Acute Responses to Diuretic Therapy in Extremely Low Gestational Age Newborns: Results from the Prematurity and Respiratory Outcomes Program Cohort Study.

OBJECTIVE: To determine if daily respiratory status improved more in extremely low gestational age (GA) premature infants after diuretic exposure compared with those not exposed in modern neonatal intensive care units. STUDY DESIGN: The Prematurity and Respiratory Outcomes Program (PROP) was a multicenter observational cohort study of 835 extremely premature infants, GAs of 230/7-286/7 weeks, enrolled in the first week of life from 13 US tertiary neonatal intensive care units. We analyzed the PROP study daily medication and respiratory support records of infants ≤34 weeks postmenstrual age. We determined whether there was a temporal association between the administration of diuretics and an acute change in respiratory status in premature infants in the neonatal intensive care unit, using an ordered categorical ranking of respiratory status. RESULTS: Infants in the diuretic exposed group of PROP were of lower mean GA and lower mean birth weight (P < .0001). Compared with infants unexposed to diuretics, the probability (adjusted for infant characteristics including GA, birth weight, sex, and respiratory status before receiving diuretics) that the exposed infants were on a higher level of respiratory support was significantly greater (OR, >1) for each day after the initial day of diuretic exposure. CONCLUSIONS: Our analysis did not support the ability of diuretics to substantially improve the extremely premature infant's respiratory status. Further study of both safety and efficacy of diuretics in this setting are warranted. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01435187.

Inclusion of pregnant and breastfeeding women in research - efforts and initiatives.

Pregnant and breastfeeding women have been rendered therapeutic orphans as they have been historically excluded from clinical trials. Labelling for most approved drugs does not provide information about safety and efficacy during pregnancy. This lack of data is mainly due to ethico-legal challenges that have remained entrenched in the post-diethylstilbestrol and thalidomide era, and that have led to pregnancy being viewed in the clinical trial setting primarily through a pharmacovigilance lens. Policy considerations that encourage and/or require the inclusion of pregnant or lactating women in clinical trials may address the current lack of available information. However, there are additional pragmatic strategies, such the employment of pharmacometric tools and the introduction of innovative clinical trial designs, which could improve knowledge about the safety and efficacy of medication use during pregnancy and lactation. This paper provides a broad overview of the pharmacoepidemiology of drugs used during pregnancy and lactation, and offers recommendations for regulators and researchers in academia and industry to increase the available pharmacokinetic and -dynamic understanding of medication use in pregnancy.

Pediatric Multiple Organ Dysfunction Syndrome: Promising Therapies.

OBJECTIVE: To describe the state of the science, identify knowledge gaps, and offer potential future research questions regarding promising therapies for children with multiple organ dysfunction syndrome presented during the Eunice Kennedy Shriver National Institute of Child Health and Human Development Workshop on Pediatric Multiple Organ Dysfunction Syndrome (March 26-27, 2015). DATA SOURCES: Literature review, research data, and expert opinion. STUDY SELECTION: Not applicable. DATA EXTRACTION: Moderated by an expert from the field, issues relevant to the association of multiple organ dysfunction syndrome with a variety of conditions were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities. DATA SYNTHESIS: Summary of presentations and discussion supported and supplemented by relevant literature. CONCLUSIONS: Among critically ill children, multiple organ dysfunction syndrome is relatively common and associated with significant morbidity and mortality. For outcomes to improve, effective therapies aimed at preventing and treating this condition must be discovered and rigorously evaluated. In this article, a number of potential opportunities to enhance current care are highlighted including the need for a better understanding of the pharmacokinetics and pharmacodynamics of medications, the effect of early and optimized nutrition, and the impact of effective glucose control in the setting of multiple organ dysfunction syndrome. Additionally, a handful of the promising therapies either currently being implemented or developed are described. These include extracorporeal therapies, anticytokine therapies, antitoxin treatments, antioxidant approaches, and multiple forms of exogenous steroids. For the field to advance, promising therapies and other therapies must be assessed in rigorous manner and implemented accordingly.

Population pharmacokinetics of oseltamivir in non-pregnant and pregnant women.

