Is the Extrapolated Adult Dose of Fosinopril Safe and Effective in Treating Hypertensive Children?

Li, Jennifer S.; Berezny, Katherine; Kilaru, Rakhi; Hazan, Lydie; Portman, Ronald J.; Hogg, Ronald J.; Jenkins, Randall; Kanani, Prapti; Cottrill, Carol M.; Mattoo, Tej K.; Zharkova, Ludmila; Козлова, Л. К.; Weisman, Irit; Deitchman, David; Califf, Robert M.

doi:10.1161/01.hyp.0000138069.68413.f0

Cited by 66 publications

(42 citation statements)

References 11 publications

(7 reference statements)

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“…These AEs are typical illnesses experienced by children in this age group, and many of them have been observed in other clinical trials of antihypertensive medications conducted in older children. 14,[17][18][19] Of note, no subjects were discontinued from the study because of AEs during the double-blind phase, and only 3 subjects were discontinued because of AEs during the open-label extension. This phenomenon has been observed in other studies incorporating a prolonged open-label treatment phase 19 and likely reflects the susceptibility of young children to common pediatric illnesses.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of the Angiotensin Receptor Blocker Valsartan in Children With Hypertension Aged 1 to 5 Years

et al. 2008

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Abstract-The efficacy and safety of valsartan were studied in 90 children (mean age: 3.2 years; 60% male; 30% black) with systolic blood pressure (SBP) Ն95th percentile. Nineteen percent received valsartan in addition to previous antihypertensive therapy. Subjects were randomly assigned to low-, medium-, or high-dose valsartan for 2 weeks (phase 1) and then reassigned randomly to placebo or to remain on the same valsartan dose for 2 additional weeks (phase 2). After this, subjects were enrolled into a 52-week, open-label phase during which valsartan was dosed to achieve SBP Ͻ95th percentile. Statistically significant reductions in SBP and diastolic blood pressure of Ϸ8.5 mm Hg and 5.7 mm Hg, respectively, were observed at the end of phase 1 in all of the valsartan dose groups. SBP and diastolic blood pressure were also significantly lower during phase 2 in valsartan recipients compared with placebo recipients. SBP Ͻ95th percentile was achieved in 77.3% of subjects during the open-label phase. Adverse events were minor and occurred at similar frequencies in each of the 3 dose groups in phase 1 and at equal frequencies in the valsartan and placebo arms in phase 2. Serious adverse events and drug-related adverse events occurred infrequently during both the double-blind (2.2% and 5.6%, respectively) and open-label (14.8% and 6.8%, respectively) portions of the study.Valsartan treatment had no demonstrable negative effects on growth and development. In this study, the first trial of an antihypertensive agent conducted in children To date, however, all of these studies have been conducted in children Ͼ6 years old, leaving a significant information deficit regarding the treatment of hypertension in younger children, most of whom have underlying kidney disease or other secondary causes of hypertension. [3][4][5] Valsartan is an angiotensin II receptor blocker approved in adults for the treatment of hypertension, heart failure, and left ventricular failure or left ventricular dysfunction postmyocardial infarction. 6 Its effects primarily result from selective blockade of the angiotensin type I receptor in vascular smooth muscle and adrenal gland. 6,7 Valsartan effectively reduces systolic blood pressure (BP; SBP) and diastolic BP (DBP) in adults, both as monotherapy and in combination with other antihypertensive agents, displaying similar antihypertensive efficacy to other antihypertensive drug classes. [7][8][9][10] Given its effects on angiotensin blockade, valsartan may also reduce proteinuria and have other beneficial effects in patients with underlying kidney disease. 10 For these reasons, valsartan is an attractive drug for use in young children with hypertension.This study was conducted to explore the efficacy of valsartan in reducing BP in children aged 1 to 5 years with hypertension. We also examined the safety and tolerability of both short-and long-term administration of valsartan in this population. MethodsThis was a double-blind, randomized, multicenter study sponsored by Novartis Pharmaceuticals and perfor...

