A large multicentre, randomized, double-blind, cross-over study in healthy volunteers to compare pharmacokinetics, pharmacodynamics and safety of a pegfilgrastim biosimilar with its US- and EU-reference biologics.

Aims: Recombinant PEGylated human granulocyte colony-stimulating factor (pegfilgrastim) is indicated for the reduction of chemotherapy-induced neutropenia and prevention of febrile neutropenia. Biosimilar pegfilgrastim is expected to reduce the financial burden of this complication of chemotherapy. The aim of this study was to demonstrate biosimilarity between Sandoz biosimilar pegfilgrastim and its US- and EU-approved reference biologics.

Differences in immunogenicity associated with non-product related variability: insights from two pharmacokinetic studies using GP2017, an adalimumab biosimilar.

: Antidrug antibody (ADA) development is known to occur with adalimumab treatment and impacts adalimumab exposure. Here, we compare the impact of immunogenicity on pharmacokinetics (PK) across two randomized PK studies of GP2017, an approved biosimilar adalimumab, in healthy subjects. : Healthy male subjects (= 107 in study GP17-104; = 90 in study GP17-103) received a single 40 mg subcutaneous injection of the same GP2017 drug product batch.

Proposed biosimilar pegfilgrastim shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects.

Aims: This study aimed to demonstrate that the pharmacokinetic (PK) and pharmacodynamic (PD) profile of Sandoz proposed biosimilar pegfilgrastim (LA-EP2006) matches reference pegfilgrastim (Neulasta ) in healthy subjects. Safety and immunogenicity were also assessed.

Methods: The phase I, randomized, double-blind, two-period crossover study consisted of two treatment periods separated by an 8-week washout period.

Application of Pharmacometric Analysis in the Design of Clinical Pharmacology Studies for Biosimilar Development.

This article provides an overview of four case studies to demonstrate the utility of pharmacometric analysis in biosimilar development to help design sensitive clinical pharmacology studies for the demonstration of biosimilarity. The two major factors that determine the sensitivity of a clinical pharmacokinetic/pharmacodynamic (PK/PD) study to demonstrate biosimilarity are the size of the potential difference to be detected (signal) and the inter-subject variability (noise), both of which can be characterized and predicted using pharmacometric approaches. To maximize the chance to detect any potential difference between the proposed biosimilar and the reference drug, the dose selected for the clinical pharmacology study should fall on the steep part of the dose-response curve.

GP2015, a proposed etanercept biosimilar: Pharmacokinetic similarity to its reference product and comparison of its autoinjector device with prefilled syringes.

Aims: To assess pharmacokinetics (PK) and safety of GP2015, a proposed etanercept biosimilar, in two studies: comparison with etanercept originator (ETN, bioequivalence study) and comparison of GP2015 administered via an autoinjector (AI) or prefilled syringes (PFS, delivery study).

Methods: Both studies were randomized, two-sequence, two-period, crossover studies conducted in healthy male subjects. In the bioequivalence study, subjects were randomized to receive a single 50 mg subcutaneous (s.

Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses.

Background: Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that binds IgE with higher affinity than omalizumab.

Objective: This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma.

Integrated pharmacokinetic, pharmacodynamic and immunogenicity profiling of an anti-CCL21 monoclonal antibody in cynomolgus monkeys.

QBP359 is an IgG1 human monoclonal antibody that binds with high affinity to human CCL21, a chemokine hypothesized to play a role in inflammatory disease conditions through activation of resident CCR7-expressing fibroblasts/myofibroblasts. The pharmacokinetics (PK) and pharmacodynamics (PD) of QBP359 in non-human primates were characterized through an integrated approach, combining PK, PD, immunogenicity, immunohistochemistry (IHC) and tissue profiling data from single- and multiple-dose experiments in cynomolgus monkeys. When compared with regular immunoglobulin typical kinetics, faster drug clearance was observed in serum following intravenous administration of 10 mg/kg and 50 mg/kg of QBP359.

Pharmacokinetic and pharmacodynamic characteristics of single-dose Canakinumab in patients with type 2 diabetes mellitus.

