Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

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.

Physiologically Based Pharmacokinetic Modeling: The Reversible Metabolism and Tissue-Specific Partitioning of Methylprednisolone and Methylprednisone in Rats.

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.

Systems pharmacodynamic model of combined gemcitabine and trabectedin in pancreatic cancer cells. Part I.Çô Effects on signal transduction pathways related to tumor growth.

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.

Systems Pharmacodynamic Model of Combined Gemcitabine and Trabectedin in Pancreatic Cancer Cells. Part II: Cell Cycle, DNA Damage Response, and Apoptosis Pathways.

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.

Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients.

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 and contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain has been shown to be correlated with reduced DCI and improved patient outcomes.

Utility of Minimal Physiologically Based Pharmacokinetic Models for Assessing Fractional Distribution, Oral Absorption, and Series-Compartment Models of Hepatic Clearance.

Minimal physiologically based pharmacokinetic (mPBPK) models are physiologically relevant, require less information than full PBPK models, and offer flexibility in pharmacokinetics (PK). The well-stirred hepatic model (WSM) is commonly used in PBPK, whereas the more plausible dispersion model (DM) poses computational complexities. The series-compartment model (SCM) mimics the DM but is easier to operate.

Anti-inflammatory effects of dexamethasone in COVID-19 patients: Translational population PK/PD modeling and simulation.

Dexamethasone (DEX) given at a dose of 6 mg once-daily for 10 days is a recommended dosing regimen in patients with coronavirus disease 2019 (COVID-19) requiring oxygen therapy. We developed a population pharmacokinetic and pharmacodynamic (PopPK/PD) model of DEX anti-inflammatory effects in COVID-19 and provide simulations comparing the expected efficacy of four dosing regimens of DEX. Nonlinear mixed-effects modeling and simulations were performed using Monolix Suite version 2021R1 (Lixoft, France).

A Complete Extension of Classical Hepatic Clearance Models Using Fractional Distribution Parameter f in Physiologically Based Pharmacokinetics.

The classical organ clearance models have been proposed to relate the plasma clearance CL to probable mechanism(s) of hepatic clearance. However, the classical models assume the intrinsic capability of drug elimination (CL) that is physically segregated from the vascular blood but directly acts upon the unbound drug concentration in the blood (fC), 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 operative in PBPK.

Minimal physiologically-based hybrid model of pharmacokinetics in pregnant women: Application to antenatal corticosteroids.

Minimal physiologically-based pharmacokinetic (mPBPK) models are an alternative to full physiologically-based pharmacokinetic (PBPK) models as they offer reduced complexity while maintaining the physiological interpretation of key model components. Full PBPK models have been developed for pregnancy, but a mPBPK model eases the ability to perform a "top-down" meta-analysis melding all available pharmacokinetic (PK) data in the mother and fetus. Our hybrid mPBPK model consists of mPBPK models for the mother and fetus with connection by the placenta.

Exploring the Pharmacokinetic Mysteries of the Liver: Application of Series Compartment Models of Hepatic Elimination.

Among the basic hepatic clearance models, the dispersion model (DM) is the most physiologically sound compared with the well-stirred model and the parallel tube model. However, its application in physiologically-based pharmacokinetic (PBPK) modeling has been limited due to computational complexities. The series compartment models (SCM) of hepatic elimination that treats the liver as a cascade of well-stirred compartments connected by hepatic blood flow exhibits some mathematical similarities to the DM but is easier to operate.

Theoretical Examination Seeking Tangible Physical Meanings of Slopes and Intercepts of Plasma Concentration-Time Relationships in Minimal Physiologically Based Pharmacokinetic Models.

In minimal physiologically based pharmacokinetic (mPBPK) models, physiological (e.g., cardiac output) and anatomical (e.

Pharmacokinetic/Pharmacodynamic Modeling of Dexamethasone Anti-Inflammatory and Immunomodulatory Effects in LPS-Challenged Rats: A Model for Cytokine Release Syndrome.

Dexamethasone (DEX) is a potent synthetic glucocorticoid used for the treatment of variety of inflammatory and immune-mediated disorders. The RECOVERY clinical trial revealed benefits of DEX therapy in COVID-19 patients. Severe SARS-CoV-2 infection leads to an excessive inflammatory reaction commonly known as a cytokine release syndrome that is associated with activation of the toll like receptor 4 (TLR4) signaling pathway.

Comparative Proteomic Analysis Identifies Key Metabolic Regulators of Gemcitabine Resistance in Pancreatic Cancer.

Pancreatic adenocarcinoma (PDAC) is highly refractory to treatment. Standard-of-care gemcitabine (Gem) provides only modest survival benefits, and development of Gem resistance (GemR) compromises its efficacy. Highly GemR clones of Gem-sensitive MIAPaCa-2 cells were developed to investigate the molecular mechanisms of GemR and implemented global quantitative differential proteomics analysis with a comprehensive, reproducible ion-current-based MS1 workflow to quantify ∼6000 proteins in all samples.

