Understanding the Relationship Between Systemic and Hepatic Exposure of Obeticholic Acid for the Treatment of Liver Disease in Patients with Cirrhosis

Obeticholic acid (OCA) is a selective and potent farnesoid X receptor (FXR) agonist in development for several chronic liver diseases. OCA is a semi-synthetic analogue of chenodeoxycholic acid (CDCA) with similar pharmacokinetic (PK) properties. There was a significant increase in systemic exposure of OCA in patients with hepatic impairment. A proportionally similar increase in systemic […]

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Using Modeling and Simulation to Support Approvals for Orphan Drugs

Suzanne Minton

Rare diseases affect fewer than 1 in 2000 people. Each one affects only a small number of patients. Yet, there are over 7000 rare diseases. And, there are no treatments for 95 percent of them. Thus, many patients suffer from these diseases. The treatments for rare diseases are often referred to as “orphan drugs.” Orphan […]

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Topics: PK/PD Modeling & Simulation

How to Optimize Your Drug Label Using Biosimulation Methodology

While biosimulation has been an important element in drug development for some time, its impact over the past 18 months with regard to label optimization has been profound. Specifically, FDA’s acceptance of Physiologically-Based Pharmacokinetic (PBPK) modeling and simulation has impacted key label elements in more than a dozen cases, driving down R&D costs and timelines, […]

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Gaining FDA Support for a Prognostic Biomarker, Giving Patients Hope

Samer Mouksassi

As a clinician scientist, I get really excited about helping sponsors develop new treatments for patients. For some diseases, the lack of a validated prognostic biomarker is an impediment to developing effective treatments. In this blog post, I’ll discuss how we worked with the Critical Path Institute (C-Path) Polycystic Kidney Disease Outcomes Consortium to gain […]

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How Do We Translate Pre-clinical and Clinical Research into Drug Labeling?

The number of submissions to the FDA involving physiologically-based pharmacokinetic (PBPK) modeling has increased significantly over the past few years. PBPK modeling can be applied in drug discovery and development from the early stages prior to lead development where limited data are available as well as in early to late drug development. There are now […]

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Chemotherapy of Second Stage Human African Trypanosomiasis: Comparison Between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys

Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines […]

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The Challenges of Determining Drug Dosing for Rare Diseases

Suzanne Minton

Most people are familiar with the leading causes of morbidity and mortality in the United States—heart disease, cancer, and diabetes. However, did you know that an estimated 350 million people worldwide suffer from rare diseases? In this blog post, I’ll be discussing what constitutes a rare disease, how developing orphan drugs to treat rare diseases […]

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Topics: PK/PD Modeling & Simulation

Ammonia Control in Children with Urea Cycle Disorders (UCDs); Phase 2 Comparison of Sodium Phenylbutyrate and Glycerol Phenylbutyrate

Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs). Study Design: Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB […]

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Pharmacokinetics of Clofarabine in Patients with High-risk Inherited Metabolic Disorders Undergoing Brain-sparing Hematopoietic Cell Transplantation

Clofarabine, a newer purine analog with reduced central nervous system toxicity, may prove advantageous in hematopoietic cell transplantation in patients for whom neurotoxicity is a natural part of disease progression. This study evaluated clofarabine pharmacokinetics in adult and pediatric patients undergoing hematopoietic cell transplantation for the treatment of high-risk, inherited metabolic disorders. Clofarabine (40 mg/m(2)/d) […]

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Pharmacology and Safety of Glycerol Phenylbutyrate in Healthy Adults and Adults with Cirrhosis

Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is […]

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Population Pharmacokinetics of Teduglutide Following Repeated Subcutaneous Administrations in Healthy Participants and in Patients with Short Bowel Syndrome and Crohn’s Disease

Teduglutide is a GLP-2 analog currently evaluated for the treatment of short bowel syndrome, Crohn’s disease, and other gastrointestinal disorders. The population pharmacokinetics (PK) of teduglutide were assessed following daily subcutaneous (SC) administrations of 2.5 to 80 mg doses in a total of 256 patients. A 1-compartment model with a site-specific rate constant of absorption […]

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Clinical Trial Simulations in Pediatric Patients Using Realistic Covariates: Application to Teduglutide, a Glucagon-like Peptide-2 Analog in Neonates and Infants with Short-bowel Syndrome

Teduglutide, a synthetic glucagon-like peptide-2 (GLP-2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short-bowel syndrome (SBS), Crohn’s disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal […]

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Pharmacokinetics, Safety, and Tolerability of Teduglutide, a Glucagon-like Peptide-2 (GLP-2) Analog, Following Multiple Ascending Subcutaneous Administrations in Healthy Subjects

Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is currently being evaluated for the treatment of short-bowel syndrome, Crohn’s disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N = 64) were assessed following daily subcutaneous administrations for 8 days in a double-blinded, randomized, placebo-controlled, ascending-dose study. Teduglutide treatments were administered […]

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