dose, n=33). Mean sitting BP decreased from baseline in the low-, medium-, and high-dose groups by 7.3, 7.6, and 6.7 mmHg, respectively, for SBP and 8.2, 5.1, and 6.7 mmHg, respectively, for DBP after 3 weeks. No dose-response relationship was established by the slope analysis on SBP (P=0.75) or DBP (P=0.64). The BP-lowering effect was observed throughout the 2-year extension. The incidence of AEs was low and comparable between groups. CONCLUSIONS: Hypertensive children aged 6 months to 6 years treated with losartan 0.1-0.7 mg/kg per day had clinically significant decreases from baseline in SBP and DBP, yet no dose-response relationship was evident. Losartan, at a dosage up to 1.4 mg/kg per day, was well tolerated.

Losartan and enalapril are comparable in reducing proteinuria in children with Alport syndrome.

BACKGROUND: A previous subgroup analysis of a 12-week, double-blind study demonstrated that losartan significantly lowered proteinuria versus placebo and amlodipine and was well tolerated in children (1-17 years old) with proteinuria secondary to Alport syndrome. The present subgroup analysis of the open-label, extension phase of this study assessed the long-term efficacy and tolerability of losartan versus enalapril. METHODS: Patients who had completed the double-blind study were re-randomized to losartan or enalapril and followed for proteinuria and renal function for up to 3 years. RESULTS: Twenty-seven patients with Alport syndrome were randomized to losartan (0.44-2.23 mg/kg/day; n = 15) or enalapril (0.07-0.72 mg/kg/day; n = 12). The least-squares (LS) mean percent change from week 12 in urinary protein to creatinine ratio (UPr/Cr was +1.1 % in the losartan group versus a further 13.9 % reduction in the enalapril group (GMR [95 % CI] = 1.2 [0.7, 2.0]); the LS mean change from week 12 in estimated glomerular filtration rate (eGFR) was -6.4 ml/min/1.73 m(2) in the losartan group versus -9.1 ml/min/1.73 m(2) in the enalapril group. The adverse event incidence was low and comparable in both treatment groups. CONCLUSIONS: In children with proteinuria secondary to Alport syndrome, losartan maintained proteinuria reduction, and enalapril produced a further proteinuria reduction over the 3-year study period. Both agents were generally well tolerated.

Pharmacokinetics of olmesartan medoxomil in pediatric patients with hypertension.

BACKGROUND: The prevalence and importance of hypertension in younger patients is becoming increasingly recognized; however, only a limited number of clinical trials have been conducted in the pediatric population. OBJECTIVE: The aim of this study was to characterize the pharmacokinetics and short-term safety of olmesartan medoxomil in children and adolescents with hypertension. METHODS: An open-label, multicenter, single-dose study was conducted in children and adolescents aged 12 months-16 years who were receiving treatment for hypertension or, if not currently treated for hypertension, had either a systolic blood pressure (SBP) or diastolic blood pressure (DBP).≥95th percentile, or SBP or DBP ≥90th percentile if diabetic or with a family history of hypertension. Patients were stratified by age: 12-23 months (Group 1; none enrolled), 2-5 years (Group 2; n = 4), 6-12 years (Group 3; n = 10), and 13-16 years (Group 4; n = 10). All patients received a single oral dose of olmesartan medoxomil based on the individual's age and bodyweight. Patients aged <6 years received an oral suspension of olmesartan medoxomil at a dose of 0.3 mg/kg of bodyweight (not to exceed 20 mg), those aged ≥6 years who weighed ≥35 kg received olmesartan medoxomil 40 mg tablets, and those who weighed <35 kg received olmesartan medoxomil 20 mg tablets. RESULTS: In Groups 2, 3, and 4, the weight-adjusted apparent total body clearance (CL/F) of olmesartan medoxomil was 0.100 ± 0.034, 0.062 ± 0.020, and 0.072 ± 0.022 L/h/kg, respectively, and the weight-adjusted apparent volume of distribution (Vd/F) was 0.32 ± 0.16, 0.33 ± 0.14, and 0.49 ± 0.23 L/kg, respectively. CL/F and Vd/F in Groups 3 and 4 were not significantly different. Statistical comparisons between Groups 3 or 4 and Group 2 were not performed due to the small sample size of Group 2 (n = 4). Plasma elimination half-life and time to maximum plasma concentration were similar across the three groups. In Groups 3 and 4, considerable interindividual variability was seen in maximum plasma concentration (C(max)), area under the curve (AUC) from time zero to the last measurable concentration, and apparent clearance, with AUC and C(max) approximately 30% greater in Group 3. Four of 24 (16.7%) patients experienced treatment-emergent adverse events that were all mild in severity and considered not drug-related. No deaths, serious adverse events, or discontinuations due to adverse events occurred in the study. CONCLUSIONS: Olmesartan medoxomil was well tolerated and demonstrated a pharmacokinetic profile in pediatric patients similar to that of adults when adjusted for body size. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00151814

