Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies.

AIMS: Idarucizumab, a humanized monoclonal anti-dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre-existing and treatment-emergent anti-idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre-existing and treatment-emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab. METHODS: Data were pooled from three Phase I, randomized, double-blind idarucizumab studies in healthy Caucasian subjects; elderly, renally impaired subjects; and healthy Japanese subjects. In plasma sampled before and after idarucizumab dosing, ADA were detected and titrated using a validated electrochemiluminescence method. ADA epitope specificities were examined using idarucizumab and two structurally related molecules. Idarucizumab PK/PD data were compared for subjects with and without pre-existing ADA. RESULTS: Pre-existing ADA were found in 33 out of 283 individuals (11.7%), seven of whom had intermittent ADA. Titres of pre-existing and treatment-emergent ADA were low, estimated equivalent to <0.3% of circulating idarucizumab after a 5 g dose. Pre-existing ADA had no impact on dose-normalized idarucizumab maximum plasma levels and exposure and, although data were limited, no impact on the reversal of dabigatran-induced anticoagulation by idarucizumab. Treatment-emergent ADA were detected in 20 individuals (19 out of 224 treated [8.5%]; 1 out of 59 received placebo [1.7%]) and were transient in ten. The majority had specificity primarily toward the C-terminus of idarucizumab. There were no adverse events indicative of immunogenic reactions. CONCLUSION: Pre-existing and treatment-emergent ADA were present at extremely low levels relative to the idarucizumab dosage under evaluation. The PK/PD of idarucizumab appeared to be unaffected by the presence of pre-existing ADA.

A phase I, randomized, proof-of-clinical-mechanism study assessing the pharmacokinetics and pharmacodynamics of the oral PDE9A inhibitor BI 409306 in healthy male volunteers.

OBJECTIVE: Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE) inhibitors are hypothesized to improve cognition in schizophrenia and Alzheimer disease by increasing cGMP levels in certain brain regions. This phase I, randomized, parallel-group, double-blind, placebo-controlled study provides proof-of-mechanism evidence for BI 409306, a novel, oral PDE9A inhibitor. METHODS: In healthy males, exposure of BI 409306 (25-, 50-, 100-, and 200-mg single dose) and placebo was assessed in plasma and cerebrospinal fluid (CSF). Effect of BI 409306 on CSF cGMP levels was evaluated, and adverse events (AEs) were monitored. RESULTS: In all enrolled subjects (N = 20), plasma BI 409306 concentration increased rapidly (median tmax : 0.75-1.25 hr) followed by rapid increases in CSF (median tmax : 1.5-2.0 hr). Maximum CSF cGMP concentrations were achieved within 2 to 5 hr, declining to baseline levels 10 to 14 hr after dosing. Dose-dependent increases in plasma and CSF exposure and CSF cGMP were shown. BI 409306 was safe and well tolerated. Most AEs were mild to moderate in intensity and study procedure-related. CONCLUSIONS: BI 409306 increased rapidly in plasma and was subsequently detected in CSF, resulting in dose-dependent increases in cGMP levels in CSF. Results indicate BI 409306 efficiently crosses the blood-CSF barrier, with an acceptable level of AEs.

Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study. METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830. FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.

First-in-human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males.

