Exploring the impact of CYP2D6 and UGT2B7 gene-drug interactions, and CYP-mediated DDI on oxycodone and oxymorphone pharmacokinetics using physiologically-based pharmacokinetic modeling and simulation.

Oxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the dose is excreted unchanged into the urine. Oxymorphone, the metabolite primarily formed by CYP2D6, has a 40- to 60-fold higher mu-opioid receptor affinity than the parent compound.

Identification of Novel and Early Biomarkers for Cisplatin-induced Nephrotoxicity and the Nephroprotective Role of Cimetidine using a Pharmacometabolomic-based Approach Coupled with In Vitro Toxicodynamic Modeling and Simulation.

Cisplatin is widely used for the treatment of various types of cancer. However, cisplatin-induced nephrotoxicity (CIN) is frequently observed in patients receiving cisplatin therapy which poses a challenge in its clinical utility. Currently used clinical biomarkers for CIN are not adequate for early detection of nephrotoxicity, hence there is a need to identify potential early biomarkers in predicting CIN.

Pharmacodynamic Modeling to Evaluate the Impact of Cimetidine, an OCT2 Inhibitor, on the Anticancer Effects of Cisplatin.

Despite potent anticancer activity, the clinical utilization of cisplatin is limited due to nephrotoxicity. As Organic Cation Transporter 2 (OCT2) has been shown to be one of the key transporters involved in the uptake of cisplatin into renal proximal tubules, OCT2 inhibitors such as cimetidine have been explored to suppress cisplatin-induced nephrotoxicity. Nonetheless, the impact of OCT2 inhibition or cimetidine on the anti-cancer effects of cisplatin has not been extensively examined.

A case study of a patient-centered reverse translational systems-based approach to understand adverse event profiles in drug development.

Adverse drug reactions (ADRs) of targeted therapy drugs (TTDs) are frequently unexpected and long-term toxicities detract from exceptional efficacy of new TTDs. In this proof-of-concept study, we explored how molecular causation involved in trastuzumab-induced cardiotoxicity changes when trastuzumab was given in combination with doxorubicin, tamoxifen, paroxetine, or lapatinib. The data analytical platform Molecular Health Effect was utilized to map population ADR data from the US Food and Drug Administration (FDA) Adverse Event Reporting System to chemical and biological databases (such as UniProt and Reactome), for hypothesis generation regarding the underlying molecular mechanisms causing cardiotoxicity.

Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study.

Thrombosis remains an important complication for children with single-ventricle physiology following the Fontan procedure, and effective thromboprophylaxis is an important unmet medical need. To obviate conventional dose-finding studies and expedite clinical development, a rivaroxaban dose regimen for this indication was determined using a model-informed drug development approach. A physiologically based pharmacokinetic rivaroxaban model was used to predict a pediatric dosing regimen that would produce drug exposures similar to that of 10 mg once daily in adults.

Perspective on model-informed drug development.

Model-informed drug development (MIDD) is a process intended to expedite drug development, enhance regulatory science, and produce benefits for patients. Quantitative modeling and simulation-principally by population pharmacokinetics (PK), exposure-response, and physiologically based pharmacokinetic (PBPK) analysis-is the technology that provides the capability to deploy MIDD across a range of applications. MIDD was codified in the 2017 Prescription Drug User Fee Act Reauthorization (PDUFA VI, 2018-2022) and a performance goal was a MIDD pilot program to hold 2 to 4 industry-U.

Brexpiprazole Pharmacokinetics in CYP2D6 Poor Metabolizers: Using Physiologically Based Pharmacokinetic Modeling to Optimize Time to Effective Concentrations.

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia, or as adjunctive treatment for major depressive disorder. As cytochrome P450 (CYP) 2D6 contributes significantly to brexpiprazole metabolism, there is a label-recommended 50% reduction in dose among patients with the CYP2D6 poor metabolizer phenotype. This study uses a whole-body physiologically based pharmacokinetic (PBPK) model to compare the pharmacokinetics of brexpiprazole in patients known to be extensive metabolizers (EMs) and poor metabolizers (PMs).

Physiologically-based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate.

The exposure-response relationship of direct acting oral anti-coagulants (DOACs) for bleeding risk is steep relative to ischemic stroke reduction. As a result, small changes in exposure may lead to bleeding events. The overall goal of this project was to determine the effect of critical formulation parameters on the pharmacokinetics (PKs) and thus safety and efficacy of generic DOACs.

Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy.

Model-informed precision dosing (MIPD) has become synonymous with modern approaches for individualizing drug therapy, in which the characteristics of each patient are considered as opposed to applying a one-size-fits-all alternative. This review provides a brief account of the current knowledge, practices, and opinions on MIPD while defining an achievable vision for MIPD in clinical care based on available evidence. We begin with a historical perspective on variability in dose requirements and then discuss technical aspects of MIPD, including the need for clinical decision support tools, practical validation, and implementation of MIPD in health care.

A Review on Drug-Induced Nephrotoxicity: Pathophysiological Mechanisms, Drug Classes, Clinical Management, and Recent Advances in Mathematical Modeling and Simulation Approaches.

