Tine Laethem

Multiple-dose pharmacodynamics and pharmacokinetics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the heteroexchange of cholesteryl esters from high‐density lipoprotein (HDL) and triglycerides to apolipoprotein B–containing lipoproteins, especially very low–density lipoproteins (LDL‐C). 1, 2

Single‐dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects

AIMS Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. METHODS Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. RESULTS Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. CONCLUSIONS Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.

Tissue Penetration by Ertapenem, a Parenteral Carbapenem Administered Once Daily, in Suction-Induced Skin Blister Fluid in Healthy Young Volunteers

ABSTRACT The penetration of 1 g of intravenous ertapenem once daily for 3 days in suction-induced skin blisters was evaluated. Ten forearm blisters were formed (n = 12) 12 h prior to the last dose. Concentrations of ertapenem in blister fluid exceeded 4 μg/ml (the MIC at which 90% of the isolates tested are eliminated) for the entire dosing interval. The area under the concentration-time curve for 0 to 24 h ratio of blister fluid to plasma was 61% (90% confidence interval, 56, 65%) suggesting good blister penetration.

Assessment of the CYP3A‐Mediated Drug Interaction Potential of Anacetrapib, a Potent Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Volunteers

In this study, midazolam was used as a probe‐sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe‐inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2‐period, fixed‐sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0‐∞ and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole—specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0‐∞ and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.

Single- and Multiple-Dose Pharmacokinetics and Tolerability of Telcagepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, in Adults

Telcagepant is a novel, orally active, and selective calcitonin gene‐related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half‐life was approximately 6 hours. A greater than dose‐proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice‐daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.

Image-derived input function for [11C]flumazenil kinetic analysis in human brain

PURPOSE We describe a method for analysis of [11C]flumazenil data using an input curve directly derived from the positron emission tomography (PET) images. PROCEDURE The shape of the tracer plasma curve was obtained from the product of the intact flumazenil fraction in plasma in six arterial samples and the internal carotid artery time-activity curve (TAC). The resulting curve was calibrated using the [11C]flumazenil concentration in three of the six samples. The curve peak was recovered by adding an exponential function to the scaled curve whose parameters were estimated from simultaneous fittings of several tissue TACs assuming that all regions share the same input. RESULTS Good agreement was found between the image-derived and the experimental plasma curves in six subjects. Distribution volumes were highly correlated with linear regression slope and intercept values between [0.94, 1.03] and [-0.10, 0.16], respectively. CONCLUSION The proposed method is suitable for benzodiazepine receptor quantification requiring only a few blood samples.

UGT2B17 Genetic Polymorphisms Dramatically Affect the Pharmacokinetics of MK-7246 in Healthy Subjects in a First-in-Human Study

MK‐7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first‐in‐human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK‐7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK‐7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild‐type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25‐ and 82‐fold greater mean dose‐normalized values of area under the plasma concentration–time curve (AUC) and peak concentration of MK‐7246, respectively, and a 24‐fold lower M3‐to‐MK‐7246 AUC ratio. The apparent half‐life of MK‐7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK‐7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first‐pass metabolism of MK‐7246.

Effect of Sitagliptin on the Pharmacokinetics of Simvastatin

P atients with type 2 diabetes are at an increased risk for cardiovascular morbidity and mortality. Treatment with HMG-CoA reductase inhibitors (statins) reduces the risk of cardiovascular events in patients with diabetes. Treatment guidelines consider diabetes as a coronary heart disease risk equivalent and recommend statin therapy for patients with diabetes. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antihyperglycemic agents. Sitagliptin, a highly selective DPP-4 inhibitor, is available in many countries for the treatment of patients with type 2 diabetes. Because sitagliptin and a statin may be commonly administered to patients with type 2 diabetes, the potential for sitagliptin to alter the pharmacokinetics of simvastatin, a CYP3A4 substrate, was evaluated in this study. The metabolism of simvastatin is complex, resulting in the generation of multiple active and inactive metabolites. Active HMG-CoA reductase inhibitors represent the total pool of pharmacologically active species in plasma following simvastatin administration (ie, simvastatin acid and other active metabolites). Therefore, assessment of the AUC0-last for active HMGCoA reductase inhibitors was the primary endpoint in this study. The pharmacokinetic parameters for simvastatin (lactone; pharmacologically inactive), simvastatin acid (active), and total HMG-CoA reductase inhibitors were secondary endpoints in this study.

A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina

Telcagepant is a calcitonin gene‐related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double‐blind, randomized, placebo‐controlled, two‐period, crossover study in patients with stable angina and reproducible exercise‐induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at Tmax (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two‐sided 90% confidence interval (CI) for the mean treatment difference (telcagepant–placebo) in TET was more than −60 s. There were no significant between‐treatment differences in TET (mean treatment difference: −6.90 (90% CI: −17.66, 3.86) seconds), maximum exercise heart rate, or time to 1‐mm ST‐segment depression using pooled data or with stratification for dose.

On-the-Road Driving Performance the Morning after Bedtime Use of Suvorexant 20 and 40 mg : A Study in Non-Elderly Healthy Volunteers

STUDY OBJECTIVE To evaluate next-morning driving performance in adults younger than 65 years, after single and repeated doses of suvorexant 20 and 40 mg. DESIGN Double-blind, placebo-controlled, 4-period crossover study. SETTING Maastricht University, The Netherlands. PARTICIPANTS 28 healthy volunteers (15 females), aged 23 to 64 years. INTERVENTIONS Suvorexant (20 and 40 mg) for 8 consecutive nights; zopiclone 7.5 mg nightly on day 1 and 8; placebo. MEASUREMENTS Performance on day 2 and 9 (9 h after dosing) using a one-hour standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo changes in SDLP > 2.4 cm were considered to reflect meaningful driving impairment. RESULTS Mean drug-placebo changes in SDLP following suvorexant 20 and 40 mg were 1.01 and 1.66 cm on day 2, and 0.48 and 1.31 cm on Day 9, respectively. The 90% CIs of these changes were all below 2.4 cm. Symmetry analysis showed that more subjects had SDLP changes > 2.4 cm than < -2.4 cm following suvorexant 20 and 40 mg on day 2, and following suvorexant 40 mg on day 9. Four female subjects requested that a total of 5 driving tests--all following suvorexant--stop prematurely due to self-reported somnolence. CONCLUSIONS As assessed by mean changes in standard deviation of lateral position (SDLP), there was no clinically meaningful residual effect of suvorexant in doses of 20 and 40 mg on next-morning driving (9 h after bedtime dosing) in healthy subjects < 65 years old. There may be some individuals who experience next-day effects, as suggested by individual changes in SDLP and prematurely stopped tests. CLINICAL TRIAL REGISTRATION clinicaltrials.gov NCT01311882.