Search

Introduction: Asundexian is a reversible and selective inhibitor of activated factor XI. It is currently under investigation for the prevention of secondary stroke in at-risk patients; these patients are often characterised by advanced age, impaired organ function and comorbidities. This article summarises results from three Phase I studies that investigated the effects of age and sex (study 1), chronic kidney disease including end-stage kidney disease (ESKD) on dialysis and dialysis-free days (study 2) and Child-Pugh A and B liver disease (study 3) on the safety, pharmacokinetics and pharmacodynamics of a single oral dose of asundexian 25 mg., Methods: Study 1 was a multicentre, randomised, single-blind, placebo-controlled group-stratification design; study 2 was a single-centre, non-randomised, non-placebo-controlled, non-blinded group-stratification design; and study 3 had a non-randomised, non-blinded, non-placebo-controlled group-stratification design., Results: Single doses of asundexian 25 mg were generally well tolerated in all three studies, with no asundexian-related bleeding events or treatment-emergent adverse events of special interest. Point estimates (geometric least squares [LS] means) (90% confidence intervals [CIs]) for the total asundexian area under the plasma concentration-time curve (AUC) for participants aged ≥ 65 to < 75 years versus ≥ 18 to < 45 years and ≥ 75 to ≤ 80 years versus ≥ 18 to < 45 years were 1.257 (1.134-1.393) and 1.288 (1.158-1.433), respectively, and for females versus males, it was 1.084 (0.995-1.182). Point estimates (geometric LS means) (90% CIs) for unbound AUC in participants in estimated glomerular filtration rate (eGFR) categories G2 (60-89 mL/min/1.73 m 2 ), G3 (30-59 mL/min/1.73 m 2 ) and G4 (15-29 mL/min/1.73 m 2 ) versus control were 1.003 (0.698-1.443), 0.791 (0.550-1.138) and 0.882 (0.606-1.285), respectively, and in participants with ESKD on dialysis-free day versus control was 0.597 (0.406-0.877). There was no effect of the dialysis procedure on the pharmacokinetics of asundexian. In participants deemed Child-Pugh class A and Child-Pugh class B, geometric LS means (90% CIs) for unbound AUC were 0.834 (0.597-1.164) and 1.143 (0.810-1.612), respectively, when compared to participants with normal liver function. Activated partial thromboplastin time (aPTT) was assessed as a pharmacodynamic variable of interest. Geometric mean maximum aPTT prolongation as a ratio to baseline after administration of asundexian 25 mg ranged from 1.45 to 1.55 in all age and sex groups, 1.49-1.59 in the control and eGFR G2 to G4 groups, 1.38-1.54 in the control and ESKD groups on dialysis and dialysis-free day and 1.38-1.89 in the healthy control and liver impairment groups., Conclusions: The effects of the investigated intrinsic factors on the exposure of asundexian were small and not considered clinically relevant. The impact of lower exposure in participants with ESKD requires further investigation. Pharmacodynamics were as expected., Clinical Trial Registration Numbers: EudraCT 2022-000196-38 and 2020-000626-25., Competing Interests: Declarations Funding This work was funded by Bayer AG, Wuppertal, Germany. Editorial support, including writing, fact checking, referencing, figure preparation, formatting, proofreading and submission was provided by Moamen Hammad, PhD, Patricia Badia Folgado, MSc and Melissa Ward, BA, all of Scion (a division of Prime, London, UK) supported by Bayer AG, Wuppertal, Germany according to Good Publication Practice guidelines (Link). Conflicts of Interest Christine Brase and Friederike Kanefendt are employees of Bayer AG and own shares or share options in the company. Sebastian Schmitz was an employee of Bayer AG at the time of the manuscript development and may own shares or share options in the company. Katharina Sommer is an employee of ClinStat GmbH and reports consulting or advisory roles of her CRO with Bayer AG. Atef Halabi has nothing to disclose. Ethics approval The conduct of the clinical studies met all local legal and regulatory requirements. The studies were conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation guideline E6: Good Clinical Practice. The protocols and other related materials were reviewed and approved by the relevant institutional boards for each study: IntegReview Institutional Review Board, Austin, Texas and QPS Bio-Kinetic, Biokinetic Clinical Applications institutional review board, Springfield, Missouri for study 1 and Ethik-Kommission der Arztekammer Schleswig-Holstein, Kiel, Germany for studies 2 and 3. Consent to Participate Informed consent was obtained from all individual participants included in the studies. Consent for Publication Not applicable. Availability of Data and Material Availability of the data underlying this publication will be determined later according to Bayer’s commitment to the EFPIA/PhRMA principles for responsible clinical trial data sharing. This pertains to scope, time point, and process of data access. As such, Bayer commits to sharing, upon request from qualified scientific and medical researchers, participant-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in participants for medicines and indications approved in the United States (US) and European Union (EU) as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 1, 2014. Interested researchers can use www.clinicalstudydatarequest.com/ to request access to anonymised participant-level data and supporting documents from clinical studies to conduct further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the study sponsor’s section of the portal. Data access will be granted to anonymised participant-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that participant privacy is safeguarded. Code Availability Not applicable. Authors’ Contributions Christine Brase and Friederike Kanefendt (all studies) and Sebastian Schmitz (studies 1 and 2) and Katharina Sommer (study 3) made substantial contributions to the conception or design of the work. Christine Brase and Friederike Kanefendt (all studies), and Sebastian Schmitz (studies 1 and 2), Katharina Sommer (study 3) and Atef Halabi (studies 2 and 3) made substantial contributions to the acquisition of the data. Christine Brase and Friederike Kanefendt (all studies) and Sebastian Schmitz (studies 1 and 2) and Katharina Sommer (study 3) made substantial contributions to the analysis of the data. Christine Brase and Friederike Kanefendt (all studies) and Sebastian Schmitz (studies 1 and 2) and Katharina Sommer (study 3) made substantial contributions to the interpretation of the results. All authors drafted the work or revised it critically for important intellectual content, approved the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved., (© 2024. The Author(s).)

