Effects of Single and Multiple Ascending Doses of BI 1358894 in Healthy Male Volunteers on Safety, Tolerability and Pharmacokinetics: Two Phase I Partially Randomised Studies.

INTRODUCTION: The transient receptor potential canonical (TRPC) ion channels have been implicated in the pathophysiology of major depressive disorder (MDD), and TRPC inhibition has been shown to reduce depressive-like behaviour in rodent models of depression. BI 1358894, a small-molecule inhibitor of TRPC ion channels, is currently being developed for the treatment of MDD. OBJECTIVE: Two phase I studies assessed the safety, tolerability, and pharmacokinetics (PK) of oral BI 1358894 in fed and fasted states following a single ascending dose (SAD) [NCT03210272/1402-0001] and multiple ascending doses (MAD) [NCT03754959/1402-0002] in healthy male volunteers. In addition, any potential food effect was evaluated after a single dose. METHODS: In both studies, eligible healthy male volunteers (aged 18-45 years; body mass index of 18.5-29.9 kg/m2) were allocated to receive BI 1358894 or placebo. In the SAD study (1402-0001), volunteers were randomised 3:1 to receive BI 1358894 or placebo in fasted (3, 6, 10, 25, 50, 100, or 200 mg) and fed states (200 mg). The food effect part was conducted as an open-label, randomised, two-way crossover study at doses of 50 and 100 mg in fasted and fed states (high-calorie, high-fat breakfast). For the MAD study (1402-0002), volunteers were randomised 4:1 to receive BI 1358894 (10, 25, 50, 100, or 200 mg) or placebo once daily for 14 days under fed conditions. Primary endpoint (both studies): number of volunteers with drug-related adverse events (DRAEs). Secondary PK endpoints for study 1402-0001: area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC∞), maximum plasma concentration (Cmax), and AUC from time zero to the last quantifiable data time point (AUC0-tz). Secondary PK endpoints for study 1402-0002: AUC over 0-24 h (AUC0-24), Cmax after the first dose, and steady-state AUC and Cmax over a uniform dosing interval (AUCτ,ss and Cmax,ss, respectively) after the last dose. RESULTS: BI 1358894 was well tolerated at doses ≤ 200 mg under all tested conditions and no dose dependency was observed in DRAE frequency for either study. In the SAD study, BI 1358894 exposure increased dose proportionally across 3-50 mg in the fasted state and across 50-200 mg in the fed state. A positive food effect was observed at the tested doses. In the MAD study, BI 1358894 exposure increased less than dose proportionally across 10-200 mg. CONCLUSIONS: These studies demonstrate that BI 1358894 is well tolerated in healthy male volunteers following single and multiple doses, with no dose dependency observed in DRAE frequency. BI 1358894 exposure increased dose dependently in both the SAD and MAD studies, with higher exposure of BI 1358894 observed in the fed state. CLINICALTRIALS REGISTRATION: These trials have been registered on ClinicalTrials.gov: NCT03210272/1402-0001 (registered on 6 July 2017) and NCT03754959/1402-0002 (registered on 27 November 2018).

Midazolam microdosing applied in early clinical development for drug-drug interaction assessment.

AIMS: We aimed to incorporate a pharmacologically inactive midazolam microdose into early clinical studies for the assessment of CYP3A drug-drug interaction liability. METHODS: Three early clinical studies were conducted with substances (Compounds A, B and C) which gave positive CYP3A perpetrator signals in vitro. A 75 µg dose of midazolam was administered alone (baseline CYP3A activity) followed by administration with the highest dose groups tested for each compound on Day 1/3 and Day 14 or Day 17. Midazolam exposure (AUC0-∞ , Cmax ) during administration with the test substances was compared to baseline data via an analysis of variance on log-transformed data. Partial AUC2-4 ratios were also compared to AUC0-∞ ratios using linear regression on log-transformed data. RESULTS: Test compound Cmax values exceeded relevant thresholds for drug-drug interaction liability. Midazolam concentrations were quantifiable over the full profiles for all subjects in all studies. Point estimates of the midazolam AUC0-∞ gMean ratios ranged from 108.3 to 127.1% for Compound A, from 93.3 to 114.5% for Compound B, and from 92.0 to 96.7% for the two highest dose groups of Compound C. Cmax gMean ratios were in the same range. Thus, no relevant drug-drug interactions were evident, based on the results of midazolam microdosing. AUC2-4 ratios from these studies were comparable to the AUC0-∞ ratios. CONCLUSION: Midazolam microdosing incorporated into early clinical studies is a feasible tool for reducing dedicated drug-drug interaction studies, meaning reduced subject burden. Limited sampling could further reduce subject burden, costs and needed resources.