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of the Angiotensin Receptor Blocker Valsartan in Children With Hypertension Aged 1 to 5 Years

et al. 2008

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“…[19][20][21][22][23][24][25][26][27][28] Furthermore, the BPCA now requires the FDA to publish the results of its internal analyses of the trial results submitted by sponsors on the Internet. 29 Never before has such a wealth of information been available about the efficacy and safety of anti-hypertensive medications in children.…”

Section: Impact Of Legislationmentioning

confidence: 99%

“…25 The authors speculated that this may have been because all the doses used were too high (the lowest dose studied was 0.1 mg/kg/day), but another factor may have been that the study's primary end point was systolic BP, which was much more variable than diastolic BP, which was the end point chosen in the enalapril and lisinopril studies. However, fosinopril did produce greater systolic BP reduction than placebo, and the study included a 52-week open label extension that provided more information about safety and tolerability than in either the enalapril or lisinopril trials.…”

Section: Angiotensin-converting Enzyme Inhibitorsmentioning

confidence: 99%

Pharmacologic treatment of hypertension in children and adolescents

Flynn

Daniels

2006

The Journal of Pediatrics

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“…Amlodipine and fosinopril, neither of which showed a dose response, both reduced blood pressure compared with placebo. 7,8 The third agent that failed, however (irbesartan), did not show a clinically meaningful reduction in blood pressure in the placebo-withdrawal stage. 19 One potential flaw in the conduct of these studies is the overall approach of study sponsors to compliance with FDA Modernization Act requirements: these studies are often designed and executed at the end of the product's period of marketing protection.…”

Section: Methodsmentioning

confidence: 99%

“…Several products that did not work (or for which a statistically significant dose response was not observed) were oral antihypertensive agents known to be effective in adults. [3][4][5][6][7][8][9][10] These trial failures have significant public health implications, because systemic hypertension occurs in Ϸ2% of the pediatric population and is rising concomitantly with obesity in children and adolescents. 11 The FDA allows for several types of trial designs in the written request for an antihypertensive agent.…”

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confidence: 99%

Pediatric Antihypertensive Trial Failures

et al. 2008

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Abstract-Historically, drugs prescribed for children have not been studied in pediatric populations. Since 1997, however, a 6-month extension of marketing rights is granted if manufacturers conduct Food and Drug Administration-defined pediatric trials. In nearly half of the drugs studied, there were unexpected results in dosing, safety, or efficacy compared with adult studies, including failure of half of the antihypertensive dose-response trials, which are pivotal for deriving dosing recommendations. We sought to define design elements that might have contributed to these trial failures by combining patient-level data from 6 dose-ranging antihypertensive efficacy trials completed for pediatric exclusivity and submitted to the Food and Drug Administration from 1998 to 2005. We evaluated dosing, primary end point, and other components to assess underlying reasons for failure to show efficacy in children. Of 6 trials examined, 3 showed a dose response; 3 did not. Eligibility criteria were similar across studies, as were subject demographics. Successful studies showed large differences in doses, with little or no overlap between low, medium, and high doses; failed trials used narrow dose ranges with considerable overlap. Successful trials also provided pediatric formulations and used reduction in diastolic, not systolic, blood pressure as the primary end point. Careful attention to pediatric pharmacology and selection of primary end points can improve trial performance. We found poor dose selection, lack of acknowledgement of differences between adult and pediatric populations, and lack of pediatric formulations to be associated with failures. More importantly, our ability to combine data across trials allowed us to evaluate and potentially improve trial design.

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Is the Extrapolated Adult Dose of Fosinopril Safe and Effective in Treating Hypertensive Children?

Cited by 66 publications

References 11 publications

Efficacy and Safety of the Angiotensin Receptor Blocker Valsartan in Children With Hypertension Aged 1 to 5 Years

Efficacy and Safety of the Angiotensin Receptor Blocker Valsartan in Children With Hypertension Aged 1 to 5 Years

Pharmacologic treatment of hypertension in children and adolescents

Pediatric Antihypertensive Trial Failures

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