Safety, Tolerability, and Pharmacokinetics of Valemetostat Tablets and the Effect of Food on Valemetostat Pharmacokinetics in Healthy Subjects: Two Phase 1 Studies.

Valemetostat is an oral, selective inhibitor of enhancer of zeste homolog-2 (EZH2) and EZH1. In a first-in-human phase-1 trial, valemetostat capsules were well tolerated and clinically active in patients with relapsed/refractory non-Hodgkin lymphoma. Subsequently, a film-coated tablet formulation was developed for future clinical trials and commercialization. We report outcomes from 2 phase 1 trials in healthy Japanese participants, assessing the safety, tolerability, and pharmacokinetics (PK) of valemetostat tablets at single ascending doses (50, 100, and 200-mg), the relative bioavailability between capsules and tablets, and the effect of food (high-fat or low-fat meals) on the PK of valemetostat tablets. In the ascending-dose study, valemetostat maximum plasma concentration (Cmax ) and area under the concentration-time curve (AUC) increased dose-proportionally. Valemetostat plasma PK parameters were similar between the capsule and tablet formulations following a single 200-mg dose. Administration of valemetostat, 200 mg after a meal, was associated with 50%-60% lower Cmax , 30%-50% lower AUC, and a median Tmax delay of 2.5-3 hours relative to fasted administration. Valemetostat was well tolerated in healthy subjects; treatment-emergent adverse events were mild (grade 1) in severity. Based on these trials, the tablet formulation of valemetostat is suitable for use in subsequent clinical trials and should be administered under fasted conditions to avoid a negative food effect.

Predictive Performance of Physiology-Based Pharmacokinetic Dose Estimates for Pediatric Trials: Evaluation With 10 Bayer Small-Molecule Compounds in Children.

Development and guidance of dosing schemes in children have been supported by physiology-based pharmacokinetic (PBPK) modeling for many years. PBPK models are built on a generic basis, where compound- and system-specific parameters are separated and can be exchanged, allowing the translation of these models from adults to children by accounting for physiological differences. Owing to these features, PBPK modeling is a valuable approach to support clinical decision making for dosing in children. In this analysis, we evaluate pediatric PBPK models for 10 small-molecule compounds that were applied to support clinical decision processes at Bayer for their predictive power in different age groups. Ratios of PBPK-predicted to observed PK parameters for the evaluated drugs in different pediatric age groups were estimated. Predictive performance was analyzed on the basis of a 2-fold error range and the bioequivalence range (ie, 0.8 ≤ predicted/observed ≤ 1.25). For all 10 compounds, all predicted-to-observed PK ratios were within a 2-fold error range (n = 27), with two-thirds of the ratios within the bioequivalence range (n = 18). The findings demonstrate that the pharmacokinetics of these compounds was successfully and adequately predicted in different pediatric age groups. This illustrates the applicability of PBPK for guiding dosing schemes in the pediatric population.

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High-Dose Intravenous Administration in Young Children With Benzodiazepine-Refractory Status Epilepticus.

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 µg/mL for LEV, 11.3 to 26.7 µg/mL for PHT and 126 to 223 µg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.

Population Pharmacokinetic Analysis of the Cathepsin K Inhibitor Odanacatib: Insights Into Intrinsic and Extrinsic Factor Effects on Exposure in Postmenopausal and Elderly Women.

This analysis developed a population pharmacokinetic (PK) model for odanacatib, characterized demographic and concomitant medication covariates effect, and provided odanacatib exposure estimates for subjects in phase 2/3 studies. Data from multiple phase 1 (P005, P025, and P014), phase 2b (P004 and P022), and phase 3 (Long-Term Odanacatib Fracture Trial; P018) studies were pooled to create a data set of 1280 postmenopausal women aged 45 to 91 years (102 from phase 1, 514 from phase 2b, and 664 from phase 3) who received weekly oral odanacatib doses ranging from 3 to 100 mg. A 1-compartment model with first-order absorption, dose-dependent relative bioavailability (F1), and first-order elimination best described odanacatib PK. F1 decreased from the 100% reference bioavailability for a 3-mg oral dose to 24.5% for a 100-mg dose. Eight statistically significant covariates were included in the final PK model: body weight, age, race, and concomitant cytochrome P450 (CYP)3A inhibitors on apparent clearance; body weight on apparent central volume of distribution; and concomitant hydrochlorothiazide, high-fat breakfast, and a study effect on F1. All fixed- and random-effects parameters were estimated with good precision (%standard error of the mean ≤29.5%). This population PK analysis provides insights into intrinsic- and extrinsic-factor effects on odanacatib exposure in postmenopausal and elderly women with osteoporosis. The magnitude of the intrinsic-factor effects was generally modest (odanacatib exposure geometric mean ratios, 0.80-1.21) even in subjects aged >80 years, or in subsets with multiple combinations of factors.

