Bonnie C. Shaddinger

Effect of treatment for 12 weeks with rilapladib, a lipoprotein-associated phospholipase A2 inhibitor, on arterial inflammation as assessed with 18F-fluorodeoxyglucose-positron emission tomography imaging.

To the Editor: Previous reports have demonstrated that lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzymatic inflammatory biomarker, is associated with increased risk of cardiovascular events [(1)][1]. Lp-PLA2 mediates formation of bioactive mediators (lysophosphatidyl choline and

Platelet Aggregation Unchanged by Lipoprotein-Associated Phospholipase A2 Inhibition: Results from an In Vitro Study and Two Randomized Phase I Trials

Background We explored the theorized upregulation of platelet-activating factor (PAF)– mediated biologic responses following lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials. Methods and Results Full platelet aggregation concentration response curves were generated in vitro to several platelet agonists in human plasma samples pretreated with rilapladib (selective Lp-PLA2 inhibitor) or vehicle. This was followed by a randomized, double-blind crossover study in healthy adult men (n = 26) employing a single-agonist dose assay of platelet aggregation, after treatment of subjects with 250 mg oral rilapladib or placebo once daily for 14 days. This study was followed by a second randomized, double-blind parallel-group trial in healthy adult men (n = 58) also treated with 250 mg oral rilapladib or placebo once daily for 14 days using a full range of 10 collagen concentrations (0–10 µg/ml) for characterizing EC50 values for platelet aggregation for each subject. Both clinical studies were conducted at the GlaxoSmithKline Medicines Research Unit in the Prince of Wales Hospital, Sydney, Australia. EC50 values derived from multiple agonist concentrations were compared and no pro-aggregant signals were observed during exposure to rilapladib in any of these platelet studies, despite Lp-PLA2 inhibition exceeding 90%. An increase in collagen-mediated aggregation was observed 3 weeks post drug termination in the crossover study (15.4% vs baseline; 95% confidence interval [CI], 3.9–27.0), which was not observed during the treatment phase and was not observed in the parallel-group study employing a more robust EC50 examination. Conclusions Lp-PLA2 inhibition does not enhance platelet aggregation. Trial Registration 1) Study 1: ClinicalTrials.gov NCT01745458 2) Study 2: ClinicalTrials.gov NCT00387257

Utility of concentration‐effect modeling and simulation in a thorough QT study of losmapimod

A thorough QT study was conducted in healthy volunteers with losmapimod. Four treatment regimens were included: a therapeutic dose (7.5 mg BID for 5 days), a supratherapeutic dose (20 mg QD for 5 days), a positive control (400 mg moxifloxacin single dose on Day 5), and placebo for 5 days. Baseline and on treatment ECGs were measured on Day 1 (3 timepoints predose) and Day 5, respectively. The primary statistical analysis failed to demonstrate a lack of effect of losmapimod on the QT interval leading to a positive finding. However, simulations using the concentration‐effect model established for QTcF vs. losmapimod concentration at concentrations 4× the maximum concentration of the therapeutic dose did not exceed the regulatory thresholds of concern of 5 milliseconds for the mean (4.57 milliseconds) and 10 milliseconds for the upper bound of the 90%CI (90%CI 2.88, 6.10). Modeling demonstrated that the discrepant results may have been due to a baseline shift after repeat dosing and baseline differences between the treatments. Considering the results of the concentration‐effect modeling, previous losmapimod data, and the high false‐positive rate associated with the ICH E14 statistical analysis, the statistical analysis was likely a false‐positive.

