A Randomized, Placebo-Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High-Density Lipoprotein Cholesterol in Subjects With Dyslipidemia.

GPR109A (HM74A), a G-protein-coupled receptor, is hypothesized to mediate lipid and lipoprotein changes and dermal flushing associated with niacin administration. GSK256073 (8-chloro-3-pentyl-1H-purine-2,6[3H,7H]-dione) is a selective GPR109A agonist shown to suppress fatty acid levels and produce mild flushing in short-term clinical studies. This study evaluated the effects of GSK256073 on lipids in subjects with low high-density lipoprotein cholesterol (HDLc).

First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment.

This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily.

Modulation of CLA, IL-12R, CD40L, and IL-2Ralpha expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275.

Cytokines interleukin (IL)-12 and IL-23 are implicated in the pathogenesis of psoriasis. IL-12 causes differentiation of CD4+ T cells to interferon-gamma (IFN-gamma)-producing T helper 1 (Th1) cells, while IL-23 induces differentiation to IL-17-producing pathogenic Th17 cells. The effects of the monoclonal antibody to IL-12/23 p40 subunit (CNTO 1275) on IL-12 receptor (IL-12R) expression, markers associated with skin homing, activation, and cytokine secretion were investigated in vitro using human peripheral blood mononuclear cells (PBMCs) from healthy donors.

Response to pneumococcal vaccine in patients with early rheumatoid arthritis receiving infliximab plus methotrexate or methotrexate alone.

Objective: We assessed whether the addition of anti-tumor necrosis factor (TNF) agent to methotrexate (MTX) therapy might alter the response of patients with rheumatoid arthritis (RA) to pneumococcal vaccination.

Methods: Seventy patients with early RA (n = 20, 36, and 14 in the infliximab 3 mg/kg plus MTX, infliximab 6 mg/kg plus MTX, and placebo plus MTX groups, respectively) were included in an analysis of patients enrolled in an ASPIRE substudy. Patients received 0.

Effect of CYP2D6 genetic polymorphism on the population pharmacokinetics of tipifarnib.

Objective: Evaluate the effect of CYP2D6 genotype on the pharmacokinetics of tipifarnib.

Methods: A total of 268 subjects included in six clinical trials were treated orally with tablet formulation of tipifarnib, as a single dose or as multiple b.i.

Cutaneous lymphocyte antigen expression on activated lymphocytes and its association with IL-12R (beta1 and beta2), IL-2Ralpha, and CXCR3.

The majority of T lymphocytes that infiltrate psoriatic lesions express cutaneous lymphocyte antigen (CLA), a skin homing receptor involved in the influx of memory T cells to cutaneous sites. We investigated CLA expression on normal human peripheral blood mononuclear cells (PBMCs) and evaluated its association with IL-12 receptors, chemokine receptor, CXCR3, and IL-2Ralpha. PBMCs were stimulated in vitro with or without polyclonal activators (mitogen, or superantigens, or anti-CD3+anti-CD28) in the presence or absence of exogenous rhIL-12.

Co-expression of IL-12 receptors along with CXCR3 and CD25 on activated peripheral blood T lymphocytes.

IL-12 receptors (IL-12R) play a critical role in maintaining IL-12 regulation of T helper-1 (Th1) type immune responses. We studied the expression of two IL-12R, beta1 and beta2 on peripheral blood mononuclear cells (PBMCs) from normal donors, stimulated with polyclonal activators in the presence or absence of exogenous rhIL-12. Unstimulated peripheral blood T lymphocytes (PBTs) expressed moderate levels of IL-12Rbeta1 and very low to undetectable levels of IL-12Rbeta2.

A one-step, competitive electrochemiluminescence-based immunoassay method for the quantification of a fully human anti-TNFalpha antibody in human serum.

A quantitative, one-step, competitive electrochemiluminescence (ECL)-based immunoassay for the determination of a fully human, anti-TNFalpha monoclonal antibody in human serum has been developed. A biotinylated, mouse anti-variable region-specific antibody and a ruthenium-labeled anti-TNFalpha antibody were the only specific reagents needed to develop the assay. A single incubation step of 2 h followed by ECL detection was used.

Validation of immunoassays used to assess immunogenicity to therapeutic monoclonal antibodies.

