A Modern Curriculum for Training Scientists in Model-Informed Drug Development: Progress Report on FDA Grant to Train Regulatory Scientists.

Under US Food and Drug Administration (FDA) grant (2U18FD005320-06), the Critical Path Institute (C-Path) and experienced private sector partners collaborated with global health organizations to create didactic video materials in an e-learning format on model-informed drug development (MIDD) topics relevant to a non-modeling audience. Several multinational pharmaceutical companies contributed case studies illustrating the application of the MIDD approach in practice. Training videos were created and divided into several modules: introducing the MIDD landscape for drug development and regulatory science, a review of various model types used for MIDD, discussions of how models inform drug development and regulatory decisions, future goals of MIDD, and discussions on the interconnectedness of models used for MIDD.

Challenging the Norm: A Multidisciplinary Perspective on Intravenous to Subcutaneous Bridging Strategies for Biologics.

The transition from intravenous (i.v.) to subcutaneous (s.

Training the next generation of pharmacometric modelers: a multisector perspective.

The current demand for pharmacometricians outmatches the supply provided by academic institutions and considerable investments are made to develop the competencies of these scientists on-the-job. Even with the observed increase in academic programs related to pharmacometrics, this need is unlikely to change in the foreseeable future, as the demand and scope of pharmacometrics applications keep expanding. Further, the field of pharmacometrics is changing.

Therapeutic Development in Polyarticular Course Juvenile Idiopathic Arthritis: Extrapolation, Dose Selection, and Clinical Trial Design.

Objective: Stakeholders met to address persistent challenges facing the development of therapeutics for polyarticular juvenile idiopathic arthritis (pJIA), which result in fewer approved therapies for children with pJIA than adults with rheumatoid arthritis (RA) and long lag times from adult RA approval to pediatric labeling. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critically important to multiple stakeholders.

Methods: The Food and Drug Administration in collaboration with the University of Maryland Center for Regulatory Science and Innovation held a public workshop entitled "Accelerating Drug Development for pJIA" on October 2, 2019, to address challenges surrounding access to new medications for children and adolescents with pJIA.

The trouble with triples: Examining the impact of measurement error in mediation analysis.

Mediation analysis is used in genetic mapping studies to identify candidate gene mediators of quantitative trait loci (QTL). We consider genetic mediation analysis of triplets-sets of three variables consisting of a target trait, the genotype at a QTL for the target trait, and a candidate mediator that is the abundance of a transcript or protein whose coding gene co-locates with the QTL. We show that, in the presence of measurement error, mediation analysis can infer partial mediation even in the absence of a causal relationship between the candidate mediator and the target.

Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient-level placebo (Standard-of-Care) data to enable model-informed drug development.

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems. Many investigational agents have failed or shown only modest effects when added to standard of care (SoC) therapy in placebo-controlled trials, and only two therapies have been approved for SLE in the last 60 years. Clinical trial outcomes have shown discordance in drug effects between clinical endpoints.

A Bayesian model selection approach to mediation analysis.

Genetic studies often seek to establish a causal chain of events originating from genetic variation through to molecular and clinical phenotypes. When multiple phenotypes share a common genetic association, one phenotype may act as an intermediate for the genetic effects on the other. Alternatively, the phenotypes may be causally unrelated but share genetic loci.

Bayesian modeling and simulation to inform rare disease drug development early decision-making: Application to Duchenne muscular dystrophy.

Rare disease clinical trials are constrained to small sample sizes and may lack placebo-control, leading to challenges in drug development. This paper proposes a Bayesian model-based framework for early go/no-go decision making in rare disease drug development, using Duchenne muscular dystrophy (DMD) as an example. Early go/no-go decisions were based on projections of long-term functional outcomes from a Bayesian model-based analysis of short-term trial data informed by prior knowledge based on 6MWT natural history literature data in DMD patients.

A Pharmacokinetic Analysis of Tobramycin in Patients Less than Five Years of Age with Cystic Fibrosis: Assessment of Target Attainment with Extended-Interval Dosing through Simulation.

Extended interval dosing of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age. We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF <5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included.

Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome.

Results from Blinded Buprenorphine OR Neonatal morphine solution (BBORN), a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE), a new trial with buprenorphine in a similar population, were to (1) optimize initial dose, up-titration to achieve symptom control and weaning steps of pharmacologic treatment and (2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores.

Quantification of the Impact of Partition Coefficient Prediction Methods on Physiologically Based Pharmacokinetic Model Output Using a Standardized Tissue Composition.

Tissue:plasma partition coefficients are key parameters in physiologically based pharmacokinetic (PBPK) models, yet the coefficients are challenging to measure in vivo. Several mechanistic-based equations have been developed to predict partition coefficients using tissue composition information and the compound's physicochemical properties, but it is not clear which, if any, of the methods is most appropriate under given circumstances. Complicating the evaluation, each prediction method was developed, and is typically employed, using a different set of tissue composition information, thereby making a controlled comparison impossible.

Latent process model of the 6-minute walk test in Duchenne muscular dystrophy : A Bayesian approach to quantifying rare disease progression.

