Characterization of Plasma Protein Alterations in Pregnant and Postpartum Individuals Living With HIV to Support Physiologically-Based Pharmacokinetic Model Development.

Background: Alterations in plasma protein concentrations in pregnant and postpartum individuals can influence antiretroviral (ARV) pharmacokinetics. Physiologically-based pharmacokinetic (PBPK) models can serve to inform drug dosing decisions in understudied populations. However, development of such models requires quantitative physiological information (e.g., changes in plasma protein concentration) from the population of interest. Objective: To quantitatively describe the time-course of albumin and α1-acid glycoprotein (AAG) concentrations in pregnant and postpartum women living with HIV. Methods: Serum and plasma protein concentrations procured from the International Maternal Pediatric Adolescent AIDS Clinical Trial Protocol 1026s (P1026s) were analyzed using a generalized additive modeling approach. Separate non-parametric smoothing splines were fit to albumin and AAG concentrations as functions of gestational age or postpartum duration. Results: The analysis included 871 and 757 serum albumin concentrations collected from 380 pregnant (~20 to 42 wks gestation) and 354 postpartum (0 to 46 wks postpartum) women, respectively. Thirty-six and 32 plasma AAG concentrations from 31 pregnant (~24 to 38 wks gestation) and 30 postpartum women (~2-13 wks postpartum), respectively, were available for analysis. Estimated mean albumin concentrations remained stable from 20 wks gestation to term (33.4 to 34.3 g/L); whereas, concentrations rapidly increased postpartum until stabilizing at ~42.3 g/L 15 wk after delivery. Estimated AAG concentrations slightly decreased from 24 wks gestation to term (53.6 and 44.9 mg/dL) while postpartum levels were elevated at two wks after delivery (126.1 mg/dL) and subsequently declined thereafter. Computational functions were developed to quantitatively communicate study results in a form that can be readily utilized for PBPK model development. Conclusion: By characterizing the trajectory of plasma protein concentrations in pregnant and postpartum women living with HIV, our analysis can increase confidence in PBPK model predictions for HIV antiretrovirals and better inform drug dosing decisions in this understudied population.

Harnessing formulation and clinical pharmacology knowledge for efficient pediatric drug development: Overview and discussions from M-CERSI pediatric formulation workshop 2019.

A pediatric formulation workshop entitled "Pediatric Formulations: Challenges of Today and Strategies for Tomorrow" was held to advance pediatric drug product development efforts in both pre-competitive and competitive environments. The workshop had four main sessions discussing key considerations of Formulation, Analytical, Clinical and Regulatory. This paper focuses on the clinical session of the workshop. It provides an overview of the discussion on the interconnection of pediatric formulation design and development, clinical development strategy and pediatric clinical pharmacology. The success of pediatric drug product development requires collaboration of multi-disciplinary teams across the pharmaceutical industry, consortiums, foundations, academia and global regulatory agencies. Early strategic planning is essential to ensure alignment among major stakeholders of different functional teams. Such an alignment is particularly critical in the collaboration between formulators and clinical pharmacology teams.

Exposure-Response Assessment in Pediatric Drug Development Studies Submitted to the US Food and Drug Administration.

Exposure-response (E-R) modeling provides a quantitative tool to leverage adult data to support pediatric trial design and drug approval. The pediatric E-R studies submitted to US Food and Drug Administration (FDA) between 2007 and 2018 were surveyed in the context of various types of trial designs supporting drug approval in the pediatric population. The applications of E-R evaluation in pediatric drug development programs are mainly focused on three areas: (i) supporting pediatric extrapolation when the E-R relationships are similar between the pediatric and adult populations; (ii) dose selection to balance the risk-benefit profile based on the change in efficacy and safety response with different exposure levels; and (iii) approval of a new formulation, new dosing regimen, or new route of administration, where E-R evaluation helps quantify the change in clinical response between the old and new strategies. E-R modeling will continue to play an expanded role in pediatric drug development in the future.

