Implementing a Bayesian approach using Stan with Torsten: Population pharmacokinetics analysis of somatrogon.

Fully Bayesian approaches are not commonly implemented for population pharmacokinetic (PK) modeling. In this paper, we evaluate the use of Stan with R and Torsten for population PK modeling of somatrogon, a recombinant long-acting growth hormone approved for the treatment of growth hormone deficiency. As a software for Bayesian inference, Stan provides an easy way to conduct MCMC sampling for a wide range of models with efficient sampling algorithms, and there are several diagnostic tools to evaluate the MCMC convergence and other potential issues.

Regulatory Framework for Drug Development in Rare Diseases.

Drug development is a highly regulated industry. Therapeutic options for rare diseases must meet the same high standards for the demonstration of safety and efficacy as do those for more common diseases. The approval of the Orphan Drug Act in 1983 has resulted in many more resources for preclinical research, the standardization of patient registries, and the use of real-world data, among other measures, that, along with the advances in drug development, has resulted in the approval of therapies for some of the most unusual diseases.

First open-label, single-arm, prospective study of real-world use of FIX replacement therapy in a predominantly pediatric hemophilia B population in China.

Background: Nonacog alfa (recombinant factor IX [FIX]) is approved in China for the control and prevention of bleeding events in patients with hemophilia B. This was the first study to assess prophylaxis and on-demand therapy with recombinant FIX replacement in a real-world setting in China. This study aimed to evaluate the safety and efficacy of nonacog alfa in Chinese patients with hemophilia B.

Once-weekly prophylaxis regimen of nonacog alfa in patients with hemophilia B: an analysis of timing of bleeding event onset.

In a pivotal, multicenter, open-label study, 25 patients aged 12-54 years with moderately severe/severe hemophilia B received on-demand nonacog alfa (6 months; dose at investigator's discretion) followed by once-weekly prophylaxis with nonacog alfa 100 IU/kg (12 months). During prophylaxis, patients had a median spontaneous annualized bleeding rate (sABR) of 1.0 and significant reductions in ABR (P < 0.

Safety and Efficacy of Moroctocog Alfa (AF-CC) in Chinese Patients with Hemophilia A: Results of Two Open-Label Studies.

Introduction: Moroctocog alfa albumin-free cell culture (AF-CC) increases plasma levels of factor VIII (FVIII) activity and, in China, is indicated for the control and prevention of bleeding episodes in patients with hemophilia A. This study aimed to evaluate the efficacy, safety, and recovery data of moroctocog alfa (AF-CC) in patients with hemophilia participating in two open-label studies, both conducted in China.

Methods: The authorization study (clinicaltrials.

Effect of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intravenous Rivipansel.

Two studies evaluated the effects of renal and hepatic impairment on pharmacokinetics and safety of rivipansel (NCT02813798, NCT02871570). A single intravenous 840-mg rivipansel dose was administered to subjects with renal impairment or normal renal function in study 1005 and subjects with moderate hepatic impairment or normal hepatic function in study 1006. Plasma (both studies) and urine (study 1005) samples were collected for 96 hours postdose.

Safety and Efficacy of Tigecycline to Treat Multidrug-resistant Infections in Pediatrics: An Evidence Synthesis.

Background: The need for antimicrobial therapies effective against multidrug resistant organisms for children remains unmet. Tigecycline shows antibacterial activity across a broad spectrum of bacteria and is approved for treating complicated skin and skin-structure infections, complicated intra-abdominal infections and, in the United States, community-acquired bacterial pneumonia for adult patients. No blinded, randomized phase 3 tigecycline clinical trials on neonates or children have been completed or planned.

A single-arm, open-label study to assess the immunogenicity, safety, and efficacy of etanercept manufactured using the serum-free, high-capacity manufacturing process administered to patients with rheumatoid arthritis.

Objective: To evaluate the immunogenicity, safety, and efficacy of etanercept (ETN) manufactured using the serum-free, high-capacity manufacturing (SFHCM) process in patients with rheumatoid arthritis (RA).

Methods: In this global, multicenter, open-label, single-arm study (NCT02378506), 187 adult patients with moderate to severe RA received ETN 50 mg once weekly for 24 weeks manufactured using the SFHCM process. Immunogenicity (presence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)) was assessed at 12 and 24 weeks.

The Path to Perfect Pediatric Posology - Drug Development in Pediatrics.

Reluctance to enroll pediatric subjects in clinical trials has left gaps in information about dosing, safety, and efficacy of medications. Pharmacotherapeutic information for pediatric patients may be available for only a small range of ages and may be deficient, as children respond differently as they grow and mature from prematurity to adolescence. Current regulations, however, require early planning for the participation of children in drug development, as pediatric plans must be submitted at the end of phase 1 (European Union) or the end of phase 2 (United States).

Assessment of the Effects of Age and Renal Function on Pharmacokinetics of Bazedoxifene in Postmenopausal Women.

Bazedoxifene (BZA), a chemically distinct selective estrogen receptor modulator, has demonstrated efficacy and long-term safety in phase 3 placebo-controlled studies for prevention and treatment of osteoporosis. Here, we assessed the potential effects of age and renal function on BZA pharmacokinetics in healthy postmenopausal women (aged 55-84 years; CLcr, 32-109 mL/min). This was an open-label, single-dose, parallel, nonrandomized inpatient study conducted in healthy postmenopausal women and postmenopausal women with impaired renal function.

