Qinying Zhao

Disease progression model for cognitive deterioration from Alzheimer's Disease Neuroimaging Initiative database

A mathematical model was developed to describe the longitudinal response in Alzheimers Disease Assessment Scale‐cognitive (ADAS‐cog) obtained from the Alzheimers Disease Neuroimaging Initiative.

Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study.

ObjectivesPonezumab is a humanized antiamyloid beta (A&bgr;) monoclonal antibody designed to treat Alzheimer disease (AD). MethodsThis randomized, double-blind, single-dose-escalation study evaluated the safety, pharmacokinetics, and pharmacodynamics of 0.1, 0.3, 1, 3, and 10 mg/kg ponezumab (n = 4, 4, 4, 6, and 8, respectively) versus placebo (n = 11) after a 2-hour intravenous infusion in subjects with mild-to-moderate AD. Cerebrospinal fluid (CSF) samples were obtained from the 1- and 10-mg/kg groups at baseline and at day 29. The subjects were followed for 1 year. ResultsAll subjects completed the trial. Ponezumab was well tolerated with no drug-attributed serious adverse events. The most common adverse events were upper respiratory tract infection, headache, and back pain, all mild to moderate. One subject (10 mg/kg) experienced a mild hypersensitivity reaction. Another subject (0.1 mg/kg) demonstrated slight enlargement of a preexisting midbrain lesion. Electrocardiography and laboratory values (including CSF) were unremarkable. No evidence of new microhemorrhage, vasogenic edema, or meningoencephalitis was noted. Plasma maximum observed concentration increased approximately dose proportionally, and the area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUCinf) increased slightly more than dose proportionally. Mean terminal half-life was approximately 6 weeks. Two subjects (10 mg/kg) had measurable CSF ponezumab concentrations (~0.5% of plasma values) at day 29. Plasma A&bgr;1-x and A&bgr;1-40 increased dose dependently, and mean CSF A&bgr;1-x increased 38% from baseline with 10 mg/kg (P = 0.002 vs placebo). ConclusionsA 2-hour infusion of 0.1 to 10 mg/kg ponezumab was well tolerated in subjects with mild-to-moderate AD. Plasma pharmacokinetic profile was approximately linear. Plasma A&bgr; increased with dose, and CSF A&bgr; increased at the highest dose, suggesting that intravenous ponezumab alters central A&bgr; levels.

Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease.

ObjectivePonezumab (PF-04360365) is a humanized anti–amyloid beta (A&bgr;) monoclonal antibody designed for treatment of Alzheimer disease (AD). A single 2-hour intravenous infusion of 0.1 to 10 mg/kg was previously shown to be safe and well tolerated in subjects with mild to moderate AD, with measurable effects on plasma and cerebrospinal fluid A&bgr;. This phase I, dose-escalation, open-label study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single 10-minute intravenous infusion. MethodsSubjects with mild to moderate AD received ponezumab 1 mg/kg (n = 3), 3 mg/kg (n = 3), 5 mg/kg (n = 4), or 10 mg/kg (n = 5). They were followed up as outpatients for 6 months. ResultsAll subjects completed the trial. Ponezumab was safe and well tolerated with no deaths, withdrawals, or drug-related moderate, severe, or serious adverse events. Mild drug-related adverse events included headache (3 patients) and lethargy and hypoesthesia (both in 1 patient). No infusion reactions, clinically meaningful laboratory abnormalities, vital sign changes, electrocardiographic changes, or antidrug antibodies were detected. There was no evidence of brain microhemorrhage, vasogenic edema, encephalitis, or other imaging abnormality. Cognitive function showed no treatment-related trends. Ponezumab displayed approximately dose-proportional increases in plasma exposure. Steady-state volume of distribution was 113 to 172 mL/kg, clearance was 2.7 to 3.0 mL/d/kg, and terminal half-life was 35 to 52 days. Plasma maximum observed concentration and the area under the plasma concentration-time profile from time 0 extrapolated to infinite time of A&bgr;1-x and A&bgr;1-40 increased dose-dependently. ConclusionsAdministration of ponezumab as a 10-minute infusion was safe and well tolerated and produced effects on plasma A&bgr; species comparable with a 2-hour infusion. Shorter infusions may provide more flexibility, comfort, and convenience for patients and caregivers.

Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.

OBJECTIVE PF-04360365 is a humanized IgG(2)Δa anti-amyloid β (Aβ) antibody designed to improve outcome in Alzheimers disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD. This Phase 1, multicenter, randomized, double-blind, dose-escalation study was the first to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of PF-04360365 in Japanese subjects. MATERIALS AND METHODS 30 subjects with mild-to-moderate AD were enrolled. In each cohort, 3 subjects received PF-04360365 (0.1, 0.5, 1, 5, or 10 mg/kg) and 1 subject received placebo as a single 2-hour intravenous infusion. Subjects were monitored as inpatients for 24 hours and then as outpatients for 1 year. RESULTS All subjects completed the study. There were no serious or National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥ 3 adverse events, hypersensitivity reactions, or antidrug antibodies. No clinical or MRI evidence of brain microhemorrhage, cerebral edema, or encephalitis was observed. PF-04360365 plasma concentrations increased with dose, and pharmacokinetics were consistent with a small steady-state volume of distribution, slow clearance, and long elimination half-life. Cerebrospinal fluid (CSF):plasma ratios were < 0.5%. Plasma Aβ species showed dose-dependent increases in C(max) and AUC(∞), but CSF biomarkers did not differ clearly between treatment arms. CONCLUSIONS PF-04360365 was safe and well tolerated in Japanese subjects. Pharmacokinetics and plasma pharmacodynamic responses in Japanese subjects were comparable to those in Western subjects. *No longer affiliated with Pfizer.

Pharmacokinetics, Safety, and Tolerability Following Multiple Oral Doses of Varenicline Under Various Titration Schedules in Elderly Nonsmokers

This study was designed to investigate the multiple‐dose pharmacokinetics, safety, and tolerability of the selective α4β2 nicotinic acetylcholine partial agonist, varenicline, in elderly (65–85 years old) nonsmokers. Fifty male and female subjects with normal renal function for their age were randomized to receive varenicline or placebo once or twice daily for 3 weeks in an investigator‐ and subject‐blinded parallel‐group design. Treatment regimens included weekly titration (n = 14; days 1–7, 0.5 mg once daily; days 8–14, 0.5 mg twice daily; days 15–21, 1 mg twice daily); 2‐week twice‐daily titration (n = 13; days 1–14, 0.5 mg once daily; days 15–21, 0.5 mg twice daily); 2‐week once‐daily titration (n = 13; days 1–14, 0.5 mg once daily; days 15–21, 1 mg once daily); and placebo (n = 10). Approximate dose‐proportional increases in systemic exposure of varenicline at steady state, based on maximum concentration and area under the plasma concentration‐time curve over the 24‐hour period at steady state, were observed across the dose range of 0.5 to 2 mg/d. Median time to maximum concentration was 3 hours. Mean elimination half‐life was estimated to be approximately 24 to 32 hours and independent of dose. Varenicline was considered to be safe and well tolerated in this elderly nonsmoking population.

Preliminary population pharmacokinetic modeling of PF-04360365, a humanized anti-amyloid monoclonal antibody, in patients with mild-to-moderate Alzheimer's disease

Introduction ● PF-04360365 is a humanized anti-amyloid IgG2 monoclonal antibody that recognizes amino acids 33–40 of the beta-amyloid (Aβ) 1–40 peptide, and requires a free carboxy terminus for binding. ● In transgenic mice that overexpress amyloid precursor protein, the murine analog of PF-04360365 has been observed to decrease Aβ levels in the central nervous system and to improve their performance in various models of learning and memory. ● PF-04360365 is currently undergoing clinical testing in patients with Alzheimer’s disease (AD) as a potential disease modifying agent to reduce brain Aβ burden and to improve clinical outcomes. ● A robust population pharmacokinetic (PK) model at an early stage of drug development can be critical in helping design more efficient clinical studies.