Second language experience impacts first language irony comprehension among bilingual adults.

Recently, core components of irony processing (e.g., mental-state reasoning, executive control, and metalinguistic awareness) have been tentatively linked to bilingual experience. Thus, we investigated whether bilingual experience modulates irony comprehension during first language (L1) reading and also how bilingual adults comprehend irony in positive versus negative contexts (i.e., ironic compliments vs. criticisms, respectively). We deliver 3 main findings. First, bilinguals are faster at processing ironic criticisms than ironic compliments, and they find ironic criticisms more sensible than ironic compliments in their L1, much like past findings among monolinguals. Second, individual differences in bilingual experience modulate comprehension of ironic statements. Specifically, readers with high global second language (L2) proficiency find ironic statements more sensible than readers with low global L2 proficiency, regardless of the valence of the preceding context. Third, individual differences in global L2 proficiency further predict the speed of L1 irony comprehension: following a positive scenario, greater global L2 proficiency patterns with faster processing of irony compared to literal statements. Together, these data suggest that second language experience may be linked to irony processing in the first language. While the precise mechanism underlying this relationship remains open, potential sources may be rooted in flexible social cognition or executive functions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Safety, pharmacokinetics and pharmacodynamics of BI 705564, a highly selective, covalent inhibitor of Bruton's tyrosine kinase, in Phase I clinical trials in healthy volunteers.

AIMS: To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising doses (MRDs) of BI 705564 and establish proof of mechanism. METHODS: BI 705564 was studied in 2 placebo-controlled, Phase I clinical trials testing single-rising doses (1-160 mg) and MRDs (1-80 mg) of BI 705564 over 14 days in healthy male volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A substudy was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies. RESULTS: All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half-life ranged from 10.1 to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single-dose administration. Functional effects of BTK signalling were demonstrated by dose-dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding-related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54.2%) treated with BI 705564. CONCLUSION: BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B-cell activation, and proof of mechanism through effects on allergic skin responses. Mild bleeding-related adverse events were probably related to inhibition of platelet aggregation by BTK inhibition.

Composite midazolam and 1'-OH midazolam population pharmacokinetic model for constitutive, inhibited and induced CYP3A activity.

CYP3A plays an important role in drug metabolism and, thus, can be a considerable liability for drug-drug interactions. Population pharmacokinetics may be an efficient tool for detecting such drug-drug interactions. Multiple models have been developed for midazolam, the typical probe substrate for CYP3A activity, but no population pharmacokinetic models have been developed for use with inhibition or induction. The objective of the current analysis was to develop a composite parent-metabolite model for midazolam which could adequately describe CYP3A drug-drug interactions. As an exploratory objective, parameters were assessed for potential cut-points which may allow for determination of drug-drug interactions when a baseline profile is not available. The final interaction model adequately described midazolam and 1'-OH midazolam concentrations for constitutive, inhibited, and induced CYP3A activity. The model showed good internal and external validity, both with full profiles and limited sampling (2, 2.5, 3, and 4 h), and the model predicted parameters were congruent with values found in clinical studies. Assessment of potential cut-points for model predicted parameters to assess drug-drug interaction liability with a single profile suggested that midazolam clearance may reasonably be used to detect inhibition (4.82-16.4 L/h), induction (41.8-88.9 L/h), and no modulation (16.4-41.8 L/h), with sensitivities for potent inhibition and induction of 87.9% and 83.3%, respectively, and a specificity of 98.2% for no modulation. Thus, the current model and cut-points could provide efficient and accurate tools for drug-drug liability detection, both during drug development and in the clinic, following prospective validation in healthy volunteers and patient populations.