Pyrimidine (imatinib, dasatinib, nilotinib and pazopanib), pyridine (sorafenib) and pyrrole (sunitinib) tyrosine kinase inhibitors (TKIs) are multi-targeted TKIs with high activity towards several families of receptor and non-receptor tyrosine kinases involved in angiogenesis, tumour growth and metastatic progression of cancer. These orally administered TKIs have quite diverse characteristics with regard to absorption from the gastrointestinal tract. Absolute bioavailability in humans has been investigated only for imatinib (almost 100%) and pazopanib (14-39%; n = 3). On the basis of human radioactivity data, dasatinib is considered to be well absorbed after oral administration (19% and 0.1% of the total radioactivity were excreted as unchanged dasatinib in the faeces and urine, respectively). Quite low absolute bioavailability under fasted conditions is assumed for nilotinib (31%), sorafenib (50%) and sunitinib (50%). Imatinib, dasatinib and sunitinib exhibit dose-proportional increases in their area under the plasma concentration-time curve values over their therapeutic dose ranges. Less than dose-proportional increases were observed for nilotinib at doses ≥400 mg/day and for sorafenib and pazopanib at doses ≥800 mg/day. At steady state, the accumulation ratios are 1.5-2.5 (unchanged imatinib), 2.0 (nilotinib once-daily dosing), 3.4 (nilotinib twice-daily dosing), 1.2-4.5 (pazopanib), 5.7-6.4 (sorafenib) and 3.0-4.5 (sunitinib). Concomitant intake of a high-fat meal does not alter exposure to imatinib, dasatinib and sunitinib but leads to considerably increased bioavailability of nilotinib and pazopanib and decreased bioavailability of sorafenib. With the exception of pazopanib, the TKIs described here have large apparent volumes of distribution, exceeding the volume of body water by at least 4-fold. Very low penetration into the central nervous system in humans has been reported for imatinib and dasatinib, but there are currently no published human data for nilotinib, pazopanib, sorafenib or sunitinib. All TKIs that have been described are more than 90% bound to the plasma proteins: α(1)-acid glycoprotein and/or albumin. They are metabolized primarily via cytochrome P450 (CYP) 3A4, the only exception being sorafenib, for which uridine diphosphate glucuronosyltransferase 1A9 is the other main enzyme involved. Active metabolites of imatinib and sunitinib contribute to their antitumour activity. Although some patient demographics have been identified as significant co-factors that partly explain interindividual variability in exposure to TKIs, these findings have not been regarded as sufficient to recommend age-, sex-, bodyweight- or ethnicity-specific dose adjustment. Systemic exposure to imatinib, sorafenib and pazopanib increases in patients with hepatic impairment, and reduction of the initial therapeutic dose is recommended in this subpopulation. The starting dose of imatinib should also be reduced in renally impaired subjects. Because the solubility of dasatinib is pH dependent, co-administration of histamine H(2)-receptor antagonists and proton pump inhibitors with dasatinib should be avoided. With the exception of sorafenib, systemic exposure to TKIs is significantly decreased/increased by co-administration of potent CYP3A4 inducers/inhibitors, and so it is strongly recommended that the TKI dose is adjusted or that such co-administration is avoided. Caution is also recommended for co-administration of CYP3A4 substrates with TKIs, especially for those with a narrow therapeutic index. However, current recommendations with regard to dose adjustment of TKIs need to be validated in clinical studies. Further investigations are needed to explain the large interindividual variability in the pharmacokinetics of these drugs and to assess theclinical relevance of their interaction potential and inhibitory effects on metabolizing enzymes and transporters.