Extrapolation of Adult Efficacy to Pediatric Patients With Chemotherapy-Induced Nausea and Vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a common treatment-related adverse event that negatively impacts the quality of life of cancer patients. During pediatric drug development, extrapolation of efficacy from adult to pediatric populations is a pathway that can minimize the exposure of children to unnecessary clinical trials, improve efficiency, and increase the likelihood of success in obtaining a pediatric indication. The acceptability of the use of extrapolation depends on a series of evidence-based assumptions regarding the similarity of disease, response to intervention, and exposure-response relationships between adult and pediatric patients. This study evaluated publicly available summaries of data submitted to the US Food and Drug Administration for drugs approved for CINV to assess the feasibility of extrapolation for future development programs. Extracted data included trial design, emetogenic potential of chemotherapy, primary end points, participant enrollment criteria, and antiemetic pharmacokinetics. Adult and pediatric clinical trial designs for assessment of efficacy and safety shared key design elements. Antiemetic drugs found to be efficacious in adults were also efficacious in pediatric patients. Systemic drug concentrations at approved doses were similar for ondansetron, granisetron, and aprepitant, but an exposure-response analysis of palonosetron in children suggested that higher palonosetron systemic exposure is necessary for the prevention of CINV in the pediatric population. For 5-hydroxytryptamine-3 and neurokinin-1 receptor antagonist antiemetic drugs, efficacy in adults predicts efficacy in children, supporting the extrapolation of effectiveness of an antiemetic product in children from adequate and well-controlled studies in adult patients with CINV.

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.

Drug development for pediatric neurogenic bladder dysfunction: dosing, endpoints, and study design.

Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas.

Alternate endpoints and clinical outcome assessments in pediatric ulcerative colitis registration trials.

OBJECTIVES: Presently, there is no consensus on endpoint measures to assess clinical outcomes for pediatric ulcerative colitis (UC). This study reviewed the endpoints used in the registration trials of approved drugs for pediatric UC. METHODS: The primary efficacy endpoints of all registration trials completed from 1950 to 2008 that led to Food and Drug Administration approval for indications in pediatric and adult UC were reviewed. RESULTS: Colazal and Remicade have been approved for pediatric UC indication, and clinical response was used as a primary endpoint in these registration trials. The clinical response in the adult Colazal trials was defined as a reduction of rectal bleeding and improvement in at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physician's global assessment) assessed by the Sutherland UC Activity Index. The pediatric Colazal trial defined clinical response using the Modified Sutherland UC Activity Index, which excluded abdominal pain and functional assessment. Both adult and pediatric Remicade trials used clinical response defined by the Mayo score as the primary endpoint. The Pediatric Ulcerative Colitis Activity Index was used to measure various secondary endpoints in the pediatric Remicade trial. CONCLUSIONS: Pediatric-specific endpoints were used, but outcome measures and definition of clinical response were not consistent in pediatric UC trials. Consensus on the definition of successful treatment outcome (clinical response and/or remission) and collaboration in the development of well-defined and reliable measures of signs and symptoms for use in conjunction with endoscopic parameters of mucosal healing will facilitate pediatric drug development.

Adolescent dosing and labeling since the Food and Drug Administration Amendments Act of 2007.

IMPORTANCE: During pediatric drug development, dedicated pharmacokinetic studies are generally performed in all relevant age groups to support dose selection for subsequent efficacy trials. To our knowledge, no previous assessments regarding the need for an intensive pharmacokinetic study in adolescents have been performed. OBJECTIVES: To compare U.S. Food and Drug Administration (FDA)-approved adult and adolescent drug dosing and to assess the utility of allometric scaling for the prediction of drug clearance in the adolescent population. DESIGN: Adult and adolescent dosing and drug clearance data were obtained from FDA-approved drug labels and publicly available databases containing reviews of pediatric trials submitted to the FDA. Dosing information was compared for products with concordant indications for adolescent and adult patients. Adolescent drug clearance was predicted from adult pharmacokinetic data by using allometric scaling and compared with observed values. MAIN OUTCOMES AND MEASURES: Adolescent and adult dosing information and drug clearance. RESULTS: There were 126 unique products with pediatric studies submitted to the FDA since the FDA Amendments Act of 2007, of which 92 had at least 1 adolescent indication concordant with an adult indication. Of these 92 products, 87 (94.5%) have equivalent dosing for adults and adolescent patients. For 18 of these 92 products, a minimum weight or body surface area threshold is recommended for adolescents to receive adult dosing. Allometric scaling predicted adolescent drug clearance with an overall mean absolute percentage error of 17.0%. CONCLUSIONS AND RELEVANCE: Approved adult and adolescent drug dosing is equivalent for 94.5% of products with an adolescent indication studied since the FDA Amendments Act of 2007. Allometric scaling may be a useful tool to avoid unnecessary dedicated pharmacokinetic studies in the adolescent population during pediatric drug development, although each development program in adolescents requires a full discussion of drug dosing with the FDA.