A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug-Drug Interaction Studies.

The calcium channel blocker and antiarrhythmic agent verapamil is recommended by the FDA for drug-drug interaction (DDI) studies as a moderate clinical CYP3A4 index inhibitor and as a clinical Pgp inhibitor. The purpose of the presented work was to develop a mechanistic whole-body physiologically based pharmacokinetic (PBPK) model to investigate and predict DDIs with verapamil. The model was established in PK-Sim®, using 45 clinical studies (dosing range 0.1-250 mg), including literature as well as unpublished Boehringer Ingelheim data. The verapamil R- and S-enantiomers and their main metabolites R- and S-norverapamil are represented in the model. The processes implemented to describe the pharmacokinetics of verapamil and norverapamil include enantioselective plasma protein binding, enantioselective metabolism by CYP3A4, non-stereospecific Pgp transport, and passive glomerular filtration. To describe the auto-inhibitory and DDI potential, mechanism-based inactivation of CYP3A4 and non-competitive inhibition of Pgp by the verapamil and norverapamil enantiomers were incorporated based on in vitro literature. The resulting DDI performance was demonstrated by prediction of DDIs with midazolam, digoxin, rifampicin, and cimetidine, with 21/22 predicted DDI AUC ratios or Ctrough ratios within 1.5-fold of the observed values. The thoroughly built and qualified model will be freely available in the Open Systems Pharmacology model repository to support model-informed drug discovery and development.

Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine.

BACKGROUND AND OBJECTIVE: A novel cocktail containing four substrates of key drug transporters was previously optimized to eliminate mutual drug-drug interactions between the probes digoxin (P-glycoprotein substrate), furosemide (organic anion transporter 1/3), metformin (organic cation transporter 2, multidrug and toxin extrusion protein 1/2-K), and rosuvastatin (organic anion transporting polypeptide 1B1/3, breast cancer resistance protein). This clinical trial investigated the effects of four commonly employed drug transporter inhibitors on cocktail drug pharmacokinetics. METHODS: In a randomized open-label crossover trial in 45 healthy male subjects, treatment groups received the cocktail with or without single oral doses of rifampin, verapamil, cimetidine or probenecid. Concentrations of the probe drugs in serial plasma samples and urine fractions were measured by validated liquid chromatography-tandem mass spectrometry assays to assess systemic exposure. RESULTS: The results were generally in accordance with known in vitro and/or clinical drug-drug interaction data. Single-dose rifampin increased rosuvastatin area under the plasma concentration-time curve up to the last quantifiable concentration (AUC0-tz) by 248% and maximum plasma concentration (Cmax) by 1025%. Probenecid increased furosemide AUC0-tz by 172% and Cmax by 23%. Cimetidine reduced metformin renal clearance by 26%. The effect of single-dose verapamil on digoxin systemic exposure was less than expected from multiple-dose studies (AUC0-tz unaltered, Cmax + 22%). CONCLUSIONS: Taking all the interaction results together, the transporter cocktail is considered to be validated as a sensitive and specific tool for evaluating transporter-mediated drug-drug interactions in drug development. CLINICAL TRIAL REGISTRATION: EudraCT number 2017-001549-29.

A Comprehensive Whole-Body Physiologically Based Pharmacokinetic Drug-Drug-Gene Interaction Model of Metformin and Cimetidine in Healthy Adults and Renally Impaired Individuals.

