Kevin Sweeney

Results of Bococizumab, A Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, from a Randomized, Placebo-Controlled, Dose-Ranging Study in Statin-Treated Subjects With Hypercholesterolemia

Bococizumab is a humanized monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. In this 24-week, multicenter, double-blind, placebo-controlled, dose-ranging study (NCT01592240), subjects with LDL-C levels≥80 mg/dl on stable statin therapy were randomized to Q14 days subcutaneous placebo or bococizumab 50, 100, or 150 mg or Q28 days subcutaneous placebo or bococizumab 200 or 300 mg. Doses of bococizumab were reduced if LDL-C levels persistently decreased to ≤25 mg/dl. The primary end point was the absolute change in LDL-C levels from baseline to week 12 after placebo or bococizumab administration. Continuation of bococizumab administration through to week 24 enabled the collection of safety data over an extended period. Of the 354 subjects randomized, 351 received treatment (placebo [n=100] or bococizumab [n=251]). The most efficacious bococizumab doses were 150 mg Q14 days and 300 mg Q28 days. Compared with placebo, bococizumab 150 mg Q14 days reduced LDL-C at week 12 by 53.4 mg/dl and bococizumab 300 mg Q28 days reduced LDL-C by 44.9 mg/dl; this was despite dose reductions in 32.5% and 34.2% of subjects at week 10 or 8, respectively. Pharmacokinetic/pharmacodynamic model-based simulation assuming no dose reductions predicted that bococizumab would lower LDL-C levels by 72.2 and 55.4 mg/dl, respectively. Adverse events were similar across placebo and bococizumab groups. Few subjects (n=7; 2%) discontinued treatment because of treatment-related adverse events. In conclusion, bococizumab significantly reduced LDL-C across all doses despite dose reductions in many subjects. Model-based simulations predicted greater LDL-C reduction in the absence of bococizumab dose reduction. The Q14 days regimen is being evaluated in phase 3 clinical trials.

Thorough QT Study with Recommended and Supratherapeutic Doses of Tolterodine

The objective of our study was to determine the QTc effects of tolterodine. A crossover‐design thorough QT study of recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo was performed. Electrocardiograms (ECGs) and pharmacokinetic samples were obtained on days 1–4; time‐matched baseline ECGs were taken on day 0. Mean placebo‐subtracted change from baseline Fridericia‐corrected QT (QTcF) during peak drug exposure on day 4 was the primary end point. Mean QTcF prolongation of moxifloxacin was 8.9 ms (machine‐read) and 19.3 ms (manual‐read). At recommended and supratherapeutic tolterodine doses, mean QTcF prolongation was 1.2 and 5.6 ms (machine‐read), respectively, and 5.0 and 11.8 ms (manual‐read), respectively. The QTc effect of tolterodine was lower than moxifloxacin. No subject receiving tolterodine exceeded the clinically relevant thresholds of 500 ms absolute QTc or 60 ms change from baseline. In conclusion, tolterodine does not have a clinically significant effect on QT interval.

The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism

BackgroundAccumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na+/K+) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra®), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound.MethodsThe effect of eplerenone and PF-03882845 on urinary Na+/K+ and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in healthy volunteers. Drug exposure-response data were modeled to evaluate the translatability of these biomarkers from rats to humans.ResultsIn Sprague-Dawley rats, eplerenone elicited a rapid effect on urinary Na+/K+ yielding an EC50 that was within 5-fold of the functional in vitro IC50. More importantly, the effect of eplerenone on urinary Na+/K+ in healthy volunteers yielded an EC50 that was within 2-fold of the EC50 generated in Sprague-Dawley rats. Similarly, the potency of PF-03882845 in elevating urinary Na+/K+ in Sprague-Dawley rats was within 3-fold of its in vitro functional potency. The effect of MR antagonism on urinary Na+/K+ was not sustained chronically; thus we studied the effect of the compounds on plasma aldosterone following chronic dosing in SHR. Modeling of drug exposure-response data for both eplerenone and PF-03882845 yielded EC50 values that were within 2-fold of that estimated from modeling of drug exposure with changes in urinary sodium and potassium excretion. Importantly, similar unbound concentrations of eplerenone in humans and SHR rats yielded the same magnitude of elevations in aldosterone, indicating a good translatability from rat to human.ConclusionsUrinary Na+/K+ and plasma aldosterone appear to be translatable biomarkers of MR antagonism following administration of single or multiple doses of compound, respectively.Trial RegistrationFor clinical study reference EE3-96-02-004, this study was completed in 1996 and falls out scope for disclosure requirements.Clinical study reference A6141115: http://clinicaltrials.gov, http://NIHclinicaltrails.gov; NCTID: NCT00990223

Does the Systemic Plasma Profile Inform the Liver Profile? Analysis Using a Physiologically Based Pharmacokinetic Model and Individual Compounds

The physiologically based pharmacokinetic (PBPK) model for liver transporter substrates has been established previously and used for predicting drug–drug interactions (DDI) and for clinical practice guidance. So far, nearly all the published PBPK models for liver transporter substrates have one or more hepatic clearance processes (i.e., active uptake, passive diffusion, metabolism, and biliary excretion) estimated by fitting observed systemic data. The estimated hepatic clearance processes are then used to predict liver concentrations and DDI involving either systemic or liver concentration. However, the accuracy and precision of such predictions are unclear. In this study, we try to address this question by using the PBPK model to generate simulated compounds for which we know both systemic and liver profiles. We then developed an approach to assess the accuracy and precision of predicted liver concentration. With hepatic clearance processes estimated using plasma data, model predictions of liver are typically accurate (i.e., true value is bounded by predicted maximum and minimum); however, only for a few compounds are predictions also precise. The results of the current study indicate that extra attention is required when using the current PBPK approach to predict liver concentration and DDI for transporter substrates dependent upon liver concentrations.

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.

Nonlinear mixed effects modeling of time dependencies in drug-free ECG data from healthy volunteers

It may be important to understand time‐dependencies in ECG data when developing models as a function of drug concentration in longitudinal studies. A model‐based analysis was employed to explore and compare the dependence of RR, QT and QTcI (individual rate‐corrected QT) on daytime temporal fluctuations.

Concentration‐QTC modeling in healthy volunteers (HV) and in subjects with major depressive disorder (MDD) for a novel antidepressant candidate

Evaluation of QTc vs. concentration relationship was undertaken to assess QTc prolongation early in drug development for a novel antidepressant.