Determinants of Biological Half-Lives and Terminal Slopes in Physiologically Based Pharmacokinetic Systems: Assessment of Limiting Conditions.

In pharmacokinetic (PK) analyses, the biological half-life T is usually determined in the terminal phase after drug administration, which is readily calculated from the relationship T = ln2/λ where λ is the terminal-phase slope obtainable from non-compartmental analysis (NCA). Since kinetic understanding of λ has been limited to the theory of a one-compartment model, this study seeks kinetic determinants of λ in more complex plasma concentration-time profiles. We utilized physiologically based pharmacokinetic (PBPK) systems that are consistent with the assumptions of NCA (e.

Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial.

Therapeutic responses of most drugs are initiated by the rate and degree of binding to their receptors or targets. The law of mass action describes the rate of drug-receptor complex association (k) and dissociation (k) where the ratio k/k is the equilibrium dissociation constant (K). Drugs with slow reversible binding (SRB) often demonstrate delayed onset and prolonged pharmacodynamic effects.

Consideration of Fractional Distribution Parameter f in the Chen and Gross Method for Tissue-to-Plasma Partition Coefficients: Comparison of Several Methods.

Purpose: The tissue-to-plasma partition coefficient (K) describes the extent of tissue distribution in physiologically-based pharmacokinetic (PBPK) models. Constant-rate infusion studies are common for experimental determination of the steady-state K, while the tissue-plasma concentration ratio (C/C) in the terminal phase after intravenous doses is often utilized. The Chen and Gross (C&G) method converts a terminal slope C/C to K based on assumptions of perfusion-limited distribution in tissue-plasma equilibration.

Pharmacokinetic/Pharmacodynamic Assessment of Selective Phosphodiesterase Inhibitors in a Mouse Model of Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a life-threatening disorder currently treated with nonspecific immunosuppressive drugs. It is postulated that phosphodiesterase (PDE) inhibitors, as agents exerting anti-inflammatory and immunomodulatory activities, may constitute a possible treatment of autoimmune disorders. This study develops a pharmacokinetic/pharmacodynamic (PK/PD) model to assess the effects of PDE-selective inhibitors, namely, cilostazol (PDE3), rolipram (PDE4), and BRL-50481 (PDE7), in a mouse model of AIH.

Assessment of the Kochak-Benet Equation for Hepatic Clearance for the Parallel-Tube Model: Relevance of Classic Clearance Concepts in PK and PBPK.

This report reviews concepts related to operation of the classic parallel-tube model (PTM) for hepatic disposition and examines two recent proposals of a newly derived equation to describe hepatic clearance (CL). It is demonstrated that the proposed equation is identical to a re-arrangement of an earlier relationship from Pang and Rowland and provides a means of calculation of intrinsic clearance (CL) rather than CL as posed. We further demonstrate how classic hepatic clearance models with an assumed CL, while subject to numerous limitations, remain highly useful and necessary in both traditional pharmacokinetics (PK) and physiologically based pharmacokinetic (PBPK) modeling.

Pharmacokinetic/pharmacodynamic modeling for dose selection for the first-in-human trial of the activated Factor XII inhibitor garadacimab (CSL312).

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein-kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first-in-class, fully human, monoclonal antibody targeting activated FXII (FXIIa).

Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species.

The objective of this study was to systematically assess literature datasets and quantitatively analyze metformin PK in plasma and some tissues of nine species. The pharmacokinetic (PK) parameters and profiles of metformin in nine species were collected from the literature. Based on a simple allometric scaling, the systemic clearances (CL) of metformin in these species highly correlate with body weight (BW) (R = 0.

Population pharmacodynamic modeling of intramuscular and oral dexamethasone and betamethasone effects on six biomarkers with circadian complexities in Indian women.

Population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed for extensive data for differing dosage forms and routes for dexamethasone (DEX) and betamethasone (BET) in 48 healthy nonpregnant Indian women in a partial and complex cross-over design. Single doses of 6 mg dexamethasone phosphate (DEX-P), betamethasone phosphate (BET-P), or 1:1 mixture of betamethasone phosphate and acetate (BET-PA) were administered orally (PO) or intramuscularly (IM) where each woman enrolled in a two-period cross-over study. Plasma concentrations collected over 96 h were described with a two-compartment model with differing PO and IM first-order absorption inputs.

Pathway-level analysis of genome-wide circadian dynamics in diverse tissues in rat and mouse.

A computational framework is developed to enable the characterization of genome-wide, multi-tissue circadian dynamics at the level of "functional groupings of genes" defined in the context of signaling, cellular/genetic processing and metabolic pathways in rat and mouse. Our aim is to identify how individual genes come together to generate orchestrated rhythmic patterns and how these may vary within and across tissues. We focus our analysis on four tissues (adipose, liver, lung, and muscle).