AIMS: The aim of the present study was to investigate the safety, tolerability, dose proportionality and relative bioavailability of tablet and oral solution formulations of BI 409306 in healthy male subjects, and to compare the safety and pharmacokinetics in subjects who were extensive metabolizers (EMs) or poor metabolizers (PMs) of cytochrome P450 (CYP)-2C19. METHODS: The present randomized, double-blind, placebo-controlled, single-centre study evaluated single rising doses of BI 409306 (0.5-500 mg) administered as a tablet or oral solution to EMs or PMs. RESULTS: Of 80 enrolled subjects (mean age 36.7 years), 79 (CYP2C19 EMs, 71; CYP2C19 PMs, eight) received treatment and completed the study. Adverse events (AEs) were mild to moderate in intensity. Overall, 17/71 (23.9%) EMs and 6/8 (75.0%) PMs experienced 28 and eight AEs, respectively, of which, 25 and seven AEs, respectively, were considered to be drug related. The most frequently reported AEs were nervous system and eye disorders; all occurred shortly (20-30 min) after administration and mostly resolved within 1-2 h. No serious AEs occurred. BI 409306 systemic absorption and elimination were rapid; peak plasma concentration (Cmax ) was reached <1 h after drug administration, and the half-life ranged from 0.99 h to 2.71 h. Both the tablet and oral solution resulted in similar exposures. In PMs, at dose levels of 10 mg and 100 mg, Cmax was 2.2-2.3-fold higher, and the area under the plasma concentration-time curve over the time interval 0 extrapolated to infinity was 4.1-5.0-fold higher compared with EMs. CONCLUSIONS: In healthy male subjects, BI 409306 was generally safe and well tolerated, with rapid absorption and elimination. Systemic exposure was higher in CYP2C19 PMs than EMs at the same dose level.

Pharmacokinetics, safety, and tolerability of faldaprevir in patients with renal impairment.

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC0-∞) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.).

Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm Phase I trial (VOLTAIRE-HCLF).

OBJECTIVE: VOLTAIRE-HCLF compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers. METHODS: Healthy volunteers (N = 200) aged 18-55 years and with body mass index of 18.5-29.9 kg/m2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days. RESULTS: The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC0-1344, AUC0-∞, and Cmax for both groups were entirely within the standard 80-125% bioequivalence acceptance range at 101.88% (93.31-111.23%), 105.38% (95.06-116.81%), and 91.29% (84.38-98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation. CONCLUSIONS: Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated. CLINICAL TRIAL REGISTRATION: NCT05203289.

Safety and efficacy of BI 695501 versus adalimumab reference product in patients with advanced Crohn's disease (VOLTAIRE-CD): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: BI 695501 is a biosimilar that has demonstrated similar efficacy, safety, and immunogenicity to adalimumab reference product in patients with rheumatoid arthritis and chronic plaque psoriasis. The VOLTAIRE-CD study aimed to compare the efficacy and safety of BI 695501 with adalimumab reference product in patients with Crohn's disease. METHODS: This phase 3, randomised, double-blind study was done at 92 centres in 12 countries across Europe and the USA in patients aged 18-80 years with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score 220-450). Patients were randomly assigned 1:1 using an interactive response technology system to the BI 695501 group or adalimumab reference product group, stratified by previous exposure to infliximab (yes vs no) and simple endoscopic score for Crohn's disease at screening (<16 vs ≥16). All investigators involved in trial assessments or procedures and all patients were masked to treatment allocation until week 24. Patients received BI 695501 (40 mg/0·8 mL formulation) or adalimumab reference product (either 40 mg/0·4 mL citrate-free or 40 mg/0·8 mL) 160 mg on day 1 and 80 mg on day 15, followed by 40 mg every 2 weeks, via subcutaneous injection. The primary endpoint was the proportion of patients with clinical response (CDAI decrease ≥70 points) at week 4, with an exploratory non-inferiority margin of 0·76 for the lower limit of the two-sided 90% CI of the risk ratio (RR). The primary analysis was done in a modified full analysis set of all patients who received at least one dose of study medication and had a baseline and at least one post-baseline CDAI assessment. Safety was assessed in all patients who received at least one dose of study medication. After week 4, responders were treated until week 46; those randomly assigned to adalimumab reference product switched to BI 695501 at week 24. This study is registered at ClinicalTrials.gov (NCT02871635) and EudraCT (2016-000612-14). FINDINGS: Between Jan 4, 2017, and April 5, 2018, 147 patients were enrolled and randomly assigned to BI 695501 (n=72) or adalimumab reference product (n=75). At week 4, 61 (90%) of 68 patients in the BI 695501 group and 68 (94%) of 72 in the adalimumab reference product group had a clinical response (adjusted RR 0·945 [90% CI 0·870-1·028]). In the safety analysis set, 45 (63%) of 72 patients in the BI 695501 group and 42 (56%) of 75 in the adalimumab reference product group had an adverse event during weeks 0-24; 31 (43%) and 34 (45%) had adverse events during weeks 24-56. The most common drug-related treatment-emergent adverse events during weeks 0-24 were weight increase (three [4%] patients in the BI 695501 group) and injection-site erythema and upper respiratory tract infection (three [4%] patients for each event) in the adalimumab reference product group. The only drug-related TEAEs reported in two or more patients during weeks 24-56 were weight increase and increased γ-glutamyltransferase, which occured in two (3%) patients each in the BI 695501 group. No drug-related TEAEs were reported in two or more patients during weeks 24-56 in the adalimumab reference product followed by BI 699501 group. Serious adverse events occurred in six (8%) patients in the BI 695501 group and eight (11%) in the adalimumab reference group between weeks 0-24, and two (3%) and nine (12%) patients between weeks 24-56. Adverse events of special interest occurred in two (3%) patients in each treatment group during weeks 0-24 (acute sinusitis and pulmonary tuberculosis in the BI 695501 group and anal abscess and postoperative wound infection in the adalimumab reference product group) and two (3%) patients in each group during weeks 24-56 (psoas abscess and hypersensitivity in the BI 695501 group and pulmonary tuberculosis and erythematous rash in the adalimumab reference product followed by BI 699501 group). INTERPRETATION: Safety and efficacy were similar in patients with Crohn's disease treated with BI 695501 or adalimumab reference product. Treatment benefits were maintained in patients receiving adalimumab reference product who switched to BI 695501. These results further support the existing licensure of BI 695501 as an alternative to adalimumab reference product for patients with Crohn's disease, as well as the other indications for which BI 695501 is approved. FUNDING: Boehringer Ingelheim.