AIMS: Physiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to evaluate systematically the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy. METHODS: A multicentre steady-state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration-time profiles were analyzed using both non-compartmental and population pharmacokinetic modelling (pop PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS. RESULTS: The systemic exposure of oseltamivir carboxylate (OC, active metabolite of OS) was reduced approximately 30 (19-36)% (P < 0.001) in pregnant women. Pregnancy significantly (P < 0.001) influenced the clearance (CL/F) and volume of distribution (V/F) of OC. Both non-compartmental and population pharmacokinetic approaches documented approximately 45 (23-62)% increase in clearance (CL/F) of OC during pregnancy. CONCLUSION: Based on the decrease in exposure of the active metabolite, the currently recommended doses of OS may need to be increased modestly in pregnant women in order to achieve comparable exposure with that of non-pregnant women.

Pharmacology and placental transport of 17-hydroxyprogesterone caproate in singleton gestation.

OBJECTIVE: The purpose of this study was to estimate pharmacokinetic parameters and to evaluate placental transport of 17-hydroxyprogesterone caproate (17-OHPC) in singleton gestation. STUDY DESIGN: Sixty-one women who received weekly injections of 17-OHPC underwent 2 pharmacokinetic studies at 20 + 0 to 24 + 6 weeks' gestation (study 1) and 31 + 0 to 34 + 6 weeks' gestation (study 2); daily blood samples were obtained between injections. In 18 women, blood samples were obtained over a 28-day period beyond the last injection (extended study). Maternal and/or cord blood were obtained at delivery. RESULTS: The half-life (median ± SD) of 17-OHPC was 16.2 ± 6 days. Concentrations of 17-OHPC were higher during study 2 than during study 1. Body mass index affected maternal 17-OHPC concentrations. Cord:maternal 17-OHPC concentration ratios averaged 0.2; 17-OHPC was detectible in cord plasma 44 days after the last maternal injection. CONCLUSION: The apparent half-life of 17-OHPC is long, and pharmacokinetic parameters vary widely between subjects and are affected by maternal body mass index. The drug crosses the placental barrier.

A Tribute to the Pioneers of Fetal Pharmacology.

Clinical pharmacology is a branch of the field of pharmacology that evolved following the recognition that the nature, duration, and intensity of drug action depend on both the intrinsic properties of the drug and an interaction with the host to whom the drug is given. Advances in drug development have placed highly specific and extremely potent therapeutic agents in the marketplace. While these advances have progressed rapidly in adult medicine, pediatric clinical pharmacology has not kept pace and until very recently has lagged behind the research and attention paid to the proper use of therapeutic and diagnostic drugs in adults. Recognition that advances in the science of developmental pharmacology and pediatric clinical pharmacology were essential in the development of new drugs to treat children came in the 1950s and 1960s mostly through the work of 2 pioneering scientists in fetal and perinatal clinical pharmacology, Drs Sumner Yaffe and Bernard Mirkin. Here we pay a tribute to these most influential pioneers in the United States who were instrumental in paving the path for advancing the field of fetal and perinatal pharmacology concepts and their incorporation into pediatric drug development programs.

We don't know what we don't study: the case for research on medication effects in pregnancy.

This Commentary addresses issues related to exposures to teratogens and makes the case for increased research into the safety of medication usage during pregnancy for mothers and fetuses. Not only are medications commonly used during pregnancy, but evidence points to an increasing prevalence and number of drug exposures experienced by the embryo or fetus, particularly during the critical first trimester of pregnancy. Although the first trimester represents a particularly vulnerable period of organogenesis, exposures during other gestational time periods may also be associated with deleterious outcomes. In addition to the changing (and in many cases unknown) risks to a developing fetus, other challenges to studying medication exposures and their effects during pregnancy include the dramatic changes in physiology that occur in pregnant women and the ethical dilemmas posed by including this vulnerable population in randomized controlled trials of safety and efficacy. However, without adequate knowledge of the pharmacokinetics, pharmacodynamics, efficacy, and safety of medication use in pregnancy, women may be under-dosed to minimize exposure or not treated at all, resulting in inadequate treatment and potential harm to the mother and her baby. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is undertaking studies on medications and teratogenic exposures during pregnancy, including alcohol, maternal diabetes, oral hypoglycemic agents, and antiviral medications, through several of its research networks. Although this is a start, there is a critical need for further research on medications used during pregnancy, especially their effects on both the mother and her developing child.

Pharmacokinetics of oseltamivir among pregnant and nonpregnant women.