Duchenne muscular dystrophy (DMD) is a rare X-linked genetic pediatric disease characterized by a lack of functional dystrophin production in the body, resulting in muscle deterioration. Lower body muscle weakness progresses to non-ambulation typically by early teenage years, followed by upper body muscle deterioration and ultimately death by the late twenties. The objective of this study was to enhance the quantitative understanding of DMD disease progression through nonlinear mixed effects modeling of the population mean and variability of the 6-min walk test (6MWT) clinical endpoint.

Morphine Dose Optimization in Critically Ill Pediatric Patients With Acute Respiratory Failure: A Population Pharmacokinetic-Pharmacogenomic Study.

Objective: To develop a pharmacokinetic-pharmacogenomic population model of morphine in critically ill children with acute respiratory failure.

Design: Prospective pharmacokinetic-pharmacogenomic observational study.

Setting: Thirteen PICUs across the United States.

Midazolam Dose Optimization in Critically Ill Pediatric Patients With Acute Respiratory Failure: A Population Pharmacokinetic-Pharmacogenomic Study.

Objectives: To develop a pharmacokinetic-pharmacogenomic population model of midazolam in critically ill children with primary respiratory failure.

Design: Prospective pharmacokinetic-pharmacogenomic observational study.

Setting: Thirteen PICUs across the United States.

Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimisation.

Background: Prospectively designed studies assessing the exposure-response profile of vedolizumab are lacking. Observational exposure-response data for vedolizumab are limited and have not been adjusted for potential confounding factors, particularly those that may affect vedolizumab clearance.

Aims: To (a) investigate the vedolizumab exposure-response relationship after adjusting for potential confounding variables; (b) propose potential target serum vedolizumab concentrations for future study; (c) ascertain whether early vedolizumab serum concentrations were associated with short- and long-term clinical outcomes in adults with ulcerative colitis in GEMINI 1.

A Population Pharmacokinetic Analysis to Study the Effect of Extracorporeal Membrane Oxygenation on Cefepime Disposition in Children.

Objectives: Limited data exist on the effects of extracorporeal membrane oxygenation on pharmacokinetics of cefepime in critically ill pediatric patients. The objective was to describe cefepime disposition in children treated with extracorporeal membrane oxygenation using population pharmacokinetic modeling.

Design: Multicenter, prospective observational study.

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana.

Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes.

The Pharmacokinetics and Pharmacodynamics of Buprenorphine in Neonatal Abstinence Syndrome.

Neonatal abstinence syndrome (NAS) is a condition affecting newborns that are exposed to an opioid in utero. In a randomized, controlled trial assessing the efficacy of buprenorphine and morphine in NAS, blood samples were analyzed from a subset of patients receiving buprenorphine along with NAS scores. The data were used to validate and adapt an existing model of buprenorphine in neonates and to identify relationships between buprenorphine or norbuprenorphine pharmacokinetics (PK) and efficacy or safety.

A model of fracture risk used to examine the link between bone mineral density and the impact of different therapeutic mechanisms on fracture outcomes in patients with osteoporosis.

A hazard model of fracture was developed using individual patient data (IPD) from the NHANES (2005-2008) database and summary-level data from an aggregate dataset (AD). The AD was built by performing a comprehensive and systematic literature search of clinical studies published from 1995 to 2015, recording fracture rate and bone mineral density (BMD) for both treatment and placebo arms. The search resulted in a metadata set comprised of 21 studies investigating the effects of various bisphosphonates, teriparatide, denosumab, and raloxifene in 65,254 patients over a cumulative 56.

A Population Pharmacokinetic Analysis to Study the Effect of Therapeutic Hypothermia on Vancomycin Disposition in Children Resuscitated From Cardiac Arrest.

Objectives: Limited data exist on the effects of therapeutic hypothermia on renal function and pharmacokinetics in pediatric patients after cardiac arrest. The objective was to describe the differences in vancomycin disposition in pediatric patients following cardiac arrest treated with either therapeutic hypothermia or normothermia using population pharmacokinetic modeling.

Design: Single-center, retrospective cohort study.

Brief Report: CYP2B6 516G>T Minor Allele Protective of Late Virologic Failure in Efavirenz-Treated HIV-Infected Patients in Botswana.

Background: CYP2B6 polymorphisms that affect efavirenz (EFV) concentrations are common, but the effect of this polymorphism on HIV virologic failure in clinical practice settings has not fully been elucidated. Our objective was to investigate the relationship between the CYP2B6 516G>T genotype and late virologic failure in patients treated with EFV in Gaborone, Botswana.

Setting: We performed a case-control study that included 1338 HIV-infected black Batswana on EFV-based antiretroviral therapy (ART).

Model-based meta-analysis for comparing Vitamin D2 and D3 parent-metabolite pharmacokinetics.

Association of Vitamin D (D3 & D2) and its 25OHD metabolite (25OHD3 & 25OHD2) exposures with various diseases is an active research area. D3 and D2 dose-equivalency and each form's ability to raise 25OHD concentrations are not well-defined. The current work describes a population pharmacokinetic (PK) model for D2 and 25OHD2 and the use of a previously developed D3-25OHD3 PK model [1] for comparing D3 and D2-related exposures.

Corrigendum: 2016 ACG Abstracts-Inflammatory Bowel Disease.

This corrects the article DOI: 10.1038/ajg.2016.