Alberto Russu

Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ-54861911, a potent oral BACE inhibitor

Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, JNJ‐54861911, were assessed after single and multiple dosing in healthy participants.

Alzheimer's disease assessment scale-cognitive 11-item progression model in mild-to-moderate Alzheimer's disease trials of bapineuzumab

The objective of this study was to estimate longitudinal changes in disease progression (measured by Alzheimers disease assessment scale‐cognitive 11‐item [ADAS‐cog/11] scale) after bapineuzumab treatment and to identify covariates (demographics or baseline characteristics) contributing to the variability in disease progression rate and baseline disease status.

Prospective dose selection and acceleration of paliperidone palmitate 3‐month formulation development using a pharmacometric bridging strategy

AIMS To prospectively select the dose of the paliperidone palmitate 3-month (PP3M) formulation, using a pharmacometric bridging strategy based on the paliperidone palmitate 1-month (PP1M) formulation previously approved for schizophrenia treatment. METHODS Pharmacokinetic (PK) data from a 6-month interim analysis of a single dose PP3M Phase I clinical trial was integrated with a previously developed PP1M population-PK model. The model was updated to incorporate formulation as a covariate on absorption parameters and to explore the most critical design element of the Phase III study: the PP1M-to-PP3M dose multiplier for patients switching formulations. Plasma paliperidone concentrations were measured at predetermined intervals during Phase III, enabling comparison of the multiple-dose PK between PP1M and PP3M. Exposure matching was assessed graphically to determine whether paliperidone plasma concentrations from the two formulations overlapped. RESULTS Prospective steady-state PK simulations revealed that a 3.5 multiple of the PP1M dose would yield a corresponding PP3M dose with comparable exposure. The prospective pharmacometric simulation and observed Phase III PK data agreed closely. Phase III results confirmed the hypothesis that efficacy of PP3M was noninferior to that of PP1M. The similarity in exposures between the two formulations was likely a key determinant of the equivalent efficacy between the two products observed in the Phase III study. CONCLUSIONS Successful prospective PP3M Phase III clinical trial dose selection was achieved through the use of pharmacometric bridging, without conducting a Phase II study and using only limited Phase I data for PP3M. We estimate that this strategy reduced development time by 3-5 years and may be applicable to other drug development projects.

Evaluating Potential QT Effects of JNJ‐54861911, a BACE Inhibitor in Single‐ and Multiple‐Ascending Dose Studies, and a Thorough QT Trial With Additional Retrospective Confirmation, Using Concentration‐QTc Analysis

Nonclinical assays with JNJ‐54861911, a β‐secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4‐way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ‐54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high‐precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first‐in‐human single‐ascending dose (SAD) and multiple‐ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo‐corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9‐18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure–response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ‐54861911 peak plasma concentrations (Cmax) comparable to those in the SAD study (∼750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; Cmax, 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ‐54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation.

Paliperidone Palmitate Long-Acting Injectable Given Intramuscularly in the Deltoid Versus the Gluteal Muscle: Are They Therapeutically Equivalent?

I n the report by Yin et al, 1 the statement that “many clinicians may misinterpret these directions (in paliperidone palmitate product monograph) to mean that these intramuscular sites (deltoid or gluteal) are interchangeable, and thus therapeutically equivalent” is, in our opinion, not correct. We are writing to clarify some statements from the Yin et al article concerning the deltoid versus gluteal intramuscular injection of paliperidone palmitate. The recommended initiation as stated in the product label of paliperidone palmitate 1-month injection is with a dose of 150mgeqon treatmentday1and100mgeq1 week later, both administered in the deltoid muscle. Here, the deltoid and gluteal injection sites are not interchangeable, and from a clinical point of view, it is important to reach therapeutic concentrations quickly when starting a new antipsychotic. However, after the second initiation dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle. The injection sites of the maintenance doses can be used interchangeably, but for deltoid injections, the appropriate needle length is based on the patients weight (1-in 23G needle for patients weighing <90 kg and 1.5-in 22G needle for patients weighing ≥90 kg). For gluteal injection, regardless of patient weight, the use of a 1.5-in 22G needle is recommended. The use of differently sized needles depending on the weight of the patient for injection into the deltoid muscle is recommended to limit the risk of drug administration into the subcutaneous tissues, which would result in a decreased rate of absorption from the intramuscular site of injection. Different distributions of muscle and adipose tissue, as well as difference in blood flow between the deltoid and gluteal sites, may affect the uptake rate of paliperidone into the circulation from the site of injection. At the deltoid site, the likelihood of an injection that is purely intramuscular is higher compared with that at the gluteal injection site. The hypovascularity of subcutaneous adipose tissue compared with

Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer’s Disease Trials of Bapineuzumab

BACKGROUND Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimers disease (AD) patients. OBJECTIVE To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling. METHODS Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers. RESULTS Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected. CONCLUSIONS Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated.