We sought to delineate the pharmacokinetics (PK) of oseltamivir and its active metabolite oseltamivir carboxylate during pregnancy. Physiologic changes of pregnancy, including increased renal filtration and secretion, may increase the clearance of oseltamivir carboxylate. Sixteen pregnant women taking oseltamivir for prophylaxis or treatment of suspected/proven influenza infection were enrolled. Twenty-three nonpregnant reproductive-age females served as the control group. The primary PK endpoint was area under the plasma concentration time curve for oseltamivir carboxylate. Pregnancy did not alter the PK parameters of the parent compound, oseltamivir. However, for oseltamivir carboxylate the area under the plasma concentration time curve was significantly lower (P = .007) and the apparent clearance significantly higher (P = .006) in pregnant women compared with nonpregnant women. Pregnancy produces lower systemic levels of oseltamivir carboxylate. Increasing the dose and/or dosing frequency of oseltamivir during pregnancy may be necessary to achieve comparable exposure in pregnant and nonpregnant women.

Dactinomycin and vincristine toxicity in the treatment of childhood cancer: a retrospective study from the Children's Oncology Group.

BACKGROUND: Dactinomycin (AMD) and vincristine (VCR) have been used for the treatment of childhood cancer over the past 40 years but evidence-based dosing guidance is lacking. METHODS: Patient AMD and VCR dose and drug-related adverse event (AE) information from four rhabdomyosarcoma (RMS) and two Wilms tumor (WT) studies were assembled. Statistical modeling was used to account for differences in AE data collection across studies, develop rate models for grade 3/4 CTCAE v3 hepatic- (AMD) and neuro- (VCR) toxicity, assess variation in toxicity rates over age and other factors, and predict toxicity risk under current dosing guidelines. RESULTS: For the same dose/body size, AMD toxicity rates were higher in patients <1 year than older patients and VCR toxicity rates increased with age. The statistical model provided estimates for AMD and VCR toxicity risk under current dosing schedules and indicated that patients of smaller body size were at lower risk of VCR toxicity than larger patients of the same age. The rate of AMD toxicity was highest early in treatment and was lower in patients who tolerated initial AMD without toxicity. CONCLUSION: The observed decrease in AMD toxicity rate with cumulative dose may indicate sensitivity in a subgroup of patients while the observed increase in VCR toxicity risk with age may indicate changing sensitivity to VCR. Current dosing practices result in a fairly uniform toxicity profile within age group. However, PK/PD studies should be done to provide further provide further information on best dosing guidelines.

The National Institutes of Health and the Best Pharmaceuticals for Children Act.

The majority of drugs used to treat children are not labeled for use in children. The Best Pharmaceuticals for Children Act of 2002, re-authorized as the US FDA Amendments Act of 2007, directs the National Institutes of Health (NIH) to sponsor pediatric clinical trials of drugs lacking patent protection, if the FDA request for studies has been declined. The NIH is currently sponsoring 17 clinical studies. Challenges encountered include a paucity of investigators who are trained in pediatric clinical pharmacology; inadequate knowledge of the mechanisms of drug action in a growing child; and lack of pediatric formulations.

What Could the Future of Safety Monitoring Look Like?

Like much of the clinical research and health care provider enterprise, the data capture and archiving for harm, probability of harm, and impact of intervention-related events is fragmented, inconsistent, and lacks standards to perform the types of operations that could inform researchers, practitioners, and patients in a timely way of actions and policies. The entire system of assessments, terminology, data formats and structure, analyses, and dissemination would benefit from changes based on adherence to a process framework of detect, describe, analyze, and react in the context of recognizing the multiple pathways and factors that lead to any specific outcome or series of outcomes. Existing tools, if properly applied, can form the basis for the next generation of data systems, processes, analyses, and sharing to address most of the current challenges.

Research Gaps in Primary Pediatric Hypertension.

