Post-Acute Effectiveness of Lithium in Pediatric Bipolar I Disorder

This study examined the long-term effectiveness of lithium for the treatment of pediatric bipolar disorder within the context of combination mood stabilizer therapy for refractory mania and pharmacological treatment of comorbid psychiatric conditions

Expediting Drug Development for Pediatric Inflammatory Bowel Disease A Discussion With Stakeholders

Lack of scientific consensus on efficacy endpoints and outcome assessments presents a hurdle for global drug development in pediatric inflammatory bowel disease (IBD). Multiple stakeholders participated in a meeting November 2015, sponsored by The Pediatric IBD Foundation, which is a 501c3 organization formed by parents of children with IBD whose mission is to improve the lives of children with Crohn disease and ulcerative colitis by supporting innovative research and educational programs (www.pedsibd.org). With representatives of the Food and Drug Administration, European Medicines Agency, pediatric gastroenterologists, and representatives of the pharmaceutical industry, this meeting was organized to harmonize present thinking about various aspects of global drug development in pediatric IBD. The meeting was designed to be interactive, allowing participants from the pharmaceutical industry, regulatory agencies, academia, and clinical practice an opportunity to collaborate in a public forum and to identify potential strategies to expedite drug evaluation in children. Before the meeting, a questionnaire focused on the hurdles hindering approval of medications used to treat children with IBD was sent to all participants and other pediatric gastroenterologists in North America and Europe with expertise in IBD. Responses were reviewed by the steering committee and results presented at the meeting. Following the presentation of the survey, participants were divided into small groups composed of representatives from academia, industry, regulatory agencies, and members of the Pediatric IBD Foundation and assigned the task of working together to find solutions to the hurdles that had been identified. Hurdles hindering approval included pediatric trials start later in the development process; lack of enrollment in pediatric trials; lack of monitoring safety registries that might expedite approval; different priorities among stakeholders. This 1-day meeting discussed how to expedite pediatric drug development in IBD therapy. Hurdles for achieving approvals of pediatric indications for treatments of IBD were identified

Expediting Drug Development for Pediatric Inflammatory Bowel Disease A Discussion With Stakeholders

Lack of scientific consensus on efficacy endpoints and outcome assessments presents a hurdle for global drug development in pediatric inflammatory bowel disease (IBD). Multiple stakeholders participated in a meeting November 2015, sponsored by The Pediatric IBD Foundation, which is a 501c3 organization formed by parents of children with IBD whose mission is to improve the lives of children with Crohn disease and ulcerative colitis by supporting innovative research and educational programs (www.pedsibd.org). With representatives of the Food and Drug Administration, European Medicines Agency, pediatric gastroenterologists, and representatives of the pharmaceutical industry, this meeting was organized to harmonize present thinking about various aspects of global drug development in pediatric IBD. The meeting was designed to be interactive, allowing participants from the pharmaceutical industry, regulatory agencies, academia, and clinical practice an opportunity to collaborate in a public forum and to identify potential strategies to expedite drug evaluation in children. Before the meeting, a questionnaire focused on the hurdles hindering approval of medications used to treat children with IBD was sent to all participants and other pediatric gastroenterologists in North America and Europe with expertise in IBD. Responses were reviewed by the steering committee and results presented at the meeting. Following the presentation of the survey, participants were divided into small groups composed of representatives from academia, industry, regulatory agencies, and members of the Pediatric IBD Foundation and assigned the task of working together to find solutions to the hurdles that had been identified. Hurdles hindering approval included pediatric trials start later in the development process; lack of enrollment in pediatric trials; lack of monitoring safety registries that might expedite approval; different priorities among stakeholders. This 1-day meeting discussed how to expedite pediatric drug development in IBD therapy. Hurdles for achieving approvals of pediatric indications for treatments of IBD were identified

Dosing Strategies for Lithium Monotherapy in Children and Adolescents with Bipolar I Disorder

OBJECTIVE: The primary goal of this exploratory study was to obtain data that could lead to evidence-based dosing strategies for lithium in children and adolescents suffering from bipolar I disorder. METHODS: Outpatients aged 7-17 years meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic criteria for bipolar I disorder (manic or mixed) were eligible for 8 weeks of open label treatment with lithium in one of three dosing arms. In Arm I, participants began treatment at a dose of 300 mg of lithium twice daily. The starting dose of lithium in Arms II and III was 300 mg thrice daily. Patients in Arms I and II could have their dose increased by 300 mg/day, depending on clinical response, at weekly visits. Patients in Arm III also had mid-week telephone interviews after which they could also have their dose of lithium increased by 300 mg per day. Youths weighing I, whereas youths weighing \u3e/=30 kg were randomly assigned to Arm I, II, or III. Randomization was balanced by age (7-11 years, 12-17 years) and sex in approximately equal numbers. A priori response criteria were defined as a Clinical Global Impressions-Improvement scale score of /= 50% improvement in Young Mania Rating Scale score, and more than half of the patients (58%) achieved response. Overall, lithium was well tolerated. All three treatment arms had similar effectiveness, side effect profiles, and tolerability of lithium. CONCLUSIONS: On the basis of these results, a dosing strategy in which pediatric patients begin lithium at a dose of 300 mg thrice daily (with an additional 300 mg increase during the first week), followed by 300 mg weekly increases until a priori stopping criteria are met, will be used in an upcoming randomized, placebo-controlled trial