BACKGROUND: Metformin is a widely prescribed antidiabetic BCS Class III drug (low permeability) that depends on active transport for its absorption and disposition. It is recommended by the US Food and Drug Administration as a clinical substrate of organic cation transporter 2/multidrug and toxin extrusion protein for drug-drug interaction studies. Cimetidine is a potent organic cation transporter 2/multidrug and toxin extrusion protein inhibitor. OBJECTIVE: The objective of this study was to provide mechanistic whole-body physiologically based pharmacokinetic models of metformin and cimetidine, built and evaluated to describe the metformin-SLC22A2 808G>T drug-gene interaction, the cimetidine-metformin drug-drug interaction, and the impact of renal impairment on metformin exposure. METHODS: Physiologically based pharmacokinetic models were developed in PK-Sim® (version 8.0). Thirty-nine clinical studies (dosing range 0.001-2550 mg), providing metformin plasma and urine data, positron emission tomography measurements of tissue concentrations, studies in organic cation transporter 2 polymorphic volunteers, drug-drug interaction studies with cimetidine, and data from patients in different stages of chronic kidney disease, were used to develop the metformin model. Twenty-seven clinical studies (dosing range 100-800 mg), reporting cimetidine plasma and urine concentrations, were used for the cimetidine model development. RESULTS: The established physiologically based pharmacokinetic models adequately describe the available clinical data, including the investigated drug-gene interaction, drug-drug interaction, and drug-drug-gene interaction studies, as well as the metformin exposure during renal impairment. All modeled drug-drug interaction area under the curve and maximum concentration ratios are within 1.5-fold of the observed ratios. The clinical data of renally impaired patients shows the expected increase in metformin exposure with declining kidney function, but also indicates counter-regulatory mechanisms in severe renal disease; these mechanisms were implemented into the model based on findings in preclinical species. CONCLUSIONS: Whole-body physiologically based pharmacokinetic models of metformin and cimetidine were built and qualified for the prediction of metformin pharmacokinetics during drug-gene interaction, drug-drug interaction, and different stages of renal disease. The model files will be freely available in the Open Systems Pharmacology model repository. Current guidelines for metformin treatment of renally impaired patients should be reviewed to avoid overdosing in CKD3 and to allow metformin therapy of CKD4 patients.

No relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone.

Nintedanib and pirfenidone are approved treatments for idiopathic pulmonary fibrosis (IPF). This open-label, two-group trial investigated the pharmacokinetic drug-drug interaction between these two drugs in patients with IPF.Subjects not treated with antifibrotics at screening (group 1, n=20) received a single nintedanib dose (150 mg) followed by pirfenidone (titrated to 801 mg thrice daily) for 3 weeks, with a further single nintedanib dose (150 mg) on the last day (day 23). Subjects treated with pirfenidone at screening (group 2, n=17) continued to receive pirfenidone alone (801 mg thrice daily) for 7 days, then co-administered with nintedanib (150 mg twice daily) for a further 7 days, before single doses of both treatments on day 16.In group 1, adjusted geometric mean (gMean) ratios (with/without pirfenidone) were 88.6% and 80.6% for nintedanib area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax), respectively. In group 2, gMean ratios (with/without nintedanib) were 97.2% and 99.5% for pirfenidone AUC and Cmax, respectively. For all parameters, the 90% confidence intervals included 100%, suggesting similar exposure for administration alone and when co-administered. Both treatments were well tolerated.These data indicate there is no relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when co-administered in IPF patients.

A phase I study to assess afatinib in combination with carboplatin or with carboplatin plus paclitaxel in patients with advanced solid tumors.