Hypertension affects >40% of the US population and is a major contributor to cardiovascular-related morbidity and mortality. Although less common among children and adolescents, hypertension affects 1% to 5% of all youth. The 2017 Clinical Practice Guideline for the Diagnosis and Management of High Blood Pressure in Children and Adolescents provided updates and strategies regarding the diagnosis and management of hypertension in youth. Despite this important information, many gaps in knowledge remain, such as the etiology, prevalence, and trends of hypertension; the utility and practicality of ambulatory blood pressure monitoring; practical goals for lifestyle modification that are generalizable; the long-term end-organ impacts of hypertension in youth; and the long-term safety and efficacy of antihypertensive therapy in youth. The Eunice Kennedy Shriver National Institute of Child Health and Human Development, in collaboration with the National Heart, Lung, and Blood Institute and the US Food and Drug Administration, sponsored a workshop of experts to discuss the current state of childhood primary hypertension. We highlight the results of that workshop and aim to (1) provide an overview of current practices related to the diagnosis, management, and treatment of primary pediatric hypertension; (2) identify related research gaps; and (3) propose ways to address existing research gaps.

Development of Drug Therapies for Newborns and Children: The Scientific and Regulatory Imperatives.

Pediatric legislation has generated information about the efficacy, safety, and dosing of more than 600 products in children. Extrapolation of adult efficacy data has been an integral part of pediatric drug development. Advances in our understanding of physiology and pharmacology have improved the approach to pediatric dose selection. However, a high percentage of pediatric trials do not meet their primary efficacy endpoint. Delays in initiating completing pediatric studies persist. This article describes these advances and provides innovative approaches to optimize pediatric drug development.

Enrollment of Neonates in More Than One Clinical Trial.

Because the highest rates of morbidity and mortality in neonates are seen in those born at <32 weeks' gestation, this group has the most urgent need for novel therapies to improve survival and outcome. Legislative efforts in the United States and Europe have attempted to address this issue by requiring the study of drugs, biological and nutritional products, devices, and other therapies in this population through a combination of high-quality regulatory and clinical trials, quality improvement initiatives, and observational studies. Because there are relatively small numbers of very preterm neonates born each year in any 1 country or continent, and because a significant number of clinical trials are recruiting at any 1 time, a neonate may meet enrollment criteria for >1 clinical trial. Neonatal units that have the infrastructure and resources to engage in research frequently face the question of whether it is permissible to enroll a neonate in >1 trial. This article examines the pertinent scientific, ethical, regulatory, and industry issues that should be taken into account when considering enrolling neonates in multiple clinical studies.

Gaps in knowledge in treating pregnant women.

Because studies are often undertaken without knowledge of the pharmacokinetics of a drug, efficacy is difficult to assess in pregnant women. To address this lack, basic and clinical research within the National Institute of Child Health and Human Development is focusing on expanding knowledge of pharmacology during pregnancy. Although medication use, including prescription, over-the-counter, and herbal products, is common during pregnancy, physicians may not be aware of the nonprescription products their patients are taking or the interactions these products may have with prescribed medications. A number of studies have found sex differences in oxidative metabolism and transport, as well as pharmacologic and toxicologic differences in hepatic metabolism, that are ultimately reflected in pharmacokinetics. Sex differences exist in distribution volumes, transport proteins, and drug clearance. Beyond these sex differences, pregnancy itself affects the absorption, distribution, metabolism, and elimination of a drug. Women experience more adverse drug reactions (ADRs) than do men, and these reactions tend to be more severe. QT prolongation (torsades de pointes) and hepatic toxicity are two of the most severe ADRs, frequently causing withdrawal of a drug from the market. Women may also metabolize drugs more quickly than do men, and drugs metabolized by cytochrome P3A4 are cleared more rapidly during pregnancy. A substantial increase in the clearance of drugs eliminated by renal mechanisms also has been noted. A significant number of women are clinically depressed during pregnancy and postpartum, and eliminating treatment for depression during pregnancy may have negative consequences for both mother and fetus. Among women with depression who are treated with selective serotonin reuptake inhibitors, the dose needed to maintain efficacy increases across the course of pregnancy. Drug disposition and response not only can differ between men and women, but also between pregnant and nonpregnant women. Research is needed to understand how pregnancy alters the pharmacokinetics and pharmacodynamics of drugs; then, efficacy trials can be initiated. Alternative strategies also need to be developed to characterize safety information.

Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase.

