Orlando Clinical Research Center

Brensocatib is an oral, competitive, and reversible dipeptidyl peptidase 1 (DPP1) inhibitor in development for the treatment of neutrophil-mediated diseases. Brensocatib is a substrate of CYP3A, P-glycoprotein, and breast cancer resistance protein (BCRP). Its absorption, distribution, metabolism, and elimination could be potentially affected by a decrease in hepatic function. This study evaluated the pharmacokinetics (PK), safety, and tolerability of brensocatib in participants with varying degrees of hepatic impairment and matched participants with normal hepatic function. In this phase 1, multicenter, open-label study, 27 participants with normal hepatic function or mild, moderate, and severe hepatic impairment, based on numerical Child-Pugh classifications, received a single, oral 25-mg dose of brensocatib. Blood and urine samples were collected to evaluate brensocatib PK, urinary excretion, and plasma protein binding. Demographic and baseline characteristics were generally similar across hepatic impairment groups and matched healthy participants. The systemic exposure (area under the curve, AUC) and renal clearance (CLr) of brensocatib were generally comparable across all groups (≤ 20% difference in AUC compared with healthy participants and CLr 1.34-1.84 L/h versus 1.66 L/h in healthy participants). The mean elimination half-life was also similar across all hepatic function groups (27.9-31.4 h). Regression analyses indicated no significant relationships between brensocatib systemic exposure and Child-Pugh scores. Unbound brensocatib in plasma slightly increased by the severity of hepatic impairment. The fraction of unbound brensocatib (Funb) was correlated with serum albumin, suggesting that brensocatib is mainly bound to albumin in plasma. Treatment-emergent adverse events (TEAEs) occurred in 14.8% (4/27) of participants; most TEAEs were mild, and two TEAEs occurring in one participant were considered severe. No new safety findings were observed. No new safety signals were identified in participants with or without hepatic impairment treated with a single dose of 25 mg brensocatib. The oral absorption and elimination of brensocatib were not significantly altered in participants with mild, moderate, or severe hepatic impairment, suggesting that dose adjustment for brensocatib treatment in patients with hepatic impairment is not necessary. Clinical Trial Registration Number: NCT05517525.

Introduction: The use of modular components provides several advantages in total knee arthroplasty (TKA), including exchange of the polyethylene insert while retaining the stable components in the revision TKA. Compared to full, non-modular component revision TKA, isolated polyethylene exchange (IPE) has the advantage of decreased morbidity, faster rehabilitation, and acceptable outcomes. Methods: A review of published literature on revision TKA was conducted, with a specific focus on studies evaluating the use of IPE for managing complications such as stiffness, instability, and periprosthetic joint infection (PJI). Results: IPE with downsizing may be considered for patients with mild stiffness and stable, well-positioned implants that have increased polyethylene thickness, though expectations for motion gain should be cautious. There is no clear consensus on IPE for instability. Some studies report high re-revision rates, while others show clinical and functional improvement when the TKA is well-aligned, well-fixed, and intraoperative gap balance is achieved. Additionally, irrigation and debridement with polyethylene exchange (IDPE) may be effective for acute TKA PJI management, particularly within the first two weeks of symptom onset. Conclusions: Based on current literature, IPE in aseptic TKA revisions may be effective for stiffness or instability when implants are well-fixed and well-aligned—particularly if polyethylene constraint can be adjusted for instability or downsized for stiffness. The role of IDPE in acute TKA PJI is better defined in the literature, with strong emphasis on its time-sensitive effectiveness—most notably within the first two weeks of symptom onset.

Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease that often leads to loss of speech, swallowing restrictions, respiratory failure, paralysis, and total physical dependence, despite preserved cognitive function. For some affected individuals, the anticipated decline in autonomy associated with ALS leads to the consideration of medical aid in dying (MAiD). In the United States (US), MAiD is legally permitted in 12 jurisdictions (11 states and Washington, DC); however, most require patients to self-administer the prescribed medications. This stipulation creates an inequitable barrier for people with late-stage ALS, as the ability to swallow medication or manipulate delivery devices is often lost well before the end of life. Patients with ALS who are considering MAiD and otherwise meet all eligibility criteria must weigh the decision to end their lives earlier than desired against the risk of prolonging life and becoming physically unable to self-administer MAiD. This paper, coauthored by a patient with bulbar-onset ALS, integrates clinical literature, legal analysis, and lived experience to examine how existing MAiD statutes in the US fail to accommodate the physical disabilities of otherwise eligible patients from using this option. Overall, legislative reform in the US is urgently needed to ensure that MAiD eligibility is based on informed consent and clinical criteria without unfair exclusion based on physical disability.

Abstract Guided by the mythopoetic energies of peace, the author engages in an innovative depth psychological inquiry into the interconnected theories of analytical psychology and peace studies, emphasizing their relevance and functions at the archetypal, cultural, and individual levels. Linking the writings of psychologists Freud, Jung, von Franz and Hillman with peace scholar Galtung and peace literacy educator Chappell, six theoretical applications are illuminated: (a) archetype; (b) symbol; (c) psychological defence mechanisms; (d) key factors of positive peace; (e) clinical temenos and kairos; and (f) an individualized positive peace care plan. Explorations into the interstices between these sister disciplines and their mutual challenges are under‐represented in the extant literature. Addressing this lacuna, the author offers an interdisciplinary analysis into the ways in which analytical psychology and peace studies theoretically support one another and work together towards promoting peace‐centred psychologies and practices. This article will interest individuals endeavouring to better understand peace through a psychological lens, and who work within the fields of analytical psychology, peace psychology, social justice, or with individuals who strive to have “peace” in their lives.

Dural venous sinus thrombosis, a subset of cerebral venous thrombosis, is an important pathology due to its significant morbidity and mortality. This process has an annual incidence of three to five cases per million adults. Although copious predisposing factors exist, the core principles revolve around Virchow's triad: venous stasis, hypercoagulability, and vascular endothelial damage. There are various risk factors related to unfavorable outcomes, which include female sex, intracranial hemorrhage, infection, cancer, and more. Trauma tends to be a risk factor, particularly in pediatric populations, as in this patient's case. Initial diagnosis in the acute setting commonly involves non-contrast CT studies to exclude hemorrhage. In subacute or chronic settings, MRI can be utilized. Anticoagulation remains the mainstay of therapy for treatment, along with treating any underlying causes of thrombosis. We present a pediatric patient with extensive post-traumatic dural venous sinus thromboses with classic imaging findings as well as full resolution of clinical symptoms after this pathologic process was recognized and treated appropriately.

This phase 1, open-label, three-arm study (NCT05098054) compared the pharmacokinetics and safety of soticlestat (TAK-935) in participants with hepatic impairment. Participants aged ≥18 to <75 years had moderate (Child-Pugh B) or mild (Child-Pugh A) hepatic impairment or normal hepatic function (matched to hepatic-impaired participants by sex, age, and body mass index). Soticlestat was administered as a single oral 300 mg dose. Pharmacokinetic parameters of soticlestat and its metabolites TAK-935-G (M3) and M-I were assessed and compared by group. The incidence of treatment-emergent adverse events (TEAEs) and other safety parameters were also monitored. The pharmacokinetic analyses comprised 35 participants. Participants with moderate hepatic impairment had lower proportions of bound and higher proportions of unbound soticlestat than participants with mild hepatic impairment and normal hepatic function. Total plasma soticlestat pharmacokinetic parameters (maximum observed concentration [Cmax], area under the concentration-time curve from time 0 to time of last quantifiable concentration [AUClast], and AUC from time 0 to infinity [AUC∞]) were approximately 115%, 216%, and 199% higher with moderate and approximately 45%, 35%, and 30% higher with mild hepatic impairment, respectively, than healthy matched participants. Moderate hepatic impairment decreased the liver's ability to metabolize soticlestat to M-I; glucuronidation to M3 was also affected. Mild hepatic impairment resulted in a lower total plasma M-I exposure, but glucuronidation was unaffected. TEAEs were similar across study arms, mild, and no new safety findings were observed. A soticlestat dose reduction is required for individuals with moderate but not mild hepatic impairment.