Usability of Functional MRI in Clinical Studies for Fast and Reliable Assessment of Renal Perfusion and Quantification of Hemodynamic Effects on the Kidney.

The purpose of this study was to evaluate contrast-media-free arterial spin labeling, a technique of functional magnetic resonance imaging (MRI), for assessment of kidney perfusion in a clinical study. We examined renal perfusion by arterial spin labeling in 15 healthy adults using a clinical 1.5-T MRI system, twice under baseline conditions and 60 minutes after a single oral dose of 50 mg captopril. Data evaluation included assessment of interstudy and interrater reproducibility in addition to the pharmacological effect of captopril on kidney perfusion and a sample size calculation for potential application of the technique in pharmacological intervention studies. Interstudy reproducibility of cortical and medullary kidney perfusion was excellent (intraclass correlation coefficients 0.77 and 0.83, respectively). Interrater reproducibility was excellent in the cortex and good in the medulla (intraclass correlation coefficients 0.97 and 0.66, respectively). Ingestion of 50 mg captopril was associated with an 11% drop of systolic blood pressure and a rise in kidney perfusion by 22% in the cortex (369 ± 48 vs 452 ± 56 mL/[min·100 g], P < .001) and 26% in the medulla (157 ± 39 to 198 ± 45 ml/[min·100 g]; P < .01). Statistical power analysis revealed that a small sample size of only 6 participants is needed in a clinical trial to capture an equal change in kidney perfusion to the one induced by 50 mg captopril with a statistical power of 82% and an α error of 0.05. In conclusion, funtional MRI with arterial spin labeling is a reliable method for quantification of kidney perfusion and for fast assessment of pharmacologically induced renal perfusion changes, allowing low case numbers.

Pharmacokinetic, Pharmacodynamic, and Safety Profile of a Novel Anti-CD28 Domain Antibody Antagonist in Healthy Subjects.

We report pharmacokinetics, pharmacodynamics, and safety of a novel anti-CD28 domain antibody antagonist (lulizumab pegol) in healthy subjects following single- or multiple-dose administration. A minimal anticipated biological effect level approach was used to select a 0.01 mg starting dose for a single-ascending-dose (SAD), double-blind, first-in-human study. Part 1 included 9 intravenous (IV; 0.01-100 mg) and 3 subcutaneous (SC; 9-50 mg) doses or placebo. In part 2, a keyhole limpet hemocyanin (KLH) immunization was performed in 16 subjects/panel, who received 1 of 3 IV doses (9-100 mg) or placebo. In a double-blind, multiple-ascending-dose (MAD) study, subjects received SC lulizumab 6.25 mg every 2 weeks, 12.5 mg weekly, 37.5 mg weekly, or placebo. Among 180 treated subjects, 169 completed the studies. Peak concentrations and areas under the curve from time 0 to infinity increased dose proportionally. Estimated SC bioavailability was 68.2%. Receptor occupancy of approximately ≥80% was maintained for ≥2 weeks at ≥9-mg doses (SAD) and throughout the dosing interval (MAD). IV doses ≥9 mg inhibited antibody production against KLH for 2 weeks. No significant cytokine or immune cell changes were observed. No immunogenicity responses persisted, and there was no correlation to adverse events. Headache occurred in 21 SAD and 4 MAD subjects receiving lulizumab; in the MAD study 5 lulizumab subjects experienced infections. Lulizumab IV or SC was safe at all doses studied, without evidence of cytokine release.

A Pharmacokinetic Study Comparing Eslicarbazepine Acetate Administered Orally as a Crushed or Intact Tablet in Healthy Volunteers.