A definitive study of the effects of PDE-5 inhibitors on cardiac repolarization in middle-age males

Patients with erectile dysfunction may use PDE5 inhibitors such as vardenafil (V) and sildenafil (S), which alter the hERG channel of transfected cells only at suprapharmacologic nonclinical concentrations. This study evaluated effects of therapeutic and supratherapeutic doses of V and S on QT/QTc duration. A placebo‐ and active‐control (moxifloxacin, M, at therapeutic dose), period balanced, double blinded, 6 way crossover study evaluated single oral doses of V 10 mg, V 80 mg, S 50 mg, S 400 mg, M 400 mg and placebo in 58 healthy men (mean age 53) with doses separated by 3 days. Six replicate 12‐lead digital ECGs were recorded at 3 time points prior to and 5 time points post dose to cover the full exposure of drugs and metabolites. An independent lab blindly analyzed the ECGs. PK blood samples were drawn at the same 5 time points post dose. For placebo, mean change in QTcF (Fridericia) duration from baseline at 1 hour post dose (approximate Tmax of V and S) was 0 msec (+/‐ 0.7 SD). QT and QTc variability was small across regimens, indicating statistically powerful results due to large sample size and number (17,000) of ECGs. M demonstrated an expected 8 msec mean change and was the only drug to prolong absolute QT. Placebo‐corrected values of mean change from baseline at 1 hour post‐dose for each regimen are shown below. QT corrected using linear and nonlinear methods and each individuals QT/HR data (QTci) yielded similar trends of drug effect on QTc. PK/PD modeling demonstrated a very shallow QTc‐concentration relationship for V and S. Therapeutic and supratherapeutic doses of V and S produced no increase of absolute QT and similar small increases in QTc interval. We conclude that these findings, and the absence of postmarketing reports of torsades de pointes with S, indicate that small increases in QTc for V and S are clinically insignificant. This study design may serve as a guide for future definitive QT assessment. (See Table )

Effect of Albiglutide on Cholecystokinin‐Induced Gallbladder Emptying in Healthy Individuals: A Randomized Crossover Study

The glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)‐induced gallbladder emptying in healthy subjects. It is unknown if all GLP‐1 RAs share this effect; therefore, the effect of the GLP‐1 RA albiglutide on gallbladder function was assessed. In this randomized, double‐blind, 2‐way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK‐induced gallbladder contractility was measured by ultrasonography. CCK (0.003 μg/kg) was infused intravenously over 50 minutes on study day 4 (3 days after dosing, to coincide with albiglutides expected time to maximum concentration). Gallbladder volume, ejection fraction, and the main pancreatic and common bile‐duct diameters were measured before, during, and following CCK infusion. Gallbladder volume was significantly greater in the albiglutide vs placebo groups before, during, and after CCK infusion, and the mean difference from placebo increased numerically during CCK infusion. The area under the volume‐effect curve was significantly greater with albiglutide (P = .029). Starting at the 30‐minute CCK infusion time point, the gallbladder ejection fraction was significantly lower with albiglutide than placebo. Changes in pancreatic duct diameter and common bile‐duct diameter were not significantly different between albiglutide and placebo. Similar incidences of adverse events were observed between the albiglutide and placebo treatment periods. No new albiglutide safety signals were detected, and no serious adverse events were reported. In conclusion, similar to other GLP‐1 RAs, albiglutide decreased CCK‐induced gallbladder emptying compared with placebo in healthy individuals. Clinical implications of the gallbladder effects are unclear at this time.

An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib.

AIM/METHODS This was a phase 1, open label, non-randomized study designed to assess the pharmacokinetics and safety/tolerability of 10 consecutive once daily 40 mg oral doses of darapladib in subjects with moderate hepatic impairment (n = 12) compared with matched healthy volunteers (n = 12). RESULTS For total darapladib, a small increase in total and peak exposure was observed in the subjects with moderate hepatic impairment compared with the subjects with normal hepatic function. The area under the plasma concentration-time curve during a dosing interval of duration τ (AUC(0,τ), geometric mean 223 ng ml(-1)  h [90% CI 158, 316 ng ml(-1 ) h], in moderate hepatic impaired subjects, vs. geometric mean 186 ng ml(-1 ) h [90% CI 159, 217 ng ml(-1 ) h], in healthy subjects) and maximum concentration (Cmax ) were 20% and 7% higher, respectively, in the subjects with moderate hepatic impairment than in the healthy control subjects and there was no change in time to maximum concentration (tmax ). Protein binding was performed to measure the amount of unbound drug vs. bound. Steady-state was achieved by day 10 for darapladib and its metabolites (M4, M3 and M10). Darapladib was generally well tolerated, with adverse events (AEs) reported by seven subjects in the hepatic impairment group and three subjects in the healthy matched group (five and one of which were drug-related AEs, respectively). The most common AEs were gastrointestinal. These AEs were mostly mild to moderate and there were no deaths, serious AEs or withdrawals due to AEs. CONCLUSIONS The results of this phase 1 study show that darapladib (40 mg) is well tolerated and its pharmacokinetics remain relatively unchanged in patients with moderate hepatic impairment.