PURPOSE: Afatinib, an irreversible ErbB family blocker, has demonstrated preclinical antitumor activity with chemotherapy. METHODS: As part of a phase I trial in patients with advanced solid tumors (NCT00809133; 3 + 3 dose-escalation design), we determined the maximum tolerated dose (MTD) of afatinib with carboplatin (A/C) or with carboplatin plus paclitaxel (A/C/P). Starting doses: afatinib 20 mg/day, carboplatin AUC6 (A/C) with paclitaxel 175 mg/m2 (A/C/P) (chemotherapy: Day 1 of 21-day cycles). The primary objective was to determine the MTDs; safety, pharmacokinetics and antitumor activity were also evaluated. RESULTS: Thirty-eight patients received A/C (n = 12) or A/C/P (n = 26). No dose-limiting toxicities (DLTs) were reported with A(20 mg)/C(AUC6). One patient experienced DLT in the A(40 mg)/C(AUC6) cohort (grade 3 acneiform rash); A(40 mg)/C(AUC6) was determined as the recommended phase II dose (RP2D) for A/C. Two patients each had DLTs with A(20 mg/day)/C(AUC6)/P(175 mg/m2): fatigue, infection, diarrhea, small intestine hemorrhage, dehydration, renal impairment, neutropenic sepsis (n = 1), mucositis (n = 1); A(40 mg)/C(AUC5)/P(175 mg/m2): febrile neutropenia (n = 1), mucositis, fatigue (n = 1); and A(30 mg)/C(AUC5)/P(175 mg/m2): stomatitis (n = 1), mucositis (n = 1). No DLT was observed with A(20 mg)/C(AUC5)/P(175 mg/m2), determined as the RP2D for A/C/P. The most frequent drug-related adverse events were (A/C; A/C/P): rash (75%; 73%), fatigue (67%; 69%), and diarrhea (58%; 88%). Drug plasma concentrations were similar between cycles, suggesting no drug-drug interactions. Objective response rates in these heavily pretreated patients were A/C, 3/12 (25%); A/C/P, 5/26 (19%). CONCLUSIONS: Afatinib 40 mg/day (approved monotherapy dose) with carboplatin AUC6, and afatinib 20 mg/day with carboplatin AUC5 and paclitaxel 175 mg/m2 demonstrated manageable safety and antitumor activity. Afatinib > 20 mg/day in the triple combination was not well tolerated.

Similar Pharmacokinetics of the Adalimumab (Humira®) Biosimilar BI 695501 Whether Administered via Subcutaneous Autoinjector or Prefilled Syringe (VOLTAIRE®-AI and VOLTAIRE®-TAI): Phase 1, Randomized, Open-Label, Parallel-Group Trials.

INTRODUCTION: BI 695501 has shown similar efficacy, safety, and immunogenicity to the adalimumab reference product, Humira®. We present two phase 1 studies comparing the pharmacokinetics, safety, and immunogenicity of BI 695501 delivered via autoinjector (AI) vs. prefilled syringe (PFS). METHODS: Both trials were randomized, open-label, parallel-group studies undertaken in subjects aged ≥ 18-65 years. VOLTAIRE®-AI (NCT02606903) recruited healthy, Caucasian, male, non-athletic volunteers with BMI ≥ 18 to ≤ 30 kg/m2. VOLTAIRE®-TAI (NCT02899338) recruited healthy men and women with BMI > 17.5 to < 35 kg/m2. In both studies, a single dose of BI 695501 40 mg was administered via AI or PFS to the abdomen (VOLTAIRE®-AI) or thigh (VOLTAIRE®-TAI). The observation period was 43/57 days and the safety follow-up was 70 days. Co-primary endpoints were AUC0-1032 or AUC0-1368, Cmax, and AUC0-∞. Safety and immunogenicity were assessed. RESULTS: Subjects (VOLTAIRE®-AI: N = 71; VOLTAIRE®-TAI: N = 162) were randomized to AI (n = 35; n = 81) or PFS (n = 36; n = 81). Baseline characteristics were balanced between treatment groups in each study. Total exposure of BI 695501 was similar for both groups; adjusted geometric mean ratios for AUC0-∞, AUC0-1032, and Cmax were 106.17, 104.09, and 114.83%, respectively, for VOLTAIRE®-AI; 103.19, 101.71 (AUC0-1368), and 100.11% for VOLTAIRE®-TAI. In both studies, similar immunogenicity was observed between groups in terms of frequency of binding and neutralizing anti-drug antibody-positive subjects. Incidence of adverse events was similar for both groups. CONCLUSIONS: Pharmacokinetics and immunogenicity of BI 695501 delivered via AI were similar to administration using a PFS, independent of injection site. No differences are expected between AI and PFS use in clinical practice. FUNDING: Boehringer Ingelheim.