The relative bioequivalence of crushed versus intact eslicarbazepine acetate (ESL) tablets (800 mg) administered orally in healthy adults was evaluated in an open-label, randomized, 2-period crossover study with a 5-day washout between treatments. Sample blood levels of eslicarbazepine and (R)-licarbazepine were determined; pharmacokinetic parameters were derived for eslicarbazepine. Bioequivalence was established if the 90% confidence intervals (CIs) for the geometric mean treatment ratios of eslicarbazepine AUC(0-∞) and Cmax were within the prespecified 80%-125% range. Twenty-seven subjects in the intent-to-treat population (n = 28) completed both treatment periods. Eslicarbazepine exposure measures were similar for crushed versus intact ESL tablets: average Cmax , 11 700 versus 11 500 ng/mL; AUC(0-∞) , 225 000 versus 234 000 ng·h/mL; AUC(0-last) , 222 000 versus 231 000 ng·h/mL, respectively. Geometric least squares mean ratios (90%CIs) comparing eslicarbazepine exposure measures were within the 80%-125% range (Cmax , 102.63% [97.07%-108.51%]; AUC(0-∞) , 96.72% [94.36%-99.13%]; AUC0-last , 96.69% [94.24%-99.21%]). In conclusion, ESL administered orally as a crushed tablet sprinkled on applesauce, or intact were bioequivalent in healthy subjects. Eslicarbazepine bioavailability was not significantly altered by crushing, indicating that ESL tablets can be administered intact or crushed.

Pharmacokinetics, pharmacodynamics and safety of CEP-26401, a high-affinity histamine-3 receptor antagonist, following single and multiple dosing in healthy subjects.

CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3R) antagonist, with potential therapeutic utility in cognition enhancement. Two randomized, double-blind, placebo-controlled dose escalation studies with single (0.02 to 5 mg) or multiple administration (0.02 to 0.5 mg once daily) of CEP-26401 were conducted in healthy subjects. Plasma and urine samples were collected to investigate CEP-26401 pharmacokinetics. Pharmacodynamic endpoints included a subset of tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and nocturnal polysomnography. Population pharmacokinetic-pharmacodynamic modeling was conducted on one CANTAB and one polysomnography parameter of interest. CEP-26401 was slowly absorbed (median tmax range 3-6 hours) and the mean terminal elimination half-life ranged from 24-60 hours. Steady-state plasma concentrations were achieved within six days of dosing. CEP-26401 exhibits dose- and time-independent pharmacokinetics, and renal excretion is a major elimination pathway. CEP-26401 had a dose-dependent negative effect on sleep, with some positive effects on certain CANTAB cognitive parameters seen at lower concentrations. The derived three compartment population pharmacokinetic model, with first-order absorption and elimination, accurately described the available pharmacokinetic data. CEP-26401 was generally well tolerated up to 0.5 mg/day with most common treatment related adverse events being headache and insomnia. Further clinical studies are required to establish the potential of low-dose CEP-26401 in cognition enhancement.

Interactions of the hepatitis C virus protease inhibitor faldaprevir with cytochrome P450 enzymes: in vitro and in vivo correlation.

The potential inhibition of the major human cytochrome P450 (CYP) enzymes by faldaprevir was evaluated both in vitro and in clinical studies (healthy volunteers and hepatitis C virus [HCV] genotype 1-infected patients). In vitro studies indicated that faldaprevir inhibited CYP2B6, CYP2C9, and CYP3A, and was a weak-to-moderate inactivator of CYP3A4. Faldaprevir 240 mg twice daily in healthy volunteers demonstrated moderate inhibition of hepatic and intestinal CYP3A (oral midazolam: 2.96-fold increase in AUC(0-24 h)), weak inhibition of hepatic CYP3A (intravenous midazolam: 1.56-fold increase in AUC(0-24 h)), weak inhibition of CYP2C9 ([S]-warfarin: 1.29-fold increase in AUC(0-120 h)), and had no relevant effects on CYP1A2, CYP2B6, or CYP2D6. Faldaprevir 120 mg once daily in HCV-infected patients demonstrated weak inhibition of hepatic and intestinal CYP3A (oral midazolam: 1.52-fold increase in AUC(0-∞)), and had no relevant effects on CYP2C9 or CYP1A2. In vitro drug-drug interaction predictions based on inhibitor concentration ([I])/inhibition constant (Ki) ratios tended to overestimate clinical effects and a net-effect model provided a more accurate approach. These studies suggest that faldaprevir shows a dose-dependent inhibition of CYP3A and CYP2C9, and does not induce CYP isoforms.