An Integrated Pharmacokinetic/Pharmacodynamic (PK/PD) Model For SB‐480848 Inhibition of Plasma Lipoprotein‐Associated Phospholipase A2 (LP‐PLA2) Enzyme Activity in Human

Clinical Pharmacology & Therapeutics (2003) 73, P86–P86; doi:

A Randomized, Double‐Blind, Single‐Dose, Crossover Study to Demonstrate the Bioequivalence of 2 Formulations of Albiglutide in Healthy Adult Participants

Albiglutide, developed for treatment of type 2 diabetes mellitus, is provided in a dual‐chamber cartridge (DCC) single‐dose pen‐injector containing lyophilized drug that must be reconstituted with diluent prior to use. A liquid formulation of albiglutide has been developed that does not require mixing. In this 2‐period, randomized, crossover, double‐blind, phase I study (NCT02660736) in 59 healthy volunteers, pharmacokinetic parameters were determined and the bioequivalence of the 2 formulations was assessed. Participants received injections from each type of pen‐injector, one containing albiglutide 50 mg and one containing placebo, followed by an 8‐week washout period between regimens: albiglutide 50‐mg liquid formulation from an auto‐injector and lyophilized placebo from a DCC pen‐injector (Regimen A), or placebo liquid from an auto‐injector and lyophilized albiglutide 50 mg from a DCC pen‐injector (Regimen B). Geometric mean total exposures (area under the drug concentration–time curve [AUC](0‐t) [1345.4 vs 1426.9 (μg · h/mL)], AUC(0‐∞) [1376.2 vs 1454.6 (μg · h/mL)], and maximum concentration of drug in blood plasma [4968.5 vs 5314.7 ng/mL]) were comparable between Regimens A and B. Ratios of geometric least square means (90% confidence interval) were 95.3% (89.49‐101.52) for AUC(0‐∞), 95.1% (89.12‐101.49) for AUC(0‐t), and 93.2% (86.76‐100.17) for maximum concentration of drug in blood plasma, falling within the 90% confidence interval of 0.80 to 1.25 for bioequivalence. No new safety concerns were observed.

The pharmacokinetics and safety of darapladib in subjects with severe renal impairment.

AIM Darapladib is a potent and reversible orally active inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2 ). The aim of the study was to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib compared with normal renal function. METHODS This was an open label, parallel group study of darapladib following 10 day once daily 160 mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated glomerular filtration rate <30 ml min(-1) 1.73 m(-2) , n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24 h on day 10. RESULTS Plasma concentrations of total and unbound darapladib as well as all three metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration vs. time curve between time zero and 24 h (AUC(0,24 h) and maximum plasma concentration (Cmax ) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than two-fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects, most of which were mild or moderate in intensity. CONCLUSIONS The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared with healthy controls. However, darapladib was generally well tolerated in both groups.

PK/PD modeling of QTC duration for vardenafil & sildenafil in healthy volunteers

A placebo‐ and positive‐controlled (Moxifloxacin, M 400 mg), double‐blind, 6‐way crossover study evaluated the effects of single oral therapeutic and supratherapeutic doses of vardenafil (V 10, 80 mg), and sildenafil (S 50, 400 mg) on QT/QTcF duration.