Pharmacokinetics and pharmacodynamics of ponezumab (PF-04360365) following a single-dose intravenous infusion in patients with mild to moderate Alzheimer's disease

Background: Ponezumab (PF-04360365) is a humanized anti-amyloid mAb under investigation for the treatment of Alzheimer’s disease (AD). The pharmacokinetics and pharmacodynamics of ponezumab were evaluated in two phase 1 studies in patients with mild-to-moderate AD, and the results compared. Methods: Placebo or ponezumab at 0.1 (n 1⁄4 6), 0.3 (n 1⁄4 6), 1 (n 1⁄4 6), 3 (n 1⁄4 8), or 10 mg/kg (n 1⁄4 11) were administered via 2-hour infusion to 37 patients with AD in a randomized, double-blind, placebo-controlled, dose-escalation study (A9951001). A second study (A9951008) was designed as an open-label, parallel-group, dose-escalation trial with ponezumab administered at 1 (n 1⁄4 3), 3 (n 1⁄4 3), 5 (n 1⁄4 4), or 10 (n 1⁄4 5) mg/kg via 10-minute infusion. Serum analytes for anti-drug antibodies (ADAs), plasma ponezumab and amyloid b (Ab), and CSF ponezumab, Ab, and tau/p-tau concentrations were quantified by validated bioanalytical methods. Plasma pharmacokinetics and pharmacodynamics were calculated using non-compartmental analysis. Results: Pharmacokinetics and pharmacodynamics were similar between the two studies. Plasma ponezumab reached maximum concentration (Cmax) shortly after infusion, followed by a biphasic decline. Cmax and area under the concentration-time curve increased in a dose-proportional manner. The pharmacokinetics of ponezumab were linear with a mean terminal half-life of 35-52 days. Ponezumab CSF concentrations at Day 29 post-dose (A9951001) were quantifiable in 2 of 8 patients administered a 10 mg/kg dose (?0.5% of plasma values). In both studies, plasma Ab concentrations and time to Cmax (Tmax) increased dose-dependently. The ratios of Cmax/baseline in plasma Ab concentrations were around 500 in the 10 mg/kg group compared with 1 in the placebo group. At the 10 mg/kg dose (A9951001), mean CSF Ab percentage change from baseline at Day 29 increased 38% (p < 0.05), 29% (p > 0.05), and 15% (p < 0.05) for Ab1-x, Ab1-40, and Ab1-42, respectively. There were no changes from baseline for CSF tau and p-tau concentrations. ADAs were not detected. Conclusions: The pharmacokinetics of ponezumab were similar between the two studies linear, with central penetration seen following the highest dose in some patients. Increases in plasma Ab biomarker response and Tmax were dose dependent. CSF Ab concentrations increased from baseline at Day 29 for the 10 mg/ kg dose. No ADAs were detected.

Safety and Pharmacokinetics Following a Single Infusion of the Anti-amyloid Monoclonal Antibody Ponezumab (pf-04360365) in Patients With Mild-to-moderate Alzheimer's Disease: Final Results

and radiological findings of MRI/CT and SPECT. We analyzed CSF phosphorylated tau (ptau-181) for every 3-4 years respectively. Results: After gene analyis, we have found four different PS1 mutations in all five FAD cases (H131R, H163R, L219R, M233L). Two siblings in FAD1 family (M233L) had common initial phenotype characterized by neurological symptoms (dementia, apraxia, apathy), with severe motor deficits since onset of the disease. A proband of FAD2 family (H163R) presented dementia and parkinsonism. MRI of two siblings in FAD1 family showed that the temporo-parietal lobes and hippocampus were atrophied at the initial stage, then atrophies of the frontal lobe were followed. Phosphorylated ptau-199 and ptau-181 in CSF slightly increased in three patints except one FAD3 case. MRI of the proband of FAD2 family showed severe temporal and fronto-temporal atrophy, corresponding to low CBF in SPECT. While two cases of FAD3 (L219R) resemble clinical and radiological findings of FAD1, FAD4 (H131R) case is reminiscent of FAD1. In time process of 5 AD cases, ptau-181 have slight decreased since initial CSF examination. Conclusions: We have demonstrated four PS1 mutations including two novel mutations (L219R, H131R) in four FAD. FAD patients showed common initial phenotype characterized by dementia, apraxia, apathy with severe motor deficits since onset of the disease. In time process of 5 AD cases, CSF ptau-181 and ptau-199 have slight decreased since initial CSF examination. We consider that AD clinical progress and CSF ptau181 may close relationship in time process, and that further deterioration of dmentia and pathological/clinical stable AD condition might decrease ptau-181.

