Candidate inflammatory biomarkers display unique relationships with alpha-synuclein and correlate with measures of disease severity in subjects with Parkinson's disease.

BACKGROUND: Efforts to identify fluid biomarkers of Parkinson's disease (PD) have intensified in the last decade. As the role of inflammation in PD pathophysiology becomes increasingly recognized, investigators aim to define inflammatory signatures to help elucidate underlying mechanisms of disease pathogenesis and aid in identification of patients with inflammatory endophenotypes that could benefit from immunomodulatory interventions. However, discordant results in the literature and a lack of information regarding the stability of inflammatory factors over a 24-h period have hampered progress. METHODS: Here, we measured inflammatory proteins in serum and CSF of a small cohort of PD (n = 12) and age-matched healthy control (HC) subjects (n = 6) at 11 time points across 24 h to (1) identify potential diurnal variation, (2) reveal differences in PD vs HC, and (3) to correlate with CSF levels of amyloid ß (Aß) and α-synuclein in an effort to generate data-driven hypotheses regarding candidate biomarkers of PD. RESULTS: Despite significant variability in other factors, a repeated measures two-way analysis of variance by time and disease state for each analyte revealed that serum IFNγ, TNF, and neutrophil gelatinase-associated lipocalin (NGAL) were stable across 24 h and different between HC and PD. Regression analysis revealed that C-reactive protein (CRP) was the only factor with a strong linear relationship between CSF and serum. PD and HC subjects showed significantly different relationships between CSF Aß proteins and α-synuclein and specific inflammatory factors, and CSF IFNγ and serum IL-8 positively correlated with clinical measures of PD. Finally, linear discriminant analysis revealed that serum TNF and CSF α-synuclein discriminated between PD and HC with a minimum of 82% sensitivity and 83% specificity. CONCLUSIONS: Our findings identify a panel of inflammatory factors in serum and CSF that can be reliably measured, distinguish between PD and HC, and monitor inflammation as disease progresses or in response to interventional therapies. This panel may aid in generating hypotheses and feasible experimental designs towards identifying biomarkers of neurodegenerative disease by focusing on analytes that remain stable regardless of time of sample collection.

Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies.

PURPOSE: The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. METHODS: In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood. RESULTS: Mean maximum plasma concentration (C max) and area under total plasma concentration­time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5­7 days for all doses. C max and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses. CONCLUSIONS: Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.

Clinical pharmacology of AMG 181, a gut-specific human anti-α4ß7 monoclonal antibody, for treating inflammatory bowel diseases.

AIMS: AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS: Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 ß7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS: Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear ß-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 µg ml(-1) . The PD effect on α4 ß7 RO showed an EC50 of 0.01 µg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS: AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.

Robust central reduction of amyloid-ß in humans with an orally available, non-peptidic ß-secretase inhibitor.

According to the amyloid cascade hypothesis, cerebral deposition of amyloid-ß peptide (Aß) is critical for Alzheimer's disease (AD) pathogenesis. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aß-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aß reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aß reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.

Pharmacokinetics, Safety, and Tolerability of a Single 500-mg or 1000-mg Intravenous Dose of Dalbavancin in Healthy Japanese Subjects.

BACKGROUND AND OBJECTIVES: Dalbavancin is a novel, once-weekly glycopeptide antibiotic approved for treatment of acute bacterial skin infections. Given the importance of understanding any pharmacokinetic variability across different patient populations, a double-blind, placebo-controlled study was conducted to evaluate the pharmacokinetics, safety, and tolerability of a single 500-mg and a single 1000-mg intravenous dose of dalbavancin in healthy Japanese subjects. METHODS: Ten subjects received intravenous dalbavancin 1000 mg, five subjects received intravenous dalbavancin 500 mg, and three subjects received intravenous placebo. RESULTS: After a single infusion of dalbavancin, the maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC) increased in a proportional manner from 500 mg to 1000 mg (C max: 157 µg/ml and 299 µg/ml; AUClast: 10,850 µg·h/ml and 22,679 µg·h/ml, on the 500-mg and 1000-mg regimens, respectively) with low inter-subject variability. The mean terminal phase half-life (t 1/2) was 204 and 193 h after the 500-mg and 1000-mg dose, respectively. Clearance and volume of distribution were similar for the two dose concentrations. Treatment-emergent adverse events reported were considered to be of mild intensity. There were no relevant changes in laboratory values or vital signs over time in subjects in either treatment group. CONCLUSIONS: Overall, dalbavancin 500 mg and dalbavancin 1000 mg, administered as a single 30-min infusion, was well tolerated in this population and resulted in plasma exposures similar to those in non-Asians.

Safety, pharmacokinetics and pharmacodynamics of four-hour intravenous infusions of eritoran in healthy Japanese and Caucasian men.

Eritoran, a synthetic analogue of lipid A, has been shown to bind to TLR4/MD-2 complex and thereby block the interaction of endotoxins with TLR4. We report here the results of a study conducted to assess the single-dose safety and tolerability, as well as the pharmacokinetics and pharmacodynamics, of eritoran infusion in Japanese and Caucasian healthy adult men. Sixty-four men (aged 20-45 years; body mass index 18-30 kg/m(2)) were randomized into four groups: 4-mg total dose (six Japanese and six Caucasian men); 12-mg total dose (12 Japanese and 12 Caucasian men); 28-mg total dose (six Japanese and six Caucasian men); and placebo (eight Japanese and eight Caucasian men). Eritoran in single doses up to 28 mg over 4 h was well tolerated, with no apparent ethnic differences noted. Plasma concentrations were slightly higher in Japanese versus Caucasian men; these differences were not significant after adjustment for differences in body mass (clearance: approximately 1.2 ml/h/kg; volume of distribution at steady state: approximately 0.07 l/kg). The ex vivo endotoxin inhibitory activity of eritoran was similar in Japanese and Caucasian men. The data do not indicate any need for clinical dose adjustment for possible ethnic-based differences in drug distribution or metabolism.

Cerebrospinal fluid beta-amyloid and dynabridging in Alzheimer's disease drug development.

Cerebrospinal fluid (CSF) has become a matrix for biomarker discovery and development in recent years. A number of biomarkers for pathogenic processes in Alzheimer's disease have been identified. Studies have revealed the diagnostic potential of CSF amyloid-beta, tau and phosphorylated tau levels. California Clinical Trials has conducted a number of studies in collaboration with drug developers that demonstrate the importance of CSF amyloid-beta peptides as biomarkers for drug development. These studies also establish the utility of CSF sampling via continuous indwelling lumbar catheterization (dynabridging) for assessing pharmacokinetic and pharmacodynamic parameters in conjunction with biomarker analysis. Corroborative approaches using multiple biomarker methods including neuroimaging and CSF biomarkers will provide a complete picture of the Alzheimer's disease brain.