The Collaborative Lithium Trials (CoLT): specific aims, methods, and implementation

BACKGROUND: Lithium is a benchmark treatment for bipolar illness in adults. However, there has been relatively little methodologically stringent research regarding the use of lithium in youth suffering from bipolarity. METHODS: Under the auspices of the Best Pharmaceuticals for Children Act (BPCA), a Written Request (WR) pertaining to the study of lithium in pediatric mania was issued by the United States Food and Drug Administration (FDA) to the National Institute of Child Health and Human Development (NICHD) in 2004. Accordingly, the NICHD issued a Request for Proposals (RFP) soliciting submissions to pursue this research. Subsequently, the NICHD awarded a contract to a group of investigators in order to conduct these studies. RESULTS: The Collaborative Lithium Trials (CoLT) investigators, the BPCA-Coordinating Center, and the NICHD developed protocols to provide data that will: (1) establish evidence-based dosing strategies for lithium; (2) characterize the pharmacokinetics and biodisposition of lithium; (3) examine the acute efficacy of lithium in pediatric bipolarity; (4) investigate the long-term effectiveness of lithium treatment; and (5) characterize the short- and long-term safety of lithium. By undertaking two multi-phase trials rather than multiple single-phase studies (as was described in the WR), the feasibility of the research to be undertaken was enhanced while ensuring all the data outlined in the WR would be obtained. The first study consists of: (1) an 8-week open-label, randomized, escalating dose Pharmacokinetic Phase; (2) a 16-week Long-Term Effectiveness Phase; (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. The second study consists of: (1) an 8-week, double-blind, parallel-group, placebo-controlled Efficacy Phase; (2) an open-label Long-Term Effectiveness lasting either 16 or 24 weeks (depending upon blinded treatment assignment during the Efficacy Phase); (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. In December of 2006, enrollment into the first of these studies began across seven sites. CONCLUSION: These innovative studies will not only provide data to inform the labeling of lithium in children and adolescents with bipolar disorder, but will also enhance clinical decision-making regarding the use of lithium treatment in pediatric bipolar illness. TRIAL REGISTRATION: NCT00442039

Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study

BACKGROUND: Lithium is a benchmark treatment for bipolar disorder in adults. Definitive studies of lithium in pediatric bipolar I disorder (BP-I) are lacking. METHODS: This multicenter, randomized, double-blind, placebo-controlled study of pediatric participants (ages 7-17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus placebo (n = 28) for up to 8 weeks. The a priori primary efficacy measure was change from baseline to the end of study (week 8/ET) in the Young Mania Rating Scale (YMRS) score, based on last-observation-carried-forward analysis. RESULTS: The change in YMRS score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03). Overall Clinical Global Impression-Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03). A statistically significant increase in thyrotropin concentration was seen with lithium (3.0 +/- 3.1 mIU/L) compared with placebo (-0.1 +/- 0.9 mIU/L; P \u3c .001). There was no statistically significant between-group difference with respect to weight gain. CONCLUSIONS: Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder

Drugs used to treat pediatric emergencies

This clinical report is a revision of “Preparing for Pediatric Emergencies: Drugs to Consider.” It updates the list, indications, and dosages of medications used to treat pediatric emergencies in the prehospital, pediatric clinic, and emergency department settings. Although it is not an all-inclusive list of medications that may be used in all emergencies, this resource will be helpful when treating a vast majority of pediatric medical emergencies. Dosage recommendations are consistent with current emergency references such as the Advanced Pediatric Life Support and Pediatric Advanced Life Support textbooks and American Heart Association resuscitation guidelines

First-dose pharmacokinetics of lithium carbonate in children and adolescents

This study examines the pharmacokinetics of oral doses of lithium carbonate immediate-release capsules after administration of 600 or 900 mg in children and adolescents with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, bipolar I disorder. Lithium plasma concentrations were followed over 48 to 72 hours in 39 subjects (20 male and 19 female subjects; ages, 7-17 years) with mixed or manic episodes enrolled at 7 clinical sites participating in the Collaborative Lithium Trials. Population pharmacokinetic modeling was performed using NONMEM, and influences of patient covariates on pharmacokinetics parameters were examined. The pharmacokinetics of lithium was best described using a 2-compartment model with a lag time and first-order absorption. There was considerable variability in lithium exposures. Lithium clearance related best to fat-free mass. Inclusion of fat-free mass as a covariate reduced the between-subject variability from 52% to 42%. Lithium clearances did not vary systematically with age group, dose, sex, or creatinine clearances. Allometrically scaled clearance and volume of distribution from the population analysis were within the range reported in adults. Single-dose profiles of lithium in young patients with BP-1 show marked variability. Therefore, ongoing serum monitoring is needed during continued therapy. The developed population pharmacokinetic model may be used to predict other dosage regimens, support scaling from adult to pediatric pharmacokinetics, and support the design of future clinical trials