Forward and reverse translational approaches to predict efficacy of neutralizing respiratory syncytial virus (RSV) antibody prophylaxis.

Background: Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.

V ACHER: Visualization of complex trial data in pharmacometric analyses with covariates.

Pharmacometric models can enhance clinical decision making, with covariates exposing potential contributions to variability of subpopulation characteristics, for example, demographics or disease status. Intuitive visualization of models with multiple covariates is needed because sparsity of data in visualizations trellised by covariate values can raise concerns about the credibility of the underlying model. V ACHER, introduced here, is a stepwise transformation of data that can be applied to a variety of static (non-ordinary-differential-equation-based) pharmacometric analyses.

Pharmacokinetics and pharmacodynamics of the cytolytic anti-CD38 human monoclonal antibody TAK-079 in monkey - model assisted preparation for the first in human trial.

We are studying the fully human, IgG1λ cytolytic monoclonal antibody TAK-079, which binds CD38. CD38 is expressed on plasma and natural killer (NK) cells constitutively and upregulated on subsets of B and T lymphocytes upon activation. TAK-079 cross-reacts with CD38 expressed by cynomolgus monkeys and depletes subsets of NK, B, and T cells.

Pharmacokinetic/Pharmacodynamic Modeling of the PDE4 Inhibitor TAK-648 in Type 2 Diabetes: Early Translational Approaches for Human Dose Prediction.

TAK-648 is a PDE4 inhibitor with demonstrated preclinical antidiabetic properties. Our objective was to develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for human type 2 diabetes (T2D) dose prediction using HbA results from a db/db mouse study. Estimated parameters in combination with tPDE4i values calculated for the clinical roflumilast dose of 500 μg were used to translate preclinical effects of TAK-648 to required exposure in humans.

The variability in beta-cell function in placebo-treated subjects with type 2 diabetes: application of the weight-HbA1c-insulin-glucose (WHIG) model.

Aim: The weight-glycosylated haemoglobin (HbA1C)-insulin-glucose (WHIG) model describes the effects of changes in weight on insulin sensitivity (IS) in newly diagnosed, obese subjects receiving placebo treatment. This model was applied to a wider population of placebo-treated subjects, to investigate factors influencing the variability in IS and β-cell function.

Methods: The WHIG model was applied to the WHIG dataset (Study 1) and two other placebo datasets (Studies 2 and 3).

Exploratory Literature Meta-Analysis to Characterize the Relationship Between Early and Longer Term Body Weight Loss for Antiobesity Compounds.

The presented analysis was performed to characterize the relationship between treatment-related early (week 4) and longer term (3-6 months) weight loss to understand the potential utility of 4-week proof-of-mechanism studies in the early decision-making process during clinical development of new antiobesity compounds. A regression-based meta-analysis was performed leveraging publically available clinical outcomes data to (1) characterize the within-trial relationship between treatment-related early and longer term body weight loss and (2) identify and quantify key covariate effects on this relationship. Data from 89 randomized clinical trials with 209 treatment arms, representing observations from 54 461 patients and 9 treatments, were available for the meta-analysis.

Population pharmacokinetic meta-analysis to bridge ferumoxytol plasma pharmacokinetics across populations.

Background: Ferumoxytol is approved for the treatment of iron-deficiency anaemia (IDA) in adult patients with chronic kidney disease (CKD). Ferumoxytol has recently been investigated for use in all-cause IDA. This analysis was employed to bridge ferumoxytol pharmacokinetics (PK) across populations of healthy subjects and patients with CKD on haemodialysis, and to then make informed inferences regarding the PK behaviour of ferumoxytol in the all-cause IDA population.

Utility of a population pharmacokinetic meta analysis during the approval process of teduglutide for the treatment of short bowel syndrome.

