Chama, Mohd Beshr

Abstract Introduction: We aimed to characterize the preclinical pharmacokinetics (PK) of a series of 20 anticancer agents in highly immunodeficient female NOD scid gamma (NSG) mice to provide clearance and exposure data for agents under investigation by the NCI PDX Development and Trial Centers Research Network (PDXNet). Methods: The series of 20 anticancer agents (inhibitors of CDK4/6, PI3K-β/PI3K-δ, ATR, MEK1/2, PI3K, microtubule, EZH2, BCL-2, PARP, histone deacetylase, γ-secretase, FGFR, SHP2, and ERK1/2, as well as a SMAC mimetic) were administered to female NSG mice via IV, PO, or IP routes to characterize plasma exposures under conditions used for PDX efficacy testing. Serial plasma samples were collected 15, 30, 60, 120, 240, 360, 480, and 1440 minutes after dosing. Drug concentrations were quantified using validated LC-MS/MS assays. PK parameters were calculated using non-compartmental analysis. Results: The PK for each agent was determined, and the clearance and half-life values are listed in the table below. The PK metrics for Navitoclax could not be calculated. Due to higher metabolic rates, mice show faster PK processes. They generally had shorter half-lives and higher weight-normalized clearance than humans. Copanlisib, Navitoclax, and Trametinib were exceptions. Conclusion: These PK data are critical for understanding the antitumor activities of agents studied by the PDXNet and will aid investigators in developing new approach methodologies for preclinical safety studies in preparation for human clinical trials. Citation Format: Mohd Beshr Chama, Emily J. Koubek, Sarah A. Buhrow, Renee A. Schoon, Joel M. Reid. Pharmacokinetics of a series of anticancer agents in immunodeficient female NOD scid gamma mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3156.

Abstract Introduction. This study aimed to characterize the population pharmacokinetics (PopPK) of nab-paclitaxel following the administration of the nano-immunoconjugate nab-paclitaxel-bevacizumab to patients with unresectable stage IV melanoma or gynecological cancers (NCT02020707). The core objective was to characterize the population mean drug concentration-time profile, understand the variability in drug concentrations and identify factors that explain differences in paclitaxel plasma clearance. Also, we sought to explore the impact of the nano-immunoconjugate formulation on paclitaxel clearance. Methods. Using Pumas AI - an advanced pharmacokinetic software program, integrating Machine Learning methods - a PopPK analysis was conducted using concentration-time data collected from 29 subjects, (681 concentration measurements). Patients received 75 - 175 mg/m2 (total dose, 160 - 360 mg). Data were fitted to a 2-compartment model based biphasic decline observed in plasma concentration following intravenous administration. A critical requirement for the model was the inclusion of saturable elimination to accurately describe the drug’s disposition. A comprehensive modeling workflow was implemented, starting with base models (mixed vs. non-linear clearance), followed by the sequential addition of covariates (Age, Sex, BSA, Tumor, Cycle). The Parsimony Principle was applied to select the most appropriate model. Results. Population estimates for paclitaxel clearance and volume of distribution were 41.7 L/hr and 312 L, respectively. The analysis found paclitaxel clearance higher when compared with published data for nab-paclitaxel alone (21.1 or 25 L/h/m2; Sparreboom et al, CCR 11:4136, 2005 and Ando et al, CCP 69:457, 2012). A covariate model incorporating BSA and Gender is the best. For every 2 m2 increase in BSA, linear clearance (CL) increases by 6.9%. Females have 16.6% lower CL than males, which successfully characterized systematic differences in PK between subgroups of subjects. Conclusion. The administration of nab-paclitaxel via the nano-immunoconjugate formulation led to increased clearance for paclitaxel consistent with known clearance mechanisms for therapeutic antibodies. The differences in drug clearance among patients were primarily attributable to covariates BSA and gender. These findings are crucial for identifying safe and effective dosing regimens and informing future clinical simulations. Citation Format: Mohd Beshr Chama, Matthew Stephen Block, Vera J. Suman, Joel M. Reid. Population pharmacokinetics of nab-paclitaxel following administration of a nano-immunoconjugate with bevacizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 301.

Background: Opalski syndrome is a rare variant of Wallenberg syndrome (lateral medullary syndrome) that demonstrates concomitant ipsilateral hemiplegia due to infarctions within the lateral medulla and the cervical spinal cord, which also extend to the post-pyramidal decussation to affect the corticospinal tract. Case presentation: A 56-year-old man initially presented with a unilateral headache with right cervical pain. Consequently, he developed symptoms that indicate Wallenberg syndrome: vertigo, dysphonia, dysarthria, right limb ataxia with a tendency to fall, and ptosis, in addition to ipsilateral hemiparesis. The diffusion-weighted imaging MRI (DWI MRI) performed initially demonstrated an acute infarct in the dorsolateral medulla. Accordingly, an axial T2-weighted MRI showed a hyperintense focal region in the same area, even as magnetic resonance angiography (MRA) revealed complete stenosis of the corresponding vertebral artery. Discussion: Opalski syndrome can result from different etiologies such as vascular occlusion or dissection. Although symptoms may vary, patients commonly present with sudden weakness, vertigo, and gait instability. Diagnosis often relies on MRI or DW-MRI. Treatment is tailored depending on individual factors and may involve medications and monitoring. Complications like respiratory failure can occur but are not directly linked to Opalski syndrome. Proper management includes addressing ischemic risk factors and ensuring appropriate nutrition. Conclusion: This case highlights the importance of including Opalski syndrome early in the differential diagnosis of patients with clinically suspected ipsilateral lateral medullary infarction and hyperacute ipsilateral hemiparesis.