Pharmacokinetics/Pharmacodynamics of Dabigatran 75 mg Twice Daily in Patients With Nonvalvular Atrial Fibrillation and Severely Impaired Renal Function.

INTRODUCTION: Dabigatran etexilate is an oral direct thrombin inhibitor. Dabigatran excretion is 80% renal, so exposure increases with severity of renal failure. The US Food and Drug Administration-approved dabigatran etexilate 75 mg twice daily (BID) for patients with nonvalvular atrial fibrillation (NVAF) having severely impaired renal function (creatinine clearance: 15-30 mL/min), based on post hoc pharmacokinetic modeling. We assessed dabigatran exposure at trough and peak levels in patients with NVAF and severely impaired renal function and compared with model predictions. METHODS: Patients received dabigatran etexilate (75 mg BID) for ≥7 days before blood sampling; Cpre,ss (steady-state predose concentration; trough) was taken 10 to 16 hours postdose (prior to next dose), and C2,ss (steady-state concentration; peak) was taken 2 hours (± 30 minutes) postdose. Pharmacodynamic parameters at baseline (Ebase), trough concentrations (Epre,ss), and peak concentrations (E2,ss) were assessed by established coagulation assays. RESULTS: Of the 150 patients screened, 60 were treated, of which 40% were male and 78.3% were white; median age was 84 years. Cpre,ss values (n = 51) were close to pharmacokinetic modeling predictions with a geometric mean (gMean) of 155 ng/mL, geometric coefficient of variation (gCV) of 76.9%, and range of 15.6 to 498 ng/mL. The C2,ss values (n = 59) had a gMean of 202 ng/mL, gCV of 70.6%, and range of 42.0 to 680 ng/mL. Pharmacodynamic effects on coagulation paralleled dabigatran concentrations. Eleven (18.3%) patients had ≥1 adverse event (AE); pharmacokinetic results for these patients versus those without AEs (n = 49) were Cpre, ss: gMean = 206 versus 145 ng/mL, gCV = 64.0% versus 78.3%; C2,ss: gMean = 243 versus 193 ng/mL, gCV = 68.9% versus 70.8%. All bleeding events (8 events in 5 patients) were considered minor by the investigators. CONCLUSION: Dabigatran exposure levels largely confirmed earlier pharmacokinetic predictions, supporting the use of dabigatran etexilate 75 mg BID in patients with NVAF and severely impaired renal function. Pharmacodynamic results were also in agreement with earlier studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01896297.

Nintedanib with Add-on Pirfenidone in Idiopathic Pulmonary Fibrosis. Results of the INJOURNEY Trial.

RATIONALE: Nintedanib and pirfenidone slow the progression of idiopathic pulmonary fibrosis (IPF), but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with nintedanib and add-on pirfenidone. OBJECTIVES: To investigate safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in patients treated with nintedanib and add-on pirfenidone versus nintedanib alone. METHODS: Patients with IPF and FVC greater than or equal to 50% predicted at screening who completed a 4- to 5-week run-in with nintedanib 150 mg twice daily without dose reduction or treatment interruption were randomized to receive nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times daily) or nintedanib 150 mg twice daily alone in an open-label manner for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to Week 12. Analyses were descriptive and exploratory. MEASUREMENTS AND MAIN RESULTS: On-treatment gastrointestinal adverse events were reported in 37 of 53 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 of 51 patients (52.9%) treated with nintedanib alone. Predose plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone. Mean (SE) changes from baseline in FVC at Week 12 were -13.3 (17.4) ml and -40.9 (31.4) ml in patients treated with nintedanib with add-on pirfenidone (n = 48) and nintedanib alone (n = 44), respectively. CONCLUSIONS: Nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF, in line with the adverse event profiles of each drug. These data support further research into combination regimens in the treatment of IPF. Clinical trial registered with www.clinicaltrials.gov (NCT02579603).

Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study.

BACKGROUND AND OBJECTIVE: Afatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib. METHODS: This was an open-label, single-dose study. Pharmacokinetic parameters after afatinib 40 mg were investigated in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate 30-59 mL/min/1.73 m2 and 15-29 mL/min/1.73 m2, respectively) and healthy matched controls (n = 14). Plasma and urine samples were collected before and up to 14 days after dosing for pharmacokinetic and plasma protein-binding assessment. Primary endpoints were area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) and maximum plasma concentration (C max) between subjects with renal impairment and healthy matched controls. RESULTS: Pharmacokinetic profiles and plasma protein binding were similar in all groups. The extent of exposure, as indicated by AUClast and C max, was generally similar between the matched treatment groups, with the exception of the geometric mean ratio of AUClast for subjects with severe renal impairment, which showed a trend towards a higher value compared with matched healthy subjects (150.0 % [90 % CI 105.3-213.7]) Inter-individual variability was moderate (geometric mean coefficient of variation 28-39 % for moderate impairment, 34-42 % for severe impairment). Afatinib was well tolerated and urinary excretion was minimal. CONCLUSION: Moderate-to-severe renal impairment had a minor influence on the pharmacokinetics of afatinib that was within the observed inter-individual variability, suggesting that afatinib treatment can be considered in this patient population. Registered at ClinicalTrials.gov as NCT02096718.

Opposing effects of hypoxia on catecholaminergic locus coeruleus and hypocretin/orexin neurons in chick embryos.

Terrestrial vertebrate embryos face a risk of low oxygen availability (hypoxia) that is especially great during their transition to air-breathing. To better understand how fetal brains respond to hypoxia, we examined the effects of low oxygen availability on brain activity in late-stage chick embryos (day 18 out of a 21-day incubation period). Using cFos protein expression as a marker for neuronal activity, we focused on two specific, immunohistochemically identified cell groups known to play an important role in regulating adult brain states (sleep and waking): the noradrenergic neurons of the Locus Coeruleus (NA-LC), and the Hypocretin/Orexin (H/O) neurons of the hypothalamus. cFos expression was also examined in the Pallium (the avian analog of the cerebral cortex). In adult mammalian brains, cFos expression changes in a coordinated way in these areas. In chick embryos, oxygen deprivation simultaneously activated NA-LC while deactivating H/O-producing neurons; it also increased cFos expression in the Pallium. Activity in one pallial primary sensory area was significantly related to NA-LC activity. These data reveal that at least some of the same neural systems involved in brain-state control in adults may play a central role in orchestrating prenatal hypoxic responses, and that these circuits may show different patterns of coordination than seen in adults.

Sleep and sleepiness in children with attention deficit / hyperactivity disorder and controls.

The present study assessed the association between habitual sleep patterns and one night of PSG measured sleep with daytime sleepiness in children with ADHD and typically developing children. Eighty-two children (26 ADHD, 56 typically developing children), between 7 and 11 years, had nighttime sleep recorded using actigraphy over five nights (habitual sleep patterns) and polysomnography during one night (immediate sleep patterns), both within their home environments. Daytime sleepiness was examined using the multiple sleep latency test within a controlled laboratory setting the following day. Using Spearman correlations, the relationships between mean sleep latencies on the multiple sleep latency test and scores on a modified Epworth Sleepiness Scale with polysomnographic measures of sleep quality and architecture and with actigraphic sleep quality measures were examined. Longer sleep latency, measured using polysomnography and actigraphy, was related to longer mean sleep latencies on the multiple sleep latency test in typically developing participants, whereas actigraphic measures of sleep restlessness (time awake and activity during the night), as well as time in slow-wave sleep, were positively related to mean sleep latency on the multiple sleep latency test in children with ADHD. These results show a differential relationship for children with ADHD and typically developing children between habitual and immediate sleep patterns with daytime sleepiness and suggest that problems initiating and maintaining sleep may be present both in nighttime and daytime sleep.