Performing and interpreting individual pharmacokinetic profiles in patients with Hemophilia A or B: Rationale and general considerations.

Objectives: In a separate document, we have provided specific guidance on performing individual pharmacokinetic (PK) studies using limited samples in persons with hemophilia with the goal to optimize prophylaxis with clotting factor concentrates. This paper, intended for clinicians, aims to describe how to interpret and apply PK properties obtained in persons with hemophilia.

Methods: The members of the Working Party on population PK (PopPK) of the ISTH SSC Subcommittee on Factor VIII and IX and rare bleeding disorders, together with additional hemophilia and PK experts, completed a survey and ranking exercise whereby key areas of interest in the field were identified.

Clinical experience with moroctocog alfa (AF-CC) in younger paediatric patients with severe haemophilia A: Two open-label studies.

Introduction: The pharmacokinetics (PK), efficacy and safety of moroctocog alfa (AF-CC) have been demonstrated in haemophilia A patients aged ≥6 years.

Aim: These studies aimed to further describe moroctocog alfa (AF-CC) experience in paediatric patients (<12 years) with severe haemophilia A (FVIII:C < 1%).

Methods: Two prospective, open-label studies enrolled patients aged <12 years: one study with 37 previously treated patients (PTPs) and another with 23 previously untreated patients (PUPs).

Assessment of Relative Bioavailability of Moroctocog Alfa and Moroctocog Alfa (AF-CC) in Subjects With Severe Hemophilia A.

Unlabelled: An open-label, single-dose, randomized, two-period, crossover study comparing the pharmacokinetics of factor VIII activity in plasma (FVIII:C) after administration of an albumin-free presentation of moroctocog alfa (test) and moroctocog alfa manufactured using the previous technique (reference) was conducted in 30 (25 evaluable) male subjects who had severe hemophilia A (FVIII:C < 1 IU/dL). Blood samples were collected for 48 h after administration of each dose.

Fviii: C was assayed using a chromogenic substrate assay.

The Education of Prescribers for Safe and Effective Use of Medications.

The transformation of medical education, with the disappearance of sequential lectures in pharmacology, clinical pharmacology, and therapeutics, has left gaps in skills needed for new physicians and other prescribers to safely incorporate medications into clinical practice. Brinkman et al. conducted a Delphi study of European Union (EU) medical school educators and practitioners to identify core competencies needed to prescribe medications.

Thrombogenicity evaluation in 221 patients with haemophilia B treated with nonacog alfa.

: Risk for thrombotic events with factor IX replacement therapy in patients with haemophilia B remains a concern for patients, those who treat them, and regulatory agencies, based on experience with early use of prothrombin complex concentrates. The current post hoc analysis assessed the incidence of thrombotic events and changes in prothrombin fragment 1 + 2, thrombin-antithrombin complex, and D-dimer in 221 patients with haemophilia B who received nonacog alfa in clinical studies. Thrombotic event and coagulation marker data were collected from 8 interventional studies utilizing on-demand, prophylactic, and preventive regimens in patients with haemophilia B.

A Pilot Dose-Finding Study of Etanercept in Rheumatoid Arthritis.

A randomized, parallel-dose study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of etanercept in 61 patients with rheumatoid arthritis (RA) who received doses from 10 mg once-weekly to 50 mg twice-weekly for 4 weeks. Empiric application of a maximal-effect (E ) model to pooled steady-state concentrations (C ) and PD markers provided half-maximal-effect concentration estimates of 567, 573, 465, 87, and 159 ng/mL for change from baseline in number of swollen joints, number of painful joints, erythrocyte sedimentation rate, interleukin-6, and matrix metalloproteinase-3, respectively. C >∼2,000 ng/mL did not appear to offer additional benefit.

Core Entrustable Professional Activities in Clinical Pharmacology for Entering Residency: Biologics.

Biologicals are a rapidly expanding class of medications used in the treatment of many different conditions. This article reviews the common characteristics of this class and the requirements for safe and effective use in patients. Several vignettes are included to illustrate common challenges.

An Open-label, Single-dose, Pharmacokinetic Study of Factor VIII Activity After Administration of Moroctocog Alfa (AF-CC) in Male Chinese Patients With Hemophilia A.

Purpose: Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety.

Correction: The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study.

[This corrects the article DOI: 10.1371/journal.pone.

Lack of Effect of Rivipansel on QTc Interval in Healthy Adult African American Male Subjects.

Rivipansel is a pan-selectin inhibitor in phase 3 development for the treatment of vaso-occlusive crises in patients with sickle cell disease. This single-dose, randomized, 3-period, 3-treatment (400 mg moxifloxacin open-label, 4 g rivipansel-blinded, and placebo-blinded) crossover study evaluated the effect of rivipansel on the QT/QTc interval in 48 healthy male African American subjects (age, 21-53 years; weight, 60-115 kg). Time-matched, placebo-adjusted change from baseline QT interval using Fridericia's correction method (QTcF) was determined using a repeated-measures mixed-effects model.

The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study.

Objective: To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes.

Methods: This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose.

Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa.

This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well.