PURPOSE: The purpose is to describe the Food and Drug Administration (FDA) review and approval of imatinib (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase. EXPERIMENTAL DESIGN: The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase, comparing imatinib with the combination of IFN-alpha and cytarabine. RESULTS: Imatinib showed clinically and statistically significantly better results for time-to-progression to accelerated phase or blast crisis, progression-free survival, complete hematological response rate, and cytogenetic response rate. With a median follow-up of 14 months, a maximum follow-up of 19.5 months, and an expected median survival of 5-6 years on the IFN-alpha/cytarabine control arm, few of the expected progressions to accelerated or blast phase or deaths have occurred. Imatinib was also better tolerated. Edema, nausea, rigors, neutropenia, and headache were more frequent in women. Only 57% of the IFN-alpha target dose was administered, and only 68% of patients received any cytarabine. However, this does not appear to adequately explain the superiority of imatinib observed in this trial. Results of a population pharmacokinetic study in a subgroup of 371 patients and a separate rifampin-imatinib drug-drug interaction study in healthy volunteers are presented. CONCLUSIONS: On December 20, 2002, imatinib was granted accelerated approval under subpart H, rather than regular approval. Follow-up is short compared with the natural history of chronic phase CML or more mature results with established therapies such as IFN-alpha or transplantation. If imatinib should stop working after 1.5-2 years, the results could be importantly different from the present analysis. As a Phase IV postmarketing commitment, the applicant has agreed to provide follow-up reports on this imatinib study annually for the next 6 years.

Review of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act: What can the obstetric community learn from the pediatric experience?

Children have been called therapeutic orphans as they have been excluded from drug research and new drug development resulting in the lack of proper labels for majority of the drugs for pediatric use. The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) are two legislative mandates to improve pediatric drug labeling. The BPCA legislation authorizes the National Institutes of Health (NIH) to implement research programs through funding clinical trials to study off-patent drugs in pediatric population. Obstetric pharmacology research gaps are in many ways similar to those in pediatrics, including off-label use of common medications, and lack of knowledge of appropriate dosing, safety, and efficacy of drugs. Much research is needed to define mechanisms of disease and drug actions in pregnant women to fill the knowledge gaps.

Evaluation of sodium nitroprusside for controlled hypotension in children during surgery.

PURPOSE: (1) To define the onset and offset of the blood-pressure-lowering effects of sodium nitroprusside (SNP) for use in developing instructions for dose titration in children undergoing a surgical or medical procedure, and (2) to assess the safety of SNP administration in pediatric patients requiring controlled reduction of blood pressure. METHODS: We conducted a randomized, double-blind, parallel-group, dose-ranging, effect-controlled, multicenter study of intravenous (IV) infusions of SNP in pediatric patients <17 years, who required controlled hypotension for at least 2 h while undergoing a surgical or medical procedure. A blinded SNP dose of 0.3, 1, 2, or 3 µg/kg/min was infused for 30 min, followed by open-label administration for at least 90 min. Both infusions were titrated to effect. RESULTS: The final intent-to-treat group comprised 203 patients. Significant reductions in mean arterial pressure (MAP) from baseline were observed for all four doses at 20 and 25 min after the start of infusion (p ≤ 0.009 and p ≤ 0.010 for each time, respectively). Overall, 98.5% of the patients achieved the target MAP; 72.9% first achieved the target MAP during the blinded infusion. The mean infusion rate at target MAP was 1.07 µg/kg/min. CONCLUSION: We determined that 0.3 µg/kg/m is a reasonable starting dose for SNP in pediatric patients requiring controlled hypotension. The infusion rate can then be increased to achieve the desired reduction in blood pressure. On the basis of our results, we found an average infusion rate of 1 µg/kg/min might be appropriate. Of note, no cyanide toxicity was reported, and no measureable cyanide levels were detected in any blood samples obtained during the study. http://clinicaltrials.gov/show/NCT00135668.

Applying Regulatory Science to Develop Safe and Effective Medicines for Neonates: Report of the US Food and Drug Administration First Annual Neonatal Scientific Workshop, October 28-29, 2014.

The First Annual Neonatal Scientific Workshop focused on the needs of the neonate by addressing the basic question: what information is required to inform decision making both at the regulatory level and at the bedside? Priority therapeutic areas include neonatal lung, brain, and gastrointestinal injury, retinopathy of prematurity, sepsis, and neonatal abstinence syndrome. Scientific progress in these therapeutic areas, regulatory standards, and the acceptable design and conduct of clinical trials must be aligned. This report will review potential approaches to enhancing neonatal drug development.