Losartan and enalapril are comparable in reducing proteinuria in children.

Angiotensin-converting enzyme inhibitors and angiotensin II type I receptor blockers delay progression of chronic kidney disease and have antiproteinuric effects beyond their effects on blood pressure. They are routinely used in adults; however, their efficacy and safety in children, in whom the causes of chronic kidney disease are significantly different relative to adults, is uncertain. Here we assessed an open-label extension of a previous 3-month blinded trial, in which the efficacy and tolerability of losartan was compared to placebo or amlodipine in 306 normotensive and hypertensive children with proteinuria. In this study, 268 children were re-randomized to losartan or enalapril and followed until 100 patients completed 3 years of follow-up for proteinuria and renal function. The least squares percent mean reduction from baseline in the urinary protein/creatinine ratio was 30.01% for losartan and 40.45% for enalapril. The least squares mean change from baseline in eGFR was 3.3 ml/min per 1.73 m2 for losartan and 7.0 ml/min per 1.73 m2 for enalapril. The incidence of specific adverse events such as hyperkalemia and renal dysfunction was low and similar in both groups. Both were generally well tolerated and, overall, fewer drug-related adverse events occurred with losartan than with enalapril. Thus, in children with proteinuria, losartan and enalapril significantly reduced proteinuria without any appreciable changes in eGFR, effects that were maintained throughout the study. Both losartan and enalapril were generally well tolerated.

Efficacy and safety of losartan in children with Alport syndrome--results from a subgroup analysis of a prospective, randomized, placebo- or amlodipine-controlled trial.

BACKGROUND: No prospective, randomized, double-blind trials of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have previously been reported in adults or children with proteinuria secondary to Alport syndrome. METHODS: This 12-week, double-blind multinational study investigated the effects of losartan 0.7-1.4 mg/kg/day compared with placebo (normotensive patients) or amlodipine 0.1-0.2 mg/kg/day up to 5 mg/day (hypertensive patients) on proteinuria [early morning-void urinary protein/creatinine ratio (UPr/Cr), baseline ≥ 34 mg/mmol] in 30 children of up to 17 years of age with Alport syndrome. RESULTS: Twelve weeks of treatment with losartan significantly reduced proteinuria compared with placebo/amlodipine: losartan -14.7 mg/mmol (interquartile range -49.7 to -5.7 mg/mmol) or 31.6% reduction using a mixed model approach versus placebo/amlodipine 2.3 mg/mmol (-26.0 to 18.1 mg/mmol), P = 0.01 or 2.3% increase using a mixed model approach. Adverse event incidence was low and comparable between losartan and placebo/amlodipine groups. CONCLUSIONS: Losartan significantly lowered proteinuria and was well tolerated after 12 weeks of treatment in children aged 1-17 years with proteinuria secondary to Alport syndrome with or without hypertension, a population that has not previously been rigorously studied.

Safety, efficacy, and pharmacokinetics of telmisartan in pediatric patients with hypertension.

