Stephen Norris

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.

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.

Pharmacokinetic Characterization of Different Dose Combinations of Coadministered Tipranavir and Ritonavir in Healthy Volunteers

Abstract Purpose: To characterize the steady-state pharmacokinetic combination of the nonpeptidic protease inhibitor tipranavir (TPV) with ritonavir (RTV) in 95 healthy adult volunteers, a phase 1, single-center, open-label, randomized, parallel-group trial was conducted. Method: Participants received 250-mg self-emulsifying drug delivery system (SEDDS) capsules of TPV at doses between 250 mg and 1250 mg twice daily for 11 days, then received one or two RTV 100-mg SEDDS capsules, in addition to the TPV capsules, for the next 21 days. Results: Coadministration of TPV and RTV (TPV/r) resulted in a greater than 20-fold increase in steady-state TPV trough concentrations (Cssmin) as compared with TPV at steady state alone. Mean TPV Cssmin was above a preliminary target threshold of 20 μM with all but one of the RTV-boosted doses; without boosting, none of the TPV-alone doses exceeded the threshold. The average steady-state Cssmin for TPV 500 mg and 750 mg with RTV 100 mg or 200 mg were 20 to 57 times the protein-adjusted TPV IC90 for protease inhibitor-resistant HIV-1. An erythromycin breath test, a surrogate marker for cytochrome P450 isoenzyme 3A4 activity, indicated that all TPV/r combinations given provided net inhibition of this isoenzyme. The most frequent treatment-related adverse events were mild gastrointestinal symptoms. Conclusion: This phase 1 study demonstrated that RTV-boosted TPV achieves concentrations that are expected to be effective in treating drug-experienced patients.

Steady-State Disposition of the Nonpeptidic Protease Inhibitor Tipranavir when Coadministered with Ritonavir

ABSTRACT The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 μCi of [14C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. Blood, urine, and feces were collected for mass balance and metabolite profiling. Metabolite profiling and identification was performed using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The median recovery of radioactivity was 87.1%, with 82.3% of the total recovered radioactivity excreted in the feces and less than 5% recovered from urine. Most radioactivity was excreted within 24 to 96 h after the dose of [14C]TPV. Radioactivity in blood was associated primarily with plasma rather than red blood cells. Unchanged TPV accounted for 98.4 to 99.7% of plasma radioactivity. Similarly, the most common form of radioactivity excreted in feces was unchanged TPV, accounting for a mean of 79.9% of fecal radioactivity. The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. In conclusion, after the coadministration of TPV and RTV, unchanged TPV represented the primary form of circulating and excreted TPV and the primary extraction route was via the feces.

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.

Biotransformation and mass balance of tipranavir, a nonpeptidic protease inhibitor, when co‐administered with ritonavir in Sprague‐Dawley rats

In this study, tipranavir (TPV) biotransformation and disposition when co‐administered with ritonavir (RTV) were characterized in Sprague–Dawley rats. Rats were administered a single intravenous (5 mg kg−1) or oral (10 mg kg−1) dose of [14C]TPV with co‐administration of RTV (10 mg kg−1). Blood, urine, faeces and bile samples were collected at specified time‐points over a period of 168 h. Absorption of TPV‐related radioactivity ranged from 53.2–59.6%. Faecal excretion was on average 86.7% and 82.4% (intravenous) and 75.0% and 82.0% (oral) of dosed radioactivity in males and females, respectively. Urinary excretion was on average 4.06% and 6.73% (intravenous) and 9.71% and 8.28% (oral) of dosed radioactivity in males and females, respectively. In bile‐duct‐cannulated rats, 39.8% of the dose was recovered in bile. After oral administration, unchanged TPV accounted for the majority of the radioactivity in plasma (85.7–96.3%), faeces (71.8–80.1%) and urine (33.3–62.3%). The most abundant metabolite in faeces was an oxidation metabolite R‐2 (5.9–7.4% of faecal radioactivity, 4.4–6.1% of dose). In urine, no single metabolite was found to be significant, and comprised <1% of dose. TPV when co‐administered with RTV to rats was mainly excreted in feces via bile and the parent compound was the major component in plasma and faeces.

A competitive ELISA for the anti-intercellular adhesion molecule-1 (anti-ICAM-1) binding activity of monoclonal antibody R6.5 in serum

A competitive ELISA was developed to measure serum concentrations of immunoreactive R6.5, a mouse IgG2a monoclonal antibody which binds to and inhibits the interactions of human intercellular adhesion molecule-1 with glycoproteins of the CD18 complex and with rhinoviruses. The assay design permitted quantitative measurement of the functional activity of the antibody in serum. The working range of the assay was from 2.15 to 215 ng ml-1, and intra-assay and inter-assay relative standard deviations averaged 13 and 20%, respectively. Serum caused interferences with the assay when spiked in vitro, but authentic serum samples obtained from intravenously dosed animals did not exhibit these interferences. Characteristics of the assay, as well as results of a pharmacokinetic study in rabbits, are presented.

Safety, pharmacokinetics and pharmacodynamics of idarucizumab, a specific dabigatran reversal agent in healthy Japanese volunteers: a randomized study

Essentials Idarucizumab, a monoclonal antibody fragment, binds dabigatran with high affinity and specificity. In this phase 1 trial, healthy Japanese males received idarucizumab alone or with dabigatran. Idarucizumab achieved immediate, complete and sustained reversal of dabigatran anticoagulation. Idarucizumab was well tolerated and demonstrated no pro‐coagulant effects.

Phase I Clinical Trial of Anti-ICAM-1 (CD54) Monoclonal Antibody Immunosuppression in Renal Allograft Recipients

Rejection and the complications of immunosuppressive therapy continue to be major causes of allograft and recipient loss following all types of clinical transplantation. Although recent advances in the management of immunosuppressed allograft recipients have improved early graft survival rates, most centers continue to report a 1-yr allograft or patient loss of approximately 20% and a subsequent relentless attrition rate of 3–5% each year (1–3). Much of this morbidity and mortality is due to the relatively nonspecific suppression of immune responses induced by currently available therapeutic protocols.

Biotransformation and mass balance of faldaprevir, a hepatitis C NS3/NS4 protease inhibitor in rats.

Abstract 1. The metabolism, pharmacokinetics, excretion and tissue distribution of a hepatitis C NS3/NS4 protease inhibitor, faldaprevir, were studied in rats following a single 2 mg/kg intravenous or 10 mg/kg oral administration of [14C]-faldaprevir. 2. Following intravenous dosing, the terminal elimination t1/2 of plasma radioactivity was 1.75 h (males) and 1.74 h (females). Corresponding AUC0–∞, CL and Vss were 1920 and 1900 ngEq · h/mL, 18.3 and 17.7 mL/min/kg and 2.32 and 2.12 mL/kg for males and females, respectively. 3. After oral dosing, t1/2 and AUC0–∞ for plasma radioactivity were 1.67 and 1.77 h and 11 300 and 17 900 ngEq · h/mL for males and females, respectively. 4. In intact rats, ≥90.17% dose was recovered in feces and only ≤1.08% dose was recovered in urine for both iv and oral doses. In bile cannulated rats, 54.95, 34.32 and 0.27% dose was recovered in feces, bile and urine, respectively. 5. Glucuronidation plays a major role in the metabolism of faldaprevir with minimal Phase I metabolism. 6. Radioactivity was rapidly distributed into tissues after the oral dose with peak concentrations of radioactivity in most tissues at 6 h post-dose. The highest levels of radioactivity were observed in liver, lung, kidney, small intestine and adrenal gland.