O3‐07‐05: Pharmacokinetics and pharmacodynamics of ponezumab (PF‐04360365) following a single‐dose intravenous infusion in patients with mild to moderate Alzheimer's disease
Qinying Zhao, Jaren W. Landen, Aaron H. Burstein, Frederick McCush, Christine W. Alvey, Clare B. Billing, Weidong Wendy Ma, James W. Kupiec, Martin M. Bednar · Alzheimer s & Dementia · 2010
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. Placebo or ponezumab at 0.1 (n = 6), 0.3 (n = 6), 1 (n = 6), 3 (n = 8), or 10 mg/kg (n = 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 = 3), 3 (n = 3), 5 (n = 4), or 10 (n = 5) mg/kg via 10-minute infusion. Serum analytes for anti-drug antibodies (ADAs), plasma ponezumab and amyloid β (Aβ), and CSF ponezumab, Aβ, and tau/p-tau concentrations were quantified by validated bioanalytical methods. Plasma pharmacokinetics and pharmacodynamics were calculated using non-compartmental analysis. 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 Aβ concentrations and time to Cmax (Tmax) increased dose-dependently. The ratios of Cmax/baseline in plasma Aβ 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 Aβ percentage change from baseline at Day 29 increased 38% (p 0.05), and 15% (p < 0.05) for Aβ1-x, Aβ1-40, and Aβ1-42, respectively. There were no changes from baseline for CSF tau and p-tau concentrations. ADAs were not detected. 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 Aβ biomarker response and Tmax were dose dependent. CSF Aβ concentrations increased from baseline at Day 29 for the 10 mg/kg dose. No ADAs were detected.