The transfer of drugs and therapeutics into human breast milk: an update on selected topics.

Many mothers are inappropriately advised to discontinue breastfeeding or avoid taking essential medications because of fears of adverse effects on their infants. This cautious approach may be unnecessary in many cases, because only a small proportion of medications are contraindicated in breastfeeding mothers or associated with adverse effects on their infants. Information to inform physicians about the extent of excretion for a particular drug into human milk is needed but may not be available. Previous statements on this topic from the American Academy of Pediatrics provided physicians with data concerning the known excretion of specific medications into breast milk. More current and comprehensive information is now available on the Internet, as well as an application for mobile devices, at LactMed (http://toxnet.nlm.nih.gov). Therefore, with the exception of radioactive compounds requiring temporary cessation of breastfeeding, the reader will be referred to LactMed to obtain the most current data on an individual medication. This report discusses several topics of interest surrounding lactation, such as the use of psychotropic therapies, drugs to treat substance abuse, narcotics, galactagogues, and herbal products, as well as immunization of breastfeeding women. A discussion regarding the global implications of maternal medications and lactation in the developing world is beyond the scope of this report. The World Health Organization offers several programs and resources that address the importance of breastfeeding (see http://www.who.int/topics/breastfeeding/en/).

Strategic biomarkers for drug development in treating rare diseases and diseases in neonates and infants.

There are similar challenges in developing a product designed to treat patients with a rare disease and drugs to treat critically ill neonates and infants. Part of the challenge in developing such products as well as identifying the optimal dosing regimen for the treatment of young children arises from the complex interrelationship between developmental changes and changes in biomarkers responsive to drug therapy. These difficulties are further compounded by our lack of understanding of the key physiological factors that cause the differences in clinical responses between adults and neonates and infants. Regulatory efforts have succeeded in overcoming these challenges in many areas of pediatric and orphan drug development. Strategic applications of biomarkers and surrogate endpoints for the development and approval of a product used to treat an orphan disease will be highlighted with examples of approved products. Continued efforts are still needed to fill in our knowledge gap and to strategically link biomarkers and surrogate endpoints to clinical responses for rare diseases and diseases affecting neonates and infants.

Extrapolation of adult data and other data in pediatric drug-development programs.

OBJECTIVES: In 1994, the US Food and Drug Administration (FDA) proposed an approach, based on extrapolation of efficacy findings from adults to the pediatric population, to maximize the use of adult data and other data when designing pediatric drug-development programs. We examined the experience of the FDA in using extrapolation to evaluate how and when it was used and any changes in scientific assumptions over time. METHODS: We reviewed 370 pediatric studies submitted to the FDA between 1998 and 2008 in response to 159 written requests (166 products) issued under the Pediatric Exclusivity Provision. We identified cases in which efficacy was extrapolated from adult data or other data, we categorized the type of pediatric data required to support extrapolation, and we determined whether the data resulted in new pediatric labeling. RESULTS: Extrapolation of efficacy from adult data occurred for 82.5% of the drug products (137 of 166). Extrapolation was defined as complete for 14.5% of the products (24 of 166) and partial for 68% of them (113 of 166). Approaches to extrapolation changed over time for 19% of the therapeutic indications studied (13 of 67). When extrapolation was used, 61% of the drug products (84 of 137) obtained a new pediatric indication or extension into a new age group; this number decreased to 34% (10 of 29) when there was no extrapolation. CONCLUSIONS: Extrapolating efficacy from adult data or other data to the pediatric population can streamline pediatric drug development and help to increase the number of approvals for pediatric use.

Improving pediatric dosing through pediatric initiatives: what we have learned.

OBJECTIVE: The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling. METHODS: We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing. RESULTS: The first 108 drugs with new or revised pediatric labeling changes had dosing changes or pharmacokinetic information (n = 23), new safety information (n = 34), information concerning lack of efficacy (n = 19), new pediatric formulations (n = 12), and extended age limits (n = 77). A product might have had > or = 1 labeling change. We selected specific examples (n = 16) that illustrate significant differences in pediatric pharmacokinetics. CONCLUSIONS: Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.