The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination.

Idarucizumab, a humanized monoclonal antibody fragment (Fab), provides rapid and sustained reversal of dabigatran-mediated anticoagulation. Idarucizumab and dabigatran are mainly eliminated via the kidneys. This analysis aimed to characterize the renal elimination of idarucizumab and investigate the influence of idarucizumab on the pharmacokinetics (PK) of dabigatran and vice versa. Studies were conducted in 5/6 nephrectomized rats, in human volunteers with and without renal impairment, and in a porcine liver trauma model. In both rats and humans, renal impairment increased idarucizumab exposure and initial half-life but did not affect its terminal half-life. Urinary excretion of unchanged idarucizumab increased with increasing idarucizumab dose, suggesting saturation of renal tubular reuptake processes at higher doses. The PK of idarucizumab was unaffected by dabigatran. In contrast, idarucizumab administration resulted in redistribution of dabigatran to the plasma, where it was bound and inactivated by idarucizumab. Urinary excretion of dabigatran after administration of idarucizumab was delayed, but total dabigatran excreted in urine was unaffected. Idarucizumab and dabigatran were eliminated together via renal pathways.

Safety, Tolerability and Pharmacokinetics of Oral BI 425809, a Glycine Transporter 1 Inhibitor, in Healthy Male Volunteers: A Partially Randomised, Single-Blind, Placebo-Controlled, First-in-Human Study.

