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Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH that contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain is an off-label intervention that has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize the population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 13 females) treated with IT nicardipine every 6 h (q6h, n = 8) or every 8 h (q8h, n = 8) for an average of 72 ± 21 doses. High-performance liquid chromatography was used to quantify CSF concentration from each sample. Our popPK analysis showed that the CSF pharmacokinetics of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time. Model parameter estimates were reliable (relative standard error <50%). Intracranial pressure influenced both the total clearance and the central volume of nicardipine (i.e., negative correlation, P <-.001). Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine., (© 2024 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Human genetic variation (polymorphisms) in genes coding proteins involved in the absorption, distribution, metabolism, and elimination (ADME) of drugs can have a strong effect on drug exposure and downstream efficacy and safety outcomes. Vamorolone, a dissociative steroidal anti-inflammatory drug for treating Duchenne muscular dystrophy (DMD), primarily undergoes oxidation by CYP3A4 and CYP3A5 and glucuronidation by UDP-glucuronosyltransferases. This work assesses the pharmacokinetics (PKs) of vamorolone and sources of interindividual variability (IIV) in 81 steroid-naïve boys with DMD aged 4 to <7 years old considering the genetic polymorphisms of CYPS3A4 (CYP3A4*22, CYP3A4*1B), CYP3A5 (CYP3A5*3), and UGT1A1 (UGT1A1*60) utilizing population PK modeling. A one-compartment model with zero-order absorption (T k0 , duration of absorption), linear clearance (CL/F), and volume (V/F) describes the plasma PK data for boys with DMD receiving a wide range of vamorolone doses (0.25-6 mg/kg/day). The typical CL/F and V/F values of vamorolone were 35.8 L/h and 119 L, with modest IIV. The population T k0 was 3.14 h yielding an average zero-order absorption rate (k 0 ) of 1.16 mg/kg/h with similar absorption kinetics across subjects at the same vamorolone dose (i.e., no IIV on T k0 ). The covariate analysis showed that none of the genetic covariates had any significant impact on the PKs of vamorolone in boys with DMD. Thus, the PKs of vamorolone is very consistent in these young boys with DMD., (© 2024, The American College of Clinical Pharmacology.)

The pharmacokinetics (PK) of methylprednisolone (MPL) exhibited tissue-specific saturable binding and reversible conversion with its metabolite, methylprednisone (MPN). Blood and 11 tissues were collected in male rats after intravenous (i.v.) bolus doses of 50 mg/kg MPL and 20 mg/kg MPN and upon i.v. infusion of MPL and MPN at 0.3, 3, and 10 mg/h per kg. The concentrations of MPL and MPN were simultaneously measured. A comprehensive physiologically based pharmacokinetic (PBPK) model was applied to describe the plasma and tissue profiles and estimate PK parameters of the MPL/MPN interconversion system. Both dosed and formed MPL and MPN were in rapid equilibrium or achieved steady-state rapidly in plasma and tissues. MPL tissue partitioning was nonlinear, with highest capacity in liver (322.9 ng/ml) followed by kidney, heart, intestine, skin, spleen, bone, brain, muscle, and lowest in adipose (2.74 ng/ml) and displaying high penetration in lung. The tissue partition coefficient of MPN was linear but widely variable (0.15∼5.38) across most tissues, with nonlinear binding in liver and kidney. The conversion of MPL to MPN occurred in kidney, lung, and intestine with total clearance of 429 ml/h, and the back conversion occurred in liver and kidney at 1342 ml/h. The irreversible elimination clearance of MPL was 789 ml/h from liver and that of MPN was 2758 ml/h with liver accounting for 44%, lung 35%, and kidney 21%. The reversible metabolism elevated MPL exposure in rats by 13%. This highly complex PBPK model provided unique and comprehensive insights into the disposition of a major corticosteroid. SIGNIFICANCE STATEMENT: Our dual physiologically based pharmacokinetic (PBPK) study and model of methylprednisolone/methylprednisone (MPL/MPN) with multiple complexities reasonably characterized and parameterized their disposition, and provided greater insights into the interpretation of their pharmacodynamics in rats. Drug knowledge gained in this study may be translatable to higher-order species to appreciate the clinical utility of MPL. The complex model itself is instructive for advanced PBPK analysis of drugs with reversible metabolism and/or nonlinear tissue partitioning features., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