Contributions of circadian tendencies and behavioral problems to sleep onset problems of children with ADHD.

BACKGROUND: Children with attention-deficit/hyperactivity disorder (ADHD) are two to three times more likely to experience sleep problems. The purpose of this study is to determine the relative contributions of circadian preferences and behavioral problems to sleep onset problems experienced by children with ADHD and to test for a moderation effect of ADHD diagnosis on the impact of circadian preferences and externalizing problems on sleep onset problems. METHODS: After initial screening, parents of children meeting inclusion criteria documented child bedtime over 4 nights, using a sleep log, and completed questionnaires regarding sleep, ADHD and demographics to assess bedtime routine prior to PSG. On the fifth night of the study, sleep was recorded via ambulatory assessment of sleep architecture in the child's natural sleep environment employing portable polysomnography equipment. Seventy-five children (26 with ADHD and 49 controls) aged 7-11 years (mean age 8.61 years, SD 1.27 years) participated in the present study. RESULTS: In both groups of children, externalizing problems yielded significant independent contributions to the explained variance in parental reports of bedtime resistance, whereas an evening circadian tendency contributed both to parental reports of sleep onset delay and to PSG-measured sleep-onset latency. No significant interaction effect of behavioral/circadian tendency with ADHD status was evident. CONCLUSIONS: Sleep onset problems in ADHD are related to different etiologies that might require different interventional strategies and can be distinguished using the parental reports on the CSHQ.

Impact of sleep extension and restriction on children's emotional lability and impulsivity.

OBJECTIVE: To examine the impact of moderate sleep extension and restriction on child behavior in school. METHODS: We conducted a randomized parallel group study to determine the impact of an experimental sleep extension (addition of 1 hour of sleep relative to baseline habitual sleep duration on weekdays) and experimental sleep restriction (elimination of 1 hour of sleep relative to baseline habitual sleep duration on weekdays) on child behavior in school. The primary outcome measures were scores on the Conners' Global Index Scale, as determined by teachers blinded to sleep status of the participants. A sample of 34 typically developing children aged 7 to 11 years with no reported sleep problems and no behavioral, medical, or academic issues participated in the study. RESULTS: Our main findings were that (1) a cumulative extension of sleep duration of 27.36 minutes was associated with detectable improvement in Conners' Global Index-derived emotional lability and restless-impulsive behavior scores of children in school and a significant reduction in reported daytime sleepiness; and (2) a cumulative restriction of sleep of 54.04 minutes was associated with detectable deterioration on such measures. CONCLUSIONS: A modest extension in sleep duration was associated with significant improvement in alertness and emotional regulation, whereas a modest sleep restriction had opposite effects.

Sleep patterns and the risk for unipolar depression: a review.

Psychological disorders, particularly mood disorders, such as unipolar depression, are often accompanied by comorbid sleep disturbances, such as insomnia, restless sleep, and restricted sleep duration. The nature of the relationship between unipolar depression and these sleep disturbances remains unclear, as sleep disturbance may be a risk factor for development, an initial manifestation of the disorder, or a comorbid condition affected by similar mechanisms. Various studies have examined the impact of sleep deprivation on the presence of (or exacerbation of) depressive symptoms, and have examined longitudinal and concurrent associations between different sleep disturbances and unipolar depression. This review examines the evidence for sleep disturbances as a risk factor for the development and presence of depression, as well as examining common underlying mechanisms. Clinical implications pertaining to the comorbid nature of various sleep patterns and depression are considered.