e19042 Background: Venetoclax is a first-in-class Bcl-2 inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia(AML) and is currently being investigated as a treatment for t(11;14)-positive relapsed/refractory multiple myeloma (MM). Renal insufficiency is a common comorbidity in patients with hematologic malignancies, and no clinical study has been conducted to assess how end stage renal disease might affect venetoclax pharmacokinetics. This study aimed to assess the pharmacokinetics of venetoclax after oral administration of a single 100 mg dose of venetoclax in subjects with normal renal function and end-stage renal disease, including those undergoing hemodialysis. Methods: Venetoclax was administered as a single 100 mg dose to 7 healthy female subjects with normal renal function (eGFR &gt; 90 ml/min) and 6 female subjects with end-stage renal disease (ESRD) (eGFR &lt; 15 ml/min) both prior to hemodialysis (Period 1) and between hemodialysis days (Period 2). Intensive PK and protein binding samples were collected from all subjects. Arterial and venous samples were collected from ESRD subjects during hemodialysis to assess the effect of hemodialysis on the pharmacokinetics of venetoclax. Pharmacokinetic parameters were estimated using non-compartmental methods. Results: There was no difference in plasma venetoclax concentrations between arterial and venous samples, suggesting that hemodialysis did not affect the PK of venetoclax. The fraction unbound (fu) of venetoclax increased approximately 2-fold for subjects with ESRD compared to subjects with normal renal function.The unbound Cmax and AUC0-48 of ESRD subjects, between dialysis days were comparable to unbound Cmax and AUC0-48 observed in the normal renal function subjects. The harmonic mean t1/2 between groups (normal renal function vs. ESRD) ranged from 11 and 12.2 hours, demonstrating that end-stage renal disease did not affect the half-life of venetoclax. Conclusions: End-stage renal disease does not alter unbound venetoclax plasma concentrations and no dose adjustment is neededfor patients with renal insufficiency based on pharmacokinetics. Clinical trial information: NCT04810598 .

SummaryBrigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. This open-label, parallel-group study investigated the effect of chronic hepatic impairment on the pharmacokinetics (PK) of brigatinib to inform dosing recommendations for these patients. Participants with hepatic impairment classified according to Child-Pugh categories of mild (A), moderate (B), or severe (C) and matched-healthy participants with normal hepatic function received a single oral dose of 90-mg brigatinib. Plasma samples were collected for the determination of brigatinib plasma protein binding and estimation of plasma PK parameters. Twenty-seven participants were enrolled (Child-Pugh A–C, n = 6 each; matched-healthy participants, n = 9). The mean fraction of free plasma brigatinib was comparable for the Child-Pugh A (11.1%), Child-Pugh B (10.8%), and healthy participant groups (8.5%); free brigatinib was higher in the Child-Pugh C group (23.1%). There were no clinically meaningful effects of mild or moderate hepatic impairment on unbound systemic exposures (area under the plasma concentration-time curve [AUC]) of brigatinib (geometric least-squares mean ratios [90% CI] of 89.32% [69.79%–114.31%] and 99.55% [77.78%–127.41%], respectively). In the severe hepatic impairment group, brigatinib unbound AUC was approximately 37% higher (geometric least-squares mean ratio [90% CI] of 137.41% [107.37%–175.86%]) compared with healthy participants with normal hepatic function. Brigatinib was well tolerated in healthy participants and in participants with hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment. The brigatinib dose should be reduced by approximately 40% for patients with severe hepatic impairment.