BACKGROUND AND OBJECTIVES: Schizophrenia and Alzheimer's disease are characterised by glutamatergic pathway abnormalities related to N-methyl-D-aspartate (NMDA) receptor hypofunction and cognitive impairment. Glycine is an NMDA receptor co-agonist; inhibition of glycine transporter 1 (GlyT1) should improve NMDA receptor hypofunction. This study evaluated safety and pharmacokinetic properties of BI 425809-a potent and selective GlyT1 inhibitor. METHODS: In the single-rising dose (SRD) component of this study, subjects were randomised to a single dose of BI 425809 [doses (mg): 0.5, 1, 2, 5, 10, 25, 50, 100 and 150], or placebo. The bioavailability/food effect (BA/FE) component investigated BI 425809 pharmacokinetics following single dosing (25-mg tablet) after overnight fasting or with a high-calorie meal or as solution (25 mg) after overnight fasting. RESULTS: Overall, 33/83 (39.8%) subjects had ≥ 1 treatment-related adverse event (AE); there were no deaths or serious AEs. Reported SRD part AEs trended towards dose dependency, occurring at the higher doses (mostly central nervous system related). BI 425809 plasma concentration-time profiles were similarly shaped across all doses and plasma exposure increased proportional to dose. In the BA/FE component, geometric mean ratios for the area under the concentration-time curve from time zero to the last measurable concentration and the maximum plasma concentration for tablet fasted versus solution fasted were 80.5 and 50.0%, respectively, and for tablet fed versus fasted were 125.9 and 142.1%, respectively. CONCLUSION: BI 425809 was generally well-tolerated at doses expected to be clinically relevant. The AE profile suggested possible GlyT1-inhibiting effects. CLINICAL TRIAL IDENTIFIER: NCT02068690.

Multiple Rising Doses of Oral BI 425809, a GlyT1 Inhibitor, in Young and Elderly Healthy Volunteers: A Randomised, Double-Blind, Phase I Study Investigating Safety and Pharmacokinetics.

BACKGROUND AND OBJECTIVE: Schizophrenia and Alzheimer's disease are characterised by abnormalities in glutamatergic pathways related to N-methyl-D-aspartate receptor hypofunction. Glycine is an N-methyl-D-aspartate receptor co-agonist; inhibition of glycine transporter 1 may improve N-methyl-D-aspartate receptor function. This phase I, randomised, two-part study evaluated the safety, tolerability and pharmacokinetic profile of BI 425809, a novel glycine transporter 1 inhibitor, in healthy male and female volunteers. METHODS: Part 1 evaluated BI 425809 10, 25, 50 or 75 mg once daily or 75 mg twice daily in young subjects, and 25 mg or 50 mg once daily in elderly subjects. Each dose group comprised 12 subjects who received BI 425809 (n = 9) or placebo (n = 3) for 14 days (day 1: single dose; days 4-14: multiple dosing). Part 2 compared pharmacokinetic profiles in 12 subjects who received a single dose of BI 425809 25 mg in the morning and evening. RESULTS: Pharmacokinetic profiles were similarly shaped for all dose groups. Median time to maximum plasma concentration was 3.0-4.5 h with steady state being reached between days 6 and 10. Pharmacokinetic parameters demonstrated dose linearity at the predicted therapeutic exposure range of BI 425809 ≤ 25 mg once daily, but increased less than dose proportionally for ≥ 50 mg once daily. All reported adverse events were of mild-to-moderate intensity, 51/84 (61%; part 1) subjects had one or more treatment-related adverse event, no serious adverse events occurred and no dose dependency was observed. CONCLUSIONS: Pharmacokinetic properties support both morning and evening dosing. BI 425809 was generally well tolerated at all tested doses. CLINICALTRIALS. GOV IDENTIFIER: NCT02337283.

The safety, tolerability and pharmacokinetics of BI 409306, a novel and potent PDE9 inhibitor: Overview of three Phase I randomised trials in healthy volunteers.