Pharmacokinetics of ponezumab (PF-04360365) following a single-dose intravenous infusion in Japanese patients with mild-to-moderate Alzheimer's disease: Preliminary results

Background: The Alzheimer’s Disease Assessment Scale Cognitive subscale (ADAS-Cog) is the most commonly used primary efficacy measure in Alzheimer’s disease clinical trials. In general, the (11 item) ADASCog has demonstrated sensitivity to change across a range of dementia severities. However, some clinical research studies now include some additional items (e.g. delayed word recall, maze test and digit cancellation) hoping to better assess the early stages of dementia as well as executive functioning. Earlier research has demonstrated considerable variability in how raters have been trained to administer and score the (11 item) ADAS-Cog in clinical trials. Additionally, with increased globalization of studies, the potential for considerable differences in rater experience exists. Initial qualification rates for raters attempting to participate in studies utilizing the 11 item ADAS-Cog were compared to studies utilizing some or all of the additional items. Methods: A proprietary database identified all raters who were trained on and who attempted to qualify to administer and score the ADAS-Cog in 32 clinical trials. Raters were stratified into 2 groups those tested on the original 11 item ADAS-Cog and those tested on scale versions that incorporated additional item(s). Testing consisted of watching and scoring a video of the scale being administered to a patient. Initial qualification rates (scoring to a predefined criteria) were compared. Results: In 26 studies employing the 11 item ADAS-Cog, 4223 of 4587 raters (92.1%) qualified to rate on their initial attempt. Additionally, 1313 raters out of 1595 (82.3%) potential raters in the 6 studies utilizing additional item(s) were successful on their initial attempts to qualify to rate. A chi-square analysis determined that this difference in initial qualification rates is significant (<0.0001). Conclusions: The incorporation of additional item(s) into the original 11 item ADAS-Cog appears to provide an added challenge to raters who attempt to qualify to rate in those studies. Possible explanations include training variability; lack of familiarity with these items, their administration and scoring, and what they aim to assess. Given the difference in initial qualification rates when additional item(s) are used, surveillance and analysis of raters’ performance on these items throughout a trial is warranted.

Population Pharmacokinetics of Eplerenone in Japanese Patients With Chronic Heart Failure

To characterize eplerenone pharmacokinetics (PK) in Japanese chronic heart failure (CHF) patients and to estimate the impact of factors that may affect eplerenone PK, population pharmacokinetic (PPK) analysis was conducted. In addition, PK of Japanese CHF and Western CHF patients from a previous clinical pharmacology study were compared in the analysis. Eplerenone PK was characterized by a 1‐compartment PPK model with first‐order absorption and lag time in Japanese CHF patients. The population mean of apparent oral clearance (CL/F) in Japanese CHF patients was estimated as 5.31 L/h, which was similar to the mean CL/F for Western CHF patients. In the full model approach, creatinine clearance (CLcr) on CL/F and body weight on apparent central volume of distribution (Vc/F) were selected as factors that may affect PK. The effect of CLcr on CL/F predicted that CL/F would be decreased by 25% when CLcr was decreased from 80 mL/min to 50 mL/min. The effect of body weight on Vc/F predicted that Vc/F would be decreased by 18% when body weight was decreased from 80 kg to 60 kg. Distribution of individual CL/F estimates for Japanese CHF patients overlapped CL/F observed values for Western CHF patients, and CL/F values for Western CHF patients were contained within the distribution of CL/F estimates for Japanese CHF patients. No obvious difference between Japanese and Western subjects was detected even in the updated model by adding the data obtained from Western CHF patients and Western healthy adults to the model constructed with data from Japanese CHF patients.