Immunogenicity has always been an important consideration in the evaluation of pharmaceutical protein biologics. In this article, method validation parameters relevant to enzyme immunoassays are described for assays applied to the analysis of anti-drug antibodies, with special considerations for immunogenicity to therapeutic monoclonal antibodies. Common strategies for experimental investigation of various validation parameters are proposed.

Population pharmacokinetic modeling of a subcutaneous depot for GnRH antagonist degarelix.

Purpose: The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone (GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose-concentration dependent absorption.

Methods: The PK analysis is made in NONMEM through joint analysis of data from two phase I clinical studies; an intravenous infusion study and a single SC dose escalation study. The SC absorption is modeled using an approximation to Ficks' second law of diffusion out of a spherical depot.

The pharmacokinetics of sumatriptan when administered with norethindrone 1 mg/ethinyl estradiol 0.035 mg in healthy volunteers.

Background: Because the majority of migraineurs are young women in their peak reproductive years, it is important to understand the possible effects on the pharmacokinetics of both medications when sumatriptan is coadministered with an oral contraceptive (OC).

Objectives: The primary objective of this study was to assess the effect of multiple dosing of the OC norethindrone 1 mg/ethinyl estradiol 0.035 mg (NE/EE) on the single-dose pharmacokinetics of sumatriptan in healthy volunteers.

Human microdialysis.

Microdialysis has been used extensively in animal studies for decades and in human pharmacokinetic studies for about 10 years. Microdialysis is based on the passive diffusion of a compound along its concentration gradient from the tissue through the membrane into the dialysate. Microdialysis samples from the interstitial space which is a defined, anatomical compartment; there is no net loss of body fluid; the sample is "purified" and no enzymatic degradation takes place because proteins do not pass through the probe membrane into the dialysate; microdialysis data relate to the intact molecule; time resolution is high compared to biopsy and skin blister techniques; radioabelling or induction of a magnetic response is not needed; microdialysis is also an alternative method to determine protein binding of a compound in vivo; microdialysis can readily be set up in clinical research units without expensive infrastructure.

The pharmacokinetics of sumatriptan when administered with clarithromycin in healthy volunteers.

Background: Macrolide antibiotics such as clarithromycin are potent inhibitors of the cytochrome P450 (CYP)3A4 isozyme and have the potential to attenuate the metabolism and increase blood concentrations of drugs metabolized by this pathway. In vitro studies have suggested that sumatriptan is metabolized primarily by the monoamine oxidase-A isozyme and not by CYP3A4.

Objective: This study sought to determine the effect of coadministration of clarithromycin dosed to steady state on the pharmacokinetics of a single dose of sumatriptan.

Simultaneous quantification of proinflammatory cytokines in human plasma using the LabMAP assay.

There is an emerging trend in the pharmaceutical industry to evaluate a variety of surrogate biomarkers in Phase I/II clinical studies with the intention of determining potential activity of drugs early in clinical development. A number of cytokines expressed in pathological conditions are currently being considered as potential surrogates of disease and/or drug activity. The quantitative measurement of such analytes (biomarkers) in biological fluids has traditionally been performed by bioassays, enzyme-linked immunosorbent assay (ELISA), ribonuclease protection assay (RPA) and polymerase chain reaction (PCR).

Pharmacokinetics and tolerability of GW420867X, a nonnucleoside reverse transcriptase inhibitor, following single escalating doses in healthy male volunteers.

The aim of the current study was to characterize the pharmacokinetics of GW420867X, a new nonnucleoside reverse transcriptase inhibitor, using a single escalating dose protocol in healthy volunteers. Four dose levels were investigated in sequential order: 300, 600, 900, and 1200 mg, with a ratio of 4:1 subjects receiving active or placebo treatment, respectively. Following single-dose administration, GW420867X was readily absorbed with a median time to peak concentration of 3 to 5 hours.

The clinical pharmacology of fluconazole.

The pharmacokinetic profile of fluconazole clearly distinguishes it from other antifungal agents; oral bioavailability is more than 90%, and plasma protein binding is 12%. The volume of distribution approximates that of total body water. Both peak and minimum plasma concentrations are linearly proportional to dose over a range of 50 to 400 mg.