Safety, tolerability and pharmacokinetics of BI 409306, a potent and selective phosphodiesterase 9A inhibitor, were assessed in healthy subjects in three Phase I, within-dose group, double-blind trials. Trial 1 randomised young and elderly subjects to receive BI 409306 25, 50, 100 mg, placebo once daily (OD) or BI 409306 50 mg twice daily (young) for 14 days. Trial 2 randomised young poor metabolisers (PM) of cytochrome P450 isoform 2C19 (CYP2C19) and elderly subjects to receive BI 409306 25, 50 mg or placebo OD for 14 days. Trial 3 randomised Chinese and Japanese extensive metabolisers of CYP2C19 to receive single doses (SD) of BI 409306 25, 50, 100 mg or placebo and Chinese (PM) to SD of BI 409306 100 mg or placebo (Part 1). Japanese PM received SD of BI 409306 100 mg or placebo (Day 1) followed by BI 409306 100 mg or placebo OD for 7 days after a 48-hour washout period (Part 2). Reported adverse events (AE) were mild-to-moderate intensity and increased with BI 409306 dose. Eye disorders were most commonly reported (Trial 1: 40.0-41.7%, Trial 2: 29.2-37.5%, Trial 3: 18.2-66.7%) and increased with dose and systemic exposure. PM reported more AEs than other treatment groups, corresponding to higher systemic exposure to BI 409306. Systemic exposure to BI 409306 produced dose-dependent increases and was slightly greater in elderly versus young subgroups (Trial 1). Steady state was achieved by Day 2-3. Overall, BI 409306 demonstrated good safety, tolerability and minor accumulation after multiple dosing.

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.

Evaluation of Pharmacokinetics and Pharmacodynamics of BI 425809, a Novel GlyT1 Inhibitor: Translational Studies.

BI 425809 is a potent and selective glycine transporter 1 (GlyT1) inhibitor being developed for the treatment of cognitive impairment in Alzheimer disease and schizophrenia. Translational studies evaluated the effects of BI 425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Oral administration of BI 425809 in rats induced a dose-dependent increase of glycine CSF levels from 30% (0.2 mg/kg, not significant) to 78% (2 mg/kg, P < 0.01), relative to vehicle. Similarly, oral administration of BI 425809 in healthy volunteers resulted in a dose-dependent increase in glycine CSF levels at steady state, with a mean 50% increase at doses as low as 10 mg. The peak plasma concentration (Cmax ) of BI 425809 was achieved earlier in plasma than in CSF (tmax 3-5 vs. 5-8 hours, respectively). Generally, BI 425809 was safe and well tolerated. These data provide evidence of functional target engagement of GlyT1 by BI 425809.

Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study.

BACKGROUND AND OBJECTIVES: Idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy. METHODS: In this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45-64 years; 16 elderly, 65-80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days. Idarucizumab doses of 1, 2.5 and 5 g or 2 × 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion ~2 h after DE at steady state. RESULTS: Dabigatran-prolonged diluted thrombin time, ecarin clotting time and activated partial thromboplastin time were reversed to baseline immediately after idarucizumab infusion in all groups. Reversal was sustained with doses ≥2.5 g. Idarucizumab was well tolerated under all conditions. No impact of age on idarucizumab pharmacokinetics was observed; however, subjects with mild or moderate renal impairment demonstrated increased exposure (up to 84 %), decreased clearance and prolonged (by up to 49 %) initial half-life of idarucizumab compared with healthy middle-aged subjects. CONCLUSIONS: Impaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity, and was safe and well tolerated in middle-aged, elderly and renally impaired volunteers. The results support the clinical use of a 5 g dose of idarucizumab. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT01955720.

Idarucizumab does not have procoagulant effects: Assessment of thrombosis biomarkers in healthy volunteers.

Idarucizumab, a humanised monoclonal antibody fragment, binds dabigatran with high affinity and immediately, completely and sustainably reverses dabigatran-induced changes on blood coagulation. The present analysis focuses on the evaluation of potential procoagulant properties of idarucizumab when administered in the absence of dabigatran. As part of two Phase I studies conducted in healthy Caucasian and Japanese male volunteers, the effect of idarucizumab (8 g as a 1-hour [h] infusion and 4 g as a 5-minute [min] infusion) and placebo on calibrated automated thrombography (CAT) was assessed using platelet-poor plasma samples. Measures were made before and 15 min after the end of infusion in Caucasian subjects, as well as pre-dose, 15 min, 4 h and 8 h in Japanese subjects. The levels of the thrombosis markers D-dimer and prothrombin fragment 1 + 2 (F1.2) were assessed over time in plasma samples up to 72 h after the end of infusion of idarucizumab and placebo. Idarucizumab had no apparent effect on endogenous thrombin formation as measured by CAT. D-dimer and F1.2 levels were highly variable in all dose groups but did not increase when compared with placebo or pre-dose levels. In conclusion, idarucizumab had no effect on endogenous thrombin generation. Additional markers of thrombosis, F1.2 and D-dimer, did not differ between placebo and idarucizumab, indicating a lack of procoagulant properties of idarucizumab.

