Donald G. Raible

Pathways Activated during Human Asthma Exacerbation as Revealed by Gene Expression Patterns in Blood

Background Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations. Methodology/Principal Findings Over the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations. Conclusions/Significance This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.

Effects of age and sex on single-dose pharmacokinetics of tigecycline in healthy subjects.

ABSTRACT The pharmacokinetics of tigecycline was evaluated in 46 healthy young and elderly men and women. Except for the volumes of distribution at steady state (approximately 350 liters in women versus 500 liters in men), there were no significant differences in tigecycline pharmacokinetic parameters. Based on pharmacokinetics, no dosage adjustment is warranted based on age or sex.

Evaluation of a Potential Tigecycline‐Warfarin Drug Interaction

Study Objective. To evaluate the potential for a clinically significant drug interaction between tigecycline and warfarin by using pharmacokinetic and anticoagulant assessments.

Absence of an interaction between tigecycline and digoxin in healthy men.

Study Objective. To evaluate a potential interaction between tigecycline and digoxin using pharmacokinetic and pharmacodynamic assessments.

Tigecycline Pharmacokinetics in Subjects With Various Degrees of Renal Function

The pharmacokinetic parameters of tigecycline were assessed in subjects with severe renal impairment (creatinine clearance <30 mL/min, n = 6), subjects receiving hemodialysis (4 received tigecycline before and 4 received tigecycline after hemodialysis), and subjects with age‐adjusted, normal renal function (n = 6) after administration of single 100‐mg doses. Serial serum and urine samples were collected and assayed using validated liquid chromatography with tandem mass spectrometer (LC/MS/MS) methods. Concentration‐time data were then analyzed using noncompartmental pharmacokinetic methods. Tigecycline renal clearance in subjects with normal renal function represented approximately 20% of total systemic clearance. Tigecycline clearance was reduced by approximately 20%, and area under the tigecycline concentration‐time curve increased by approximately 30% in subjects with severe renal impairment. Tigecycline was not efficiently removed by dialysis; thus, it can be administered without regard to timing of hemodialysis. Based on these pharmacokinetic data, tigecycline requires no dosage adjustment in patients with renal impairment.

Integrated Population Pharmacokinetics of Etanercept in Healthy Subjects and in Patients With Rheumatoid Arthritis Ankylosing Spondylitis

Etanercept pharmacokinetics in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis were assessed separately with distinct models using population pharmacokinetics methods of limited precision. The different model structures and associated significant covariates identified by these earlier methods made it difficult to compare etanercept pharmacokinetics among disease groups. This integrated analysis aimed to establish a framework to evaluate previously established population pharmacokinetic models of etanercept, and to identify consistent and important demographic and disease factors that affected etanercept pharmacokinetics in a diverse population of healthy subjects and patients with RA and AS. In this integrated analysis, cumulative rich and sparse etanercept concentration data from 53 healthy volunteers, 212 patients with RA, and 346 patients with AS were examined and compared using nonlinear mixed effect methodology implemented the in NONMEM VI software package. A more precise estimation method (FOCEi) was employed and compared with the first‐order method in population pharmacokinetics model building and evaluation. The integrated analysis found that an optimal population pharmacokinetics model with a 2‐compartment structure adequately characterized etanercept pharmacokinetics in all subject groups. Health status or disease type did not significantly affect etanercept pharmacokinetics. In adult patients with RA and AS, age and body weight do not significantly affect etanercept pharmacokinetics.

Pharmacokinetic‐Pharmacodynamic Modeling of Apratastat: A Population‐Based Approach

Apratastat is an orally active, potent, and reversible dual inhibitor of tumor necrosis factor‐α converting enzyme (TACE) and matrix metalloproteinases (MMPs). This study characterizes the pharmacodynamic (PD) effect of apratastat following oral administration on tumor necrosis factor‐alpha (TNF‐α) release. Data were obtained from 3 clinical studies carried out in healthy subjects. Apratastat was administered orally in these studies as single doses or multiple doses (twice daily). The inhibition of TNF‐α release by apratastat was investigated in studies of in vitro, ex vivo, and in vivo. Inhibitory Emax models were used to characterize the inhibition of TNF‐α release in both in vitro and ex vivo studies. Apratastat inhibited TNF‐α release with a population mean IC50 of 144 ng/mL in vitro and of 81.7 ng/mL ex vivo, respectively. The relationship between TNF‐α and apratastat plasma concentration in the endotoxin‐challenged study in healthy subjects was well characterized by a mechanism‐based PD population model with IC50 of 126 ng/mL. Apratastat can potently inhibit the release of TNF‐α in vitro, ex vivo, and in vivo. Even though the dosage provided adequate exposure to inhibit TNF‐α release, apratastat was not efficacious in rheumatoid arthritis (RA). This inconsistency between TNF‐α inhibition and the clinical response requires further investigation.