Purpose: Interleukin (IL)-1β, an inflammatory molecule, contributes to the development of atherothrombosis and worsening of islet β-cell function. Canakinumab, a human monoclonal antibody, targets IL-1β-dependent inflammation and reduces the vascular inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), and other inflammatory cardiovascular biomarkers. Here, we aimed to assess the pharmacokinetic (PK) and pharmacodynamic characteristics, including the effect on hsCRP, of canakinumab in patients with type 2 diabetes mellitus (T2DM) after a 2-hour single-dose intravenous infusion.

Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects.

Background: Using a monoclonal antibody with greater affinity for IgE than omalizumab, we examined whether more complete suppression of IgE provided greater pharmacodynamic effects, including suppression of skin prick responses to allergen.

Objective: To explore the pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity humanized monoclonal IgG1κ anti-IgE.

Methods: Preclinical assessments and two randomized, placebo-controlled, double-blind clinical trials were conducted in atopic subjects.

Safety and tolerability of canakinumab, an IL-1β inhibitor, in type 2 diabetes mellitus patients: a pooled analysis of three randomised double-blind studies.

Background: We aimed to assess the safety and tolerability of different doses of canakinumab versus placebo in patients with type 2 diabetes mellitus (T2DM).

Methods: Data were pooled from three studies in 1026 T2DM patients with different routes of administration, treatment regimens and follow-up duration. Canakinumab groups were categorised as low (0.

Pharmacokinetic and pharmacodynamic properties of canakinumab in patients with gouty arthritis.

Pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1β monoclonal antibody, canakinumab, in gouty arthritis patients from three studies are reported. Canakinumab has low serum clearance (0.214 L/day), low steady-state volume of distribution (7.

Bioequivalence of canakinumab liquid pre-filled syringe and reconstituted lyophilized formulations following 150 mg subcutaneous administration: a randomized study in healthy subjects.

Background: Canakinumab is a human anti-interleukin-1beta antibody approved for the treatment of cryopyrin associated periodic syndrome currently formulated as a lyophilized powder requiring reconstitution. A new formulation (solution for injection as pre-filled syringe) has been developed to avoid reconstitution.

Objective: The objective of this study was to evaluate the bioequivalence of pre-filled syringe and reconstituted formulations following 150 mg administration in healthy subjects.

A phase I study of zoledronic acid and low-dose cyclophosphamide in recurrent/refractory neuroblastoma: a new approaches to neuroblastoma therapy (NANT) study.

Background: Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases.

Investigation of the pharmacokinetic interactions of deferasirox, a once-daily oral iron chelator, with midazolam, rifampin, and repaglinide in healthy volunteers.

Deferasirox, a newly developed iron chelator, was coadministered orally with either a known inducer of drug metabolism or with cosubstrates for cytochrome P450 (CYP) to characterize the potential for drug-drug interactions. In the induction assessment, single-dose deferasirox pharmacokinetics were obtained in the presence and absence of a repeated-dose regimen of rifampin. In the CYP3A interaction evaluation, midazolam and its active hydroxylated metabolite were assessed after single doses of midazolam in the presence and absence of steady-state concentrations of deferasirox.

In vitro and in vivo induction of cytochrome p450: a survey of the current practices and recommendations: a pharmaceutical research and manufacturers of america perspective.

Cytochrome P450 (P450) induction is one of the factors that can affect the pharmacokinetics of a drug molecule upon multiple dosing, and it can result in pharmacokinetic drug-drug interactions with coadministered drugs causing potential therapeutic failures. In recent years, various in vitro assays have been developed and used routinely to assess the potential for drug-drug interactions due to P450 induction. There is a desire from the pharmaceutical industry and regulatory agencies to harmonize assay methodologies, data interpretation, and the design of clinical drug-drug interaction studies.

Biodistribution and plasma protein binding of zoledronic acid.