OBJECTIVE: To assess the safety, pharmacokinetics (PKs), and blood pressure (BP)-lowering efficacy of telmisartan in pediatric (6 to <18 years) patients with hypertension. STUDY DESIGN: Patients with diagnosed hypertension were randomized to 4 weeks of treatment with placebo, or with 1 of 2 nominal telmisartan dose levels (1 mg/kg/d or 2 mg/kg/d). The primary end point was change in seated systolic BP (SBP) from baseline to study end. RESULTS: A total of 77 patients were randomized and received at least 1 dose of study medication (placebo, n = 16; low-dose telmisartan, n = 30; high-dose telmisartan, n = 31). Adjusted mean changes (standard errors) in SBP from baseline to study end were -6 (2.4), -14 (1.7), and -9.7 (1.7) mm Hg, respectively, in the placebo, high-dose telmisartan, and low-dose telmisartan groups. CONCLUSIONS: Telmisartan may be an appropriate therapy for treatment of pediatric hypertension, although more extensive studies are required in patients younger than age 12.

Randomized, double-blind, controlled study of losartan in children with proteinuria.

BACKGROUND AND OBJECTIVES: No large, randomized, double-blind trials in children with proteinuria treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have previously been reported. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This 12-week, double-blind, multinational study investigated the effects of losartan 0.7 to 1.4 mg/kg per day compared with placebo (normotensive stratum) or amlodipine 0.1 to 0.2 mg/kg per day up to 5 mg/d (hypertensive stratum) on proteinuria (morning-void urinary protein-creatinine ratio, baseline > or =0.3 g/g) in 306 children up to 17 years of age. RESULTS: Twelve weeks of treatment with losartan significantly reduced proteinuria compared with amlodipine/placebo: losartan -35.8% (95% confidence interval: -27.6% to -43.1%) versus amlodipine/placebo 1.4% (95% confidence interval: -10.3% to 14.5%), P < or = 0.001. Significance remained after adjustment for differences across treatment groups in change in BP (losartan produced incremental systolic and diastolic BP reductions versus amlodipine of 5.4 and 4.6 mmHg, respectively; and versus placebo of 3.8 and 4.0 mmHg, respectively). Proteinuria reduction was consistently observed in the normotensive (-34.4% losartan; 2.6% placebo) and hypertensive (-41.5% losartan; 2.4% amlodipine) strata, and in all prespecified subgroups, including age, gender, race, Tanner stage, weight, prior therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, as well as among the most common etiologies of proteinuria. Adverse event incidence was low and comparable in all groups. CONCLUSIONS: Losartan significantly lowered proteinuria and was well tolerated after 12 weeks in children aged 1 to 17 years with proteinuria with or without hypertension, a population that has not previously been rigorously studied.

Candesartan cilexetil effectively reduces blood pressure in hypertensive children.

BACKGROUND: The angiotensin-receptor blocker candesartan cilexetil is a well-tolerated antihypertensive agent with demonstrated benefits in adults with hypertension. However, there are few data supporting its use in children with hypertension. OBJECTIVE: To determine the efficacy and tolerability of candesartan cilexetil in the treatment of pediatric hypertension. METHODS: In an open-label, uncontrolled pilot study, hypertensive pediatric patients were eligible for participation if untreated systolic and/or diastolic blood pressure (BP) exceeded the 95th percentile for sex, age, and height. Patients underwent a 7-day washout period prior to initiation of weight-based dosing of candesartan cilexetil (2-8 mg daily). The dose was doubled after 7 days of therapy if inadequate antihypertensive response was determined by clinic-measured casual BP monitoring (CBPM) and home BP monitoring (HBPM). Three methods of BP measurement were compared before and after 2 weeks of treatment with the final dose of candesartan cilexetil: CBPM, HBPM, and 24-hour continuous ambulatory BP monitoring (ABPM). Self-reported adverse effects and clinical laboratory analyses were used to determine tolerability. RESULTS: Eleven patients (mean age 14.2 y) received a final candesartan cilexetil median daily dose of 8 mg (0.13 mg/kg, range 2-16 mg). Study treatment resulted in significant reductions in systolic and diastolic BP as measured by CBPM (-7.4%, p = 0.03 and -5.9%, p = 0.01, respectively) and by ABPM (-6.0%, p = 0.03 and -10.8%, p = 0.006, respectively), but no significant reductions as measured by HBPM. No clinically significant changes in laboratory measures were observed, and patients reported nonspecific mild adverse effects. CONCLUSIONS: Candesartan cilexetil effectively reduced BP as demonstrated by CBPM and ABPM measurements and was well tolerated in this group of hypertensive children.