Objective: Teduglutide is a recombinant analogue of human glucagonlike peptide-2 (GLP-2) that was recently approved by the US and European regulatory agencies FDA and EMA for the treatment of short bowel syndrome (SBS). The objectives of this work were, firstly, to develop a population pharmacokinetic (popPK) model based on the available PK data of the entire clinical development program and, secondly, to utilize the model for the justification of the proposed dosing regimen. The exploratory analysis was based on a previously established structural PK model and focused primarily on the investigation of covariate effects.

An innovative phase I population pharmacokinetic approach to investigate the pharmacokinetics of an intranasal fentanyl spray in healthy subjects.

Background: Intranasal Fentanyl Spray (INFS) was developed for the treatment of breakthrough pain (BTP) in cancer patients using a new route of administration. Dose strengths of 50, 100, and 200 μg INFS (Instanyl®) are currently on the market, however, some adult cancer patients with BTP may require higher doses up to 400 μg INFS.

Objective: As pharmacokinetic (PK) samples from cancer patients with BTP are hard to obtain, PK of 400 μg INFS was investigated in healthy volunteers.

Pharmacokinetics of linezolid in bone tissue investigated by in vivo microdialysis.

Pharmacokinetics of unbound anti-infectives in bone is difficult to characterize. The aim of this study was to assess the feasibility of the microdialysis technique to cancellous bone for single dose pharmacokinetic investigations of the anti-infective linezolid. Serial bone biopsies (left tibia) and microdialysate samples (right tibia: 2 catheters) as well as plasma and bone marrow samples were obtained from 10 pigs.

Effect of severity of sepsis on tissue concentrations of linezolid.

Objectives: In the present study, we examined whether differences in the severity of sepsis translate to differences in the pharmacokinetic profile of linezolid in plasma and the interstitium of target tissues after a single intravenous dose of 600 mg by means of the microdialysis technique.

Patients And Methods: A total of 24 patients were included in the trial. Sixteen patients suffered from septic shock and eight patients presented with severe sepsis.

Does linezolid inhibit its own metabolism? Population pharmacokinetics as a tool to explain the observed nonlinearity in both healthy volunteers and septic patients.

Few studies investigating the population pharmacokinetics of linezolid in critically ill patients have been reported, yielding controversial results. Therefore, a population pharmacokinetic analysis using NONMEM was performed to thoroughly understand the pharmacokinetics of unbound linezolid in plasma. Data were obtained from 10 healthy volunteers and 24 septic patients.

Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of critically ill patients after multiple dosing using microdialysis.

The antimicrobial agent linezolid is approved for the treatment of severe infections caused by, e.g., methicillin-resistant Staphylococcus strains.

Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings.

Therapeutic drug monitoring (TDM) is gaining importance for improving the success of antiretroviral treatment in human immunodeficiency virus-infected patients. However, enfuvirtide (ENF) concentrations are not regularly determined. The objective of this work was to study the pharmacokinetics (PK) of ENF in patients treated in routine clinical settings, to develop a population PK model describing the concentration-time profile, and to establish PK reference values.

Urea as an endogenous surrogate in human microdialysis to determine relative recovery of drugs: analytics and applications.

During in vivo microdialysis studies time-consuming and laborious bedside calibration methods, e.g. retrodialysis, have to be performed.

Microdialysis--theoretical background and recent implementation in applied life-sciences.

In the past decade microdialysis has become a method of choice in the study of unbound tissue concentrations of both endogenous and exogenous substances. Microdialysis has been shown to offer information about substances directly at the site of action while being well tolerable and safe. The large variety of its field of application has been demonstrated.

Successful management of discovered pH dependence in vancomycin recovery studies: novel HPLC method for microdialysis and plasma samples.

Vancomycin is a glycopeptide antibiotic approved for the treatment of serious infections or patients allergic to beta-lactams. A rapid HPLC assay using UV detection for the determination in microdialysate and human plasma was developed. After sample preparation, using methanol and trichloroacetic acid for plasma and water for microdialysate, 20 microL were injected and separated on a RP(18) column.