Breast implant surveillance reports to the U.S. Food and Drug Administration: maternal-child health problems.

There is continuing concern that women who receive breast implants may be at increased risk for adverse reproductive outcomes or experience problems with breastfeeding. It is unknown whether exposure to biomaterials in breast implants may have teratogenic effects or leach into breast milk causing postnatalproblems. We studied the Food and Drug Administration (FDA) experience by analyzing a case series of adverse event reports received and entered into the FDA's Manufacturer and User Facility Device Experience (MAUDE) database or the Device Experience Network (DEN) database by December 31, 2002 regarding women with breast implants. Reports were critically reviewed for lactation difficulties, reproductive problems (spontaneous abortion, delayed conception) and medical conditions among offspring, including neonatal, infant, and childhood diseases and congenital defects that were attributed to implants. We identified 339 reports that described maternal-child adverse events. Nearly half of these reports (46%) described actual problems with breastfeeding or expressed concern that implants would be unsafe or interfere with breastfeeding. Forty-four percent of reports (n=149) described either nonspecific or specific signs, symptoms, or illnesses in children. An additional 3.5% of reports (n=12) detailed a congenital anomaly believed by the reporter to be caused by breast implants.

Cardiovascular support in preterm infants.

BACKGROUND: Despite increasing investigation in the area of cardiovascular instability in preterm infants, huge gaps in knowledge remain. None of the current treatments for hypotension, including the use of inotropic agents, have been well studied in the preterm population, and data regarding safety and efficacy are lacking. Thus, the labeling information regarding the use of inotropes as therapeutic agents in this population is inadequate. OBJECTIVE: This article reviews the current deficiencies in knowledge with respect to measuring and achieving normal organ perfusion; summarizes the clinical, methodological, and ethical issues to consider when designing trials to evaluate medications for hemodynamic instability in the preterm neonate; and proposes 2 possible trial designs. Unanswered questions and potential obstacles for the systematic study of drugs to treat cardiovascular instability in preterm neonates are discussed. METHODS: The neonatal Cardiology Group was established in 2003 by the US Food and Drug Administration (FDA) and the National Institute of Child Health and Human Development (NICHD) as part of the Newborn Drug Development Initiative. The Cardiology Group conducted a number of teleconferences and one meeting to develop a document addressing gaps in knowledge regarding cardiovascular drugs commonly used in low-birth-weight neonates and possible approaches to investigate these drugs. This work was presented at a workshop cosponsored by the NICHD and the FDA held in March 2004 in Baltimore, Maryland. Information for this article was gathered during this initiative. RESULTS: To develop rational, evidence-based guidelines corroborated by robust scientific data for cardiovascular support in newborns, well-designed and adequately powered pharmacologic studies and clinical trials are needed to evaluate the safety and efficacy of inotropic agents and to determine the short- and long-term effects of these drugs. Trials investigating the currently available and novel therapies for cardiovascular instability in neonates will provide information that can be incorporated into product labeling and a scientific framework for cardiovascular management in critically ill neonates. The Cardiology Group identified and prioritized 2 conditions for investigation of therapeutic options for the management of neonatal cardiovascular instability: (1) cardiovascular instability in preterm neonates; and (2) cardiac dysfunction in neonates after cardiopulmonary bypass surgery. Key research questions in the area of cardiovascular instability in the preterm infant include determining optimal blood pressure (BP) in preterm infants; identifying better measures than BP to determine organ perfusion; optimizing hemodynamic treatments; and clarifying any associations between BP or therapy for low BP and mortality, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity, and neurodevelopmental outcome. The Cardiology Group concluded that the study of inotropic agents in neonates using outcomes of importance to patients will require a complicated trial design to address the elements discussed. The group proposed 2 clinical trial designs: (1) a placebo-controlled trial with rescue therapy for symptomatic infants; and (2) a targeted BP trial. CONCLUSION: This summary is intended to stimulate and assist future research in the area of cardiovascular support for preterm infants.

The newborn drug development initiative.