Measurement of dabigatran plasma concentrations by calibrated thrombin clotting time in comparison to LC-MS/MS in human volunteers on dialysis.

INTRODUCTION: Dabigatran etexilate is an oral direct thrombin inhibitor. Although routine anticoagulation monitoring with dabigatran is not usually required, a simple and precise laboratory test to measure dabigatran concentrations in patient plasma may be useful in certain clinical circumstances, such as emergency situations. The HEMOCLOT(®) Thrombin Inhibitors assay has demonstrated accurate and precise determination of dabigatran concentrations within a range of 50-500 ng/ml. The objective of this study was to assess comparability of dabigatran concentrations determined by HEMOCLOT(®) and by liquid chromatography/tandem mass spectrometry (LC-MS/MS) in plasma samples from human volunteers with end-stage renal disease (ESRD) undergoing regular haemodialysis (HD) during a Phase I study. MATERIALS AND METHODS: Overall, 304 plasma samples were obtained from seven ESRD patients in dabigatran steady-state for measurement by HEMOCLOT(®) (calibrated diluted thrombin time [dTT]) and by LC-MS/MS. Agreement of dabigatran concentrations was assessed by regression analysis and difference plots. RESULTS: The measurements of calibration standards of the HEMOCLOT(®) assay showed excellent precision with coefficients of variation <5%. Accuracy determined by analysis of two quality control samples was 90% and 111%. HEMOCLOT(®)-derived dabigatran plasma concentrations paralleled those obtained by LC-MS/MS. The mean ratio of the LC-MS/MS and dTT-derived concentrations was 0.955 (67% limits of agreement: 0.771-1.18). CONCLUSIONS: The HEMOCLOT(®) Thrombin Inhibitors assay is suitable for measuring dabigatran plasma concentrations in volunteers with ESRD undergoing haemodialysis. The agreement between dabigatran concentrations determined by the HEMOCLOT(®) assay and the LC-MS/MS reference method met bioanalytical acceptance criteria.

A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran.

Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.

Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease.

Dabigatran, a specific, reversible direct thrombin inhibitor, is used to prevent ischaemic and haemorrhagic strokes in patients with atrial fibrillation. As with every anticoagulant, there is a need to rapidly reverse its effects in emergency situations. In an open-label, single-centre phase I study with two fixed multiple dosing periods, we investigated the pharmacokinetics, pharmacodynamics and safety of dabigatran before, during and after 4 hour haemodialysis sessions with either 200 or 400 ml/min targeted blood flow in seven end-stage renal disease patients without atrial fibrillation. Dabigatran was administered over three days in a regimen designed to achieve peak plasma concentrations comparable to those observed in atrial fibrillation patients receiving 150 mg b.i.d. and to attain adequate distribution of dabigatran in the central and peripheral compartments. Plasma concentration-time profiles were similar in both periods on Day 3 (Cmax: 176 and 159 ng/ml). Four hours of haemodialysis removed 48.8% and 59.3% of total dabigatran from the central compartment with 200 and 400 ml/minute targeted blood flow, respectively. The anticoagulant activity of dabigatran was linearly related to its plasma levels. There was a minor redistribution of dabigatran (<16%) after the end of the haemodialysis session. In conclusion, a 4 hour haemodialysis session can rapidly eliminate a substantial amount of dabigatran from the central compartment with a concomitant marked reduction in its anticoagulant activity. There was a clinically negligible redistribution of dabigatran after haemodialysis. These results demonstrate that haemodialysis can be a suitable approach to eliminate dabigatran in emergency situations.