PHARMACODYNAMICS OF THE ORAL BACE INHIBITOR JNJ-54861911 IN EARLY ALZHEIMER'S DISEASE

cebo were studied. Comprehensive neuropathological assessments were performed ranging from 4 months to 14 years after the trial. Large coronal paraffin sections of cerebral hemisphere were immunostained for Ab, scanned, then (i) the entire neocortical ribbon was scored for plaques in a CERAD-like manner (frequent1⁄43, moderate1⁄42, sparse1⁄41, none1⁄40) and (ii) false coloured to permit visualisation of staining patterns at low power. Results: 16/21 had a distribution of tangles and at least some residual Ab pathology indicating the cause of dementia had been AD, whereas 5/21 had alternative causes for dementia (PSP1⁄41, DLB1⁄41, VaD1⁄41and FTDTDP431⁄42). 18/21 had received the active agent and 3/21 the placebo. Scanning and false colouration of large Ab immunostained sections generated images suitable for comparison with amyloid PET scans as used in current immunotherapy trials. 13/15 AD subjects receiving the active agent had evidence of plaque removal (almost complete removal1⁄45, extensive patches of removal1⁄44, small patches of removal1⁄44, no plaque removal1⁄42). In the immunised AD group the mean plaque score was 1.46 (range1⁄40.05-2.9) vs. 2.4 for the single placebo AD case. There was a significant inverse correlation between peripheral blood anti-Ab titres and plaque scores. Conclusions: AD patients actively immunised against Ab can remain virtually plaque–free for up to 14 years. Nearly a quarter of the patients examined in this study did not have neuropathologically verified AD. Neuropathology follow up of patients in therapeutic trials for AD provides valuable information on the cause of dementia and effects of treatment.

Alzheimer's disease progression model using disability assessment for dementia scores from bapineuzumab trials

Disability assessment for dementia (DAD) measurements from two phase‐3 studies of bapineuzumab in APOE ε4 noncarrier and carrier Alzheimers disease (AD) patients were integrated to develop a disease progression model.

Maintenance dose conversion between oral risperidone and paliperidone palmitate 1 month: Practical guidance based on pharmacokinetic simulations

We assessed the dosage strengths of paliperidone palmitate 1‐month (PP1M) long‐acting injectable resulting in similar steady‐state (SS) exposures to the dosage strengths of oral risperidone using pharmacokinetic (PK) simulations.

PHARMACOKINETIC/PHARMACODYNAMIC MODELING OF CSF AB1-40 REDUCTION IN AN EARLY ALZHEIMER'S DISEASE STUDY OF JNJ-54861911, AN ORAL BACE1 INHIBITOR

analysis. Results: No clinical abnormalities were identified and no significant changes on safety ECG, telemetry, vital signs, or labs were observed up to 360 mg single dose. Doses were escalated up to the pre-defined exposure limit and maximum tolerated dose has not been established. Following single doses under fasted condition, PF-06648671 was absorbed rapidly with median tmax of 1 to 1.5 hours. The mean terminal t1/2 was 13.9 to 23.1 hours. The Cmax and AUCinf increased by approximately 88and 140-fold over the dose range of 2 to 360 mg. With high-fat meal, a delayed median tmax of 4 hours was observed. AUCinf slightly increased by 23% while Cmaxdecreased by 24% compared to the fasted state. Significant, dose-dependent reductions in plasma Abeta42, 40 and total were observed. The placebo-adjusted maximal change from baseline was -56.9% and -68.8% for plasma Abeta42 and 40, respectively, after a single dose of 360 mg. As expected, the reduction in Abeta total was substantially less than in Abeta40 and 42. Conclusions: PF-06648671 was generally safe and well tolerated in healthy subjects after single oral doses up to 360 mg. Robust and dose-dependent reductions in plasma Ab40 and Ab42 were observed following single dose administrations. A multiple ascending dose study in healthy adult and elderly is ongoing with CSF Ab effect evaluated at steady state.