The Best Pharmaceuticals for Children Act (BPCA; Pub L 107-109) was enacted in January 2002 and will sunset in October 2007. The BPCA established processes for studying off-patent and on-patent drugs that are used in pediatric population. Although some drugs have been successfully developed for the neonate (eg, surfactant, nitric oxide), drug development for the youngest, least mature, and most vulnerable pediatric patients is generally lacking. Most drugs are empirically administered to newborns once efficacy has been demonstrated in adults and usefulness is suspected or demonstrated in the older pediatric population. Unfortunately, this process undermines the ability to perform the appropriate studies necessary to demonstrate a drug's short- and long-term safety and efficacy and establish appropriate dosing in neonates. The Newborn Drug Development Initiative Workshop I (held March 29-30, 2004) specifically addressed scientific, clinical, and ethical concerns in the development of trials of pediatric therapeutic agents for neonates. Implementation of the BPCA for all pediatric populations will foster collaboration among federal agencies and academic institutions on scientific investigation, clinical-study design, and consideration of the weight of evidence and address ethical issues related to the performance of drug studies.

Children's violent television viewing: are parents monitoring?

OBJECTIVE: Violent media exposure has been associated with aggressive behavior, and it has been suggested that child health professionals counsel families on limiting exposure. Effective violence prevention counseling requires an understanding of norms regarding parental attitudes, practices, and influencing factors. Both theories of reasoned action and planned behavior emphasize that subjective norms and attitudes affect people's perceptions and intended behavior. Few data exist on violent television viewing and monitoring from a cross-section of families. By understanding the spectrum of parental attitudes, community-sensitive interventions for violence prevention can be developed. The objective of this study was to assess attitudes about and monitoring of violent television viewing from the perspective of parents. METHODS: An anonymous self-report assisted survey was administered to a convenience sample of parents/guardians who visited child health providers at 3 sites: an urban children's hospital clinic, an urban managed care clinic, and a suburban private practice. The parent questionnaire included questions on child-rearing attitudes and practices and sociodemographic information. RESULTS: A total of 1004 adults who accompanied children for health visits were recruited for the study; 922 surveys were completed (participation rate: 92%). A total of 830 (90%) respondents were parents and had complete child data. Of the 830 respondents, 677 had questions on television viewing included in the survey and were the focus of this analysis. Seventy-five percent of families reported that their youngest child watched television. Of these, 53% reported always limiting violent television viewing, although 73% believed that their children viewed television violence at least 1 time a week. Among television viewers, 81% reported usually or always limiting viewing of sexual content on television and 45% reported usually or always watching television with their youngest child. Among children who watched television, parents reported that they spent an average of 2.6 hours per day watching television. Limitation of television violence was associated with female parents and younger children. CONCLUSIONS: There was variability in attitudes and practices regarding television violence viewing and monitoring among parents. Attitudes and practices varied on the basis of the age of the child and the gender of the parent.

Community norms on toy guns.

OBJECTIVE: Toy gun play has been associated with aggressive behavior, and it has been suggested that child health professionals counsel families on limiting exposure. Effective violence prevention counseling requires an understanding of norms regarding parental attitudes, practices, and influencing factors. Both theories of reasoned action and planned behavior emphasize that subjective norms and attitudes affect people's perceptions and intended behavior. Few normative data exist on this issue from a cross-section of families. By establishing behavioral norms and understanding the spectrum of parental attitudes, community-sensitive and community-specific interventions for violence prevention can be developed. The objective of this study was to assess community norms on the topic of toy gun play from the perspective of parents. METHODS: An anonymous self-report assisted survey was administered to a convenience sample of parents/guardians who visited child health providers at 3 sites: an urban children's hospital clinic, an urban managed care clinic, and a suburban private practice. The parent questionnaire included questions on child rearing attitudes, practice, and sociodemographic information. RESULTS: A total of 1004 eligible participants were recruited for the study; 922 surveys were completed (participation rate 92%). The 830 (90%) respondents who were parents and had complete child data were the focus of additional analysis. Regarding toy guns, 67% of parents believed that it was never "OK for a child to play with toy guns," and 66% stated that they never let their children play with toy guns. Parents who thought that it was okay for children to play with toy guns and allowed them to play with toy guns were more likely to be male parents, have male children, and be white. CONCLUSIONS: There is variability in norms regarding toy gun play among parents, with most discouraging toy gun play. Norms varied based on gender of the child, gender of the parent, and race. Understanding norms is a first step in designing effective community-sensitive interventions.