The bisphosphonate zoledronic acid is a potent inhibitor of osteoclast-mediated bone resorption. To investigate drug biodistribution and elimination, (14)C-zoledronic acid was administered intravenously to rats and dogs in single or multiple doses and assessed for its in vitro blood distribution and plasma protein binding in rat, dog, and human. Drug exposure in plasma, bones, and noncalcified tissues was investigated up to 240 days in rats and 96 h in dogs using radiometry after dissection.

The clinical pharmacokinetics of darifenacin.

Darifenacin hydrobromide is a selective muscarinic M(3) receptor antagonist that is indicated for use in treatment of overactive bladder disorder. Darifenacin was found to have a short terminal elimination half-life after intravenous and immediate-release oral dosage forms (3-4 hours) but this increased with a prolonged-release (PR) formulation (14-16 hours). The absolute bioavailability of darifenacin from 7.

FTY720, a novel immunomodulator in de novo kidney transplant patients: pharmacokinetics and exposure-response relationship.

The pharmacokinetics, safety, and preliminary efficacy of FTY720, a novel immunomodulator, were examined in de novo renal transplant patients. Both noncompartmental and population methods were used to estimate pharmacokinetic estimates in the patients. The steady-state plasma concentrations of FTY720 increased in accordance with maintenance dose level, indicating linearity in clearance and volume of distribution over the 0.

QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M3 selective receptor antagonist for the treatment of overactive bladder.

Prolongation of QT interval on an electrocardiogram is a valuable predictor of a drug's ability to cause potentially fatal ventricular tachyarrhythmia (torsades de pointes). Darifenacin is a muscarinic M3 selective receptor antagonist developed for the treatment of overactive bladder, a debilitating condition that is particularly prevalent in the older population. This 7-day, randomized, parallel-group study (n=188) measured QT/QTc interval in healthy volunteers receiving once-daily darifenacin at steady-state therapeutic (15 mg) and supratherapeutic (75 mg) doses, alongside controls receiving placebo or moxifloxacin (positive control, 400 mg) once daily.

Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients.

FTY720 is a new and effective immunosuppressive agent, which produces peripheral blood lymphopenia through a lymphocyte homing effect. We investigated the relationship between the dose of FTY720 or blood concentration (pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23 kidney transplant recipients randomized to receive FTY720 (0.25-2.

Bioavailability and bioequivalence trials: statistics & pharmacokinetic principles.

This document has been prepared as a set of workshop material, which will be presented in the International Congress on Medical and Care Compunetics in June 2004 in Den Hague, The Netherlands. The workshop is divided into two parts and deals with the fundamentals of the bioavailability and bioequivalence studies. First part of the workshop deals with the pharmacokinetic principles, and the second part discusses the statistical approaches and the data analysis using the Statistical Analysis Software (SAS).

Effect of age on the pharmacokinetics of duloxetine in women.

Aims: The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence.

Methods: Twenty-four healthy subjects (12 women 65-77 years, and 12 women 32-50 years) were given a single 40-mg oral dose of duloxetine in Study 1. Plasma concentration-time data were analysed by noncompartmental pharmacokinetic methods.

Comparative bioequivalence studies with Estradot and Menorest transdermal systems.

Objectives: To compare the relative bioavailability of Estradot, a small size, new generation estradiol transdermal system (ETS) to Menorest, in healthy postmenopausal women.

Methods: In two open-label, single center, randomized, crossover, bioequivalence studies, healthy postmenopausal women aged 40-65 years received treatment with all the test regimens. In Study 1 (single-dose study), patients wore 5 cm(2) (50 microg/day), 10 cm(2) (100 microg/day) Estradot and 29 cm(2) (100 microg/day) Menorest for 84 h.

Dose proportionality study of four doses of an estradiol transdermal system, Estradot.

Objectives: To establish dose proportionality among four doses of a new estradiol transdermal system (ETS), Estradot, in healthy postmenopausal women and to evaluate the wear and irritation properties of the ETS.

Methods: In an open label, single-dose, randomized, four-period crossover study, healthy postmenopausal women, age range 44-64 years, wore four different sizes of Estradot, 2.5, 3.