The classical organ clearance models have been proposed to relate the plasma clearance CL p to probable mechanism(s) of hepatic clearance. However, the classical models assume the intrinsic capability of drug elimination (CL u,int ) that is physically segregated from the vascular blood but directly acts upon the unbound drug concentration in the blood (f ub C avg ), and do not handle the transit-time delay between the inlet/outlet concentrations in their closed-form clearance equations. Therefore, we propose unified model structures that can address the internal blood concentration patterns of clearance organs in a more mechanistic/physiological manner, based on the fractional distribution parameter f d operative in PBPK. The basic partial/ordinary differential equations for four classical models are revisited/modified to yield a more complete set of extended clearance models, i.e., the Rattle, Sieve, Tube, and Jar models, which are the counterparts of the dispersion, series-compartment, parallel-tube, and well-stirred models. We demonstrate the feasibility of applying the resulting extended models to isolated perfused rat liver data for 11 compounds and an example dataset for in vitro-in vivo extrapolation of the intrinsic to the systemic clearances. Based on their feasibilities to handle such real data, these models may serve as an improved basis for applying clearance models in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is often chemotherapy-resistant, and novel drug combinations would fill an unmet clinical need. Previously we reported synergistic cytotoxic effects of gemcitabine and trabectedin on pancreatic cancer cells, but underlying protein-level interaction mechanisms remained unclear. We employed a reliable, sensitive, comprehensive, quantitative, high-throughput IonStar proteomic workflow to investigate the time course of gemcitabine and trabectedin effects, alone and combined, upon pancreatic cancer cells. MiaPaCa-2 cells were incubated with vehicle (controls), gemcitabine, trabectedin, and their combinations over 72 hours. Samples were collected at intervals and analyzed using the label-free IonStar liquid chromatography-mass spectrometry (LC-MS/MS) workflow to provide temporal quantification of protein expression for 4,829 proteins in four experimental groups. To characterize diverse signal transduction pathways, a comprehensive systems pharmacodynamic (SPD) model was developed. The analysis is presented in two parts. Here, Part I describes drug responses in cancer cell growth and migration pathways included in the full model: receptor tyrosine kinase- (RTK), integrin-, G-protein coupled receptor- (GPCR), and calcium-signaling pathways. The developed model revealed multiple underlying mechanisms of drug actions, provides insight into the basis of drug interaction synergism, and offers a scientific rationale for potential drug combination strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Despite decades of research efforts, pancreatic adenocarcinoma (PDAC) continues to present a formidable clinical challenge, demanding innovative therapeutic approaches. In a prior study, we reported the synergistic cytotoxic effects of gemcitabine and trabectedin on pancreatic cancer cells. To investigate potential mechanisms underlying this synergistic pharmacodynamic interaction, liquid chromatography-mass spectrometry-based proteomic analysis was performed, and a systems pharmacodynamics model (SPD) was developed to capture pancreatic cancer cell responses to gemcitabine and trabectedin, alone and combined, at the proteome level. Companion report Part I describes the proteomic workflow and drug effects on the upstream portion of the SPD model related to cell growth and migration, specifically the RTK-, integrin-, GPCR-, and calcium-signaling pathways. This report presents Part II of the SPD model. Here we describe drug effects on pathways associated with cell cycle, DNA damage response (DDR), and apoptosis, and provide insights into underlying mechanisms. Drug combination effects on protein changes in the cell cycle- and apoptosis pathways contribute to the synergistic effects observed between gemcitabine and trabectedin. The SPD model was subsequently incorporated into our previously-established cell cycle model, forming a comprehensive, multi-scale quantification platform for evaluating drug effects across multiple scales, spanning the proteomic-, cellular-, and subcellular levels. This approach provides a quantitative mechanistic framework for evaluating drug-drug interactions in combination chemotherapy, and could potentially serve as a tool to predict combinatorial efficacy and assist in target selection., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)