A multicenter study of the pharmacokinetics of lisinopril in pediatric patients with hypertension.

The pharmacokinetic (PK) parameters of lisinopril were obtained in 46 children aged 6 months to 15 years. A lisinopril suspension (0.15 mg/kg per day) was administered to patients <6 years of age; the remaining children received lisinopril tablets, the daily dose being adjusted according to body weight, i.e., 2.5 mg if <25 kg, 5 mg if 25-45 kg, and 10 mg if >45 kg. Blood was drawn predose and on eight occasions postdose in children aged 4-15 years, and on five occasions in those aged <4 years. PK data are reported for the 46 children in terms of age groups: Group I (n=9), aged 6-23 months; Group II (n=8), aged 2-5 years; Group III (n=12), aged 6-11 years; Group IV (n=17), aged 12-15 years. The dose of lisinopril ranged from 3.07 mg/m(2) per day in Group I to 4.78 mg/m(2) per day in Group IV. C(max) of lisinopril, which occurred 5-6 h postdose, varied from 22 ng/ml in Groups I and II to 44 ng/ml in Groups III and IV; AUC(0-24 h) ranged from 301-311 ng.h/ml in Groups I and II to 550-570 ng.h/ml in Groups III and IV. No serious adverse events related to lisinopril were reported.

Levofloxacin pharmacokinetics in children.

Levofloxacin is a broad-spectrum fluoroquinolone antibiotic with activity against many pathogens that cause bacterial infections in children, including penicillin-resistant pneumococci. To provide dosing guidance for children, 3 single-dose, multicenter pharmacokinetic studies were conducted in 85 children in 5 age groups: 6 months to <2 years, 2 to <5 years, 5 to <10 years, 10 to <12 years, and 12 to 16 years. Each child received a single 7-mg/kg dose of levofloxacin (not to exceed 500 mg) intravenously or orally. Plasma and urine samples were collected through 24 hours after dose. Pharmacokinetic parameters were estimated and compared among the 5 age groups and to previously collected adult data. Levofloxacin absorption (as indicated by C(max) and t(max)) and distribution in children are not age dependent and are comparable to those in adults. Levofloxacin elimination (reflected by t1/2 and clearance), however, is age dependent. Children younger than 5 years of age clear levofloxacin nearly twice as fast (intravenous dose, 0.32+/-0.08 L/h/kg; oral dose, 0.28+/-0.05 L/h/kg) as adults and, as a result, have the total systemic exposure (area under the plasma drug concentration-time curve) approximately one half that of adults. The levofloxacin area under the plasma drug concentration-time curve (dose normalized) in children receiving a single dose of the oral liquid formulation is comparable to that in children receiving the intravenous formulation. To provide compatible levofloxacin exposures associated with clinical effectiveness and safety in adults, children > or =5 years need a daily dose of 10 mg/kg, whereas children 6 months to <5 years should receive 10 mg/kg every 12 hours.

Famotidine disposition in children and adolescents with chronic renal insufficiency.

The pharmacokinetics of intravenous famotidine (0.5 mg/kg, maximum 20 mg) were evaluated in 18 pediatric patients (ages 1-18 years) with stable, chronic renal insufficiency. Subjects were stratified by calculated creatinine clearance (Clcr) into mild (Clcr > or = 50 to < 90 mL/min/1.73 m2), moderate (Clcr > or = 25 to < 50 mL/min/1.73 m2), and severe (Clcr < or = 10 mL/min/1.73 m2) renal insufficiency groups. Significant differences between the mild, moderate, and severe groups were found for elimination rate (Kel), apparent elimination half-life (t1/2), area under the curve (AUC), and total plasma clearance (Clp) (p < 0.01). Famotidine renal clearance (Clr) was found to be significantly different between the mild and severe groups (p < 0.05). A linear relationship was observed between Clcr and Clp (p < 0.0001; R2 = 0.70). No significant differences in nonrenal clearance (Clnr) were found between groups; however, Clnr as a percentage of Clp was significantly different in the severe group (92.9% +/- 7.3% Clnr) compared to the combined mild and moderate groups (21.9% +/- 45.6% Clnr) (p < 0.05). It was concluded that the pharmacokinetics of famotidine are significantly altered in children with chronic renal insufficiency; accordingly, dosing should be based on glomerular filtration rate (i.e., Clcr).

24-hour ambulatory blood pressure monitoring in male children receiving stimulant therapy.

OBJECTIVE: To determine whether cardiac indices are altered as assessed by 24-hour ambulatory blood pressure monitoring (ABPM) in male children receiving either chronic methylphenidate or dextroamphetamine/levoamphetamine (Adderall) therapy. METHODS: Boys 7-11 years old who were receiving methylphenidate or Adderall for a minimum of 2 months were asked to participate. Subjects wore ambulatory blood pressure monitors for 24-hour periods both off and on stimulant therapy. RESULTS: Subjects (n = 17; 8 methylphenidate, 9 Adderall) were well matched. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate differed between off and on stimulant therapy (p < 0.05). DBP load calculated from ABPM reference data was increased significantly (9.0% +/- 5.6% on and 4.8% +/- 4.5% off therapy; p < 0.05) while subjects were taking Adderall. There was a trend toward a greater elevation in blood pressure load during awake hours and a more pronounced decrease during the asleep hours for periods on compared with off-stimulant therapy. This trend resulted in significant (p < 0.05) nocturnal dipping on-stimulant phases compared with off-stimulant therapy for both SBP and DBP (Adderall) and SBP (methylphenidate). Two subjects (1 Adderall, 1 methylphenidate) met the criteria to be considered hypertensive based both on mean awake and 24-hour blood pressure load assessments during their on-treatment period. One additional subject receiving Adderall therapy met the criteria to be considered hypertensive based on blood pressure load criteria while off therapy only. Positive correlation coefficients (p < 0.05) were found when comparing stimulant dose (mg/kg) with the percent change of mean SBP, DBP, and heart rate between off and on therapy (r = 0.56, 0.61, and 0.58, respectively). CONCLUSIONS: These preliminary data suggest that blood pressure and heart rate appear to be altered in male patients while receiving stimulant therapy for attention-deficit hyperactivity disorder. Blood pressure and heart rate screening and monitoring during stimulant therapy to determine whether alterations become clinically significant is encouraged.

Antihypertensive therapy: basic pharmacokinetic and pharmacodynamic principles as applied to infants and children.

Increased attention has been paid to the study of antihypertensive agents in children following the Food and Drug Administration Modernization Act. Many short-term studies of drug effectiveness and safety are underway or recently completed. Defining the disposition of antihypertensive agents in the pediatric population has become an important part of ongoing efforts to label antihypertensive agents for use in children. In comparison with larger trials done in the adult population, relatively few pediatric subjects will be studied. Hence, it is important to gather as much information as possible for each agent during pediatric trials. Appropriate study design is dependent not only on a working knowledge of the unique features of hypertension in children, but also on a practical assessment of factors that affect drug disposition in children. Basic principles of pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD modeling as applied to pediatric antihypertensive therapy are briefly considered.