A variety of marketed drugs belonging to various therapeutic classes are known to cause nephrotoxicity. Nephrotoxicity can manifest itself in several forms depending on the specific site involved as well as the underlying pathophysiological mechanisms. As they often coexist with other pathophysiological conditions, the steps that can be taken to treat them are often limited.

Quantitative Systems Pharmacology Model-Based Predictions of Clinical Endpoints to Optimize Warfarin and Rivaroxaban Anti-Thrombosis Therapy.

Background: Tight monitoring of efficacy and safety of anticoagulants such as warfarin is imperative to optimize the benefit-risk ratio of anticoagulants in patients. The standard tests used are measurements of prothrombin time (PT), usually expressed as international normalized ratio (INR), and activated partial thromboplastin time (aPTT).

Objective: To leverage a previously developed quantitative systems pharmacology (QSP) model of the human coagulation network to predict INR and aPTT for warfarin and rivaroxaban, respectively.

Semi-mechanistic modelling platform to assess cardiac contractility and haemodynamics in preclinical cardiovascular safety profiling of new molecular entities.

Background And Purpose: Cardiovascular safety is one of the most frequent causes of safety-related attrition both preclinically and clinically. Preclinical cardiovascular safety is routinely assessed using dog telemetry monitoring key cardiovascular functions. The present research was to develop a semi-mechanistic modelling platform to simultaneously assess changes in contractility (dPdt ), heart rate (HR) and mean arterial pressure (MAP) in preclinical studies.

A clinical population pharmacokinetic/pharmacodynamic model for BIIB059, a monoclonal antibody for the treatment of systemic and cutaneous lupus erythematosus.

A population pharmacokinetic/pharmacodynamic (popPK/PD) model for BIIB059 (anti-blood dendritic cell antigen 2 [anti-BDCA2]), a humanized immunoglobulin G1 monoclonal antibody currently under development for the treatment of SLE and CLE, is presented. BIIB059 binds BDCA2, a plasmacytoid dendritic cell (pDC)-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. Phase 1 PK and PD data of healthy adult volunteers (HV, n = 87) and SLE subjects (n = 22) were utilized for the development of the popPK/PD model.

Association of Oral Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding Events in Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function.

Importance: Direct oral anticoagulants (DOACs) are purported to have fewer drug-drug interactions than warfarin. However, potential interactions with coprescribed medications are still a safety concern. Verapamil hydrochloride and diltiazem hydrochloride are combined P-glycoprotein (P-gp) and CYP3A4 inhibitors and may be associated with increases in the risk of bleeding with DOACs.

Study of pharmacogenomic information in FDA-approved drug labeling to facilitate application of precision medicine.

Pharmacogenomics (PGx), studying the relationship between drug response and genetic makeup of an individual, is accelerating advances in precision medicine. The FDA includes PGx information in the labeling of approved drugs to better inform on their safety and effectiveness. We herein present a summary of PGx information found in 261 prescription drug labeling documents by querying the publicly available FDALabel database.

Evaluating the Clinical Impact of Formulation Variability: A Metoprolol Extended-Release Case Study.

The objective of this research was to evaluate the impact of changes in the formulation of metoprolol extended-release (ER) tablets on dissolution, pharmacokinetic, and exercise-induced heart rate (EIHR) using a combined physiologically based absorption pharmacokinetic, and population pharmacokinetic/pharmacodynamic modeling and simulation approach. Using a previously developed physiologically based absorption pharmacokinetic model in DDDPlus and GastroPlus, we simulated the changes in drug release and exposure as the result of quantitative changes in the release-controlling excipient, hydroxylpropylmethylcellulose, for 50 and 200 mg. The similarity of dissolution profiles was assessed using the f test, and bioequivalence was tested on the simulated pharmacokinetic profiles.

Physiologically Based Pharmacokinetic Modeling to Evaluate Formulation Factors Influencing Bioequivalence of Metoprolol Extended-Release Products.

The University of Florida Center for Pharmacometrics and Systems Pharmacology and the Food and Drug Administration Office of Generic Drugs have collaborated on a research project to develop a mechanism- and risk-based strategy that systematically investigates postmarketing reports of therapeutic inequivalence following the switch between brand and generic drug products. In this study we developed and qualified a physiologically based pharmacokinetic model to systematically investigate the influence of drug- and formulation-related properties on the oral absorption and bioequivalence of modified-release products using metoprolol as an example. Our findings show that the properties of the release-controlling polymer are the critical attributes for in vitro dissolution, in vivo absorption, and systemic exposure (ie, pharmacokinetics) and, thus, the bioequivalence of metoprolol extended-release products rather than the properties of the drug itself.

Is Bioequivalence Established Based on the Reference-Scaled Average Bioequivalence Approach Relevant to Chronic Administration of Phenytoin? Perspectives Based on Population Pharmacokinetic Modeling and Simulations.

Phenytoin demonstrates time-dependent and nonlinear pharmacokinetics (PK) within the therapeutic range of 10 to 20 μg/mL. There are discussions on the relevance of bioequivalence (BE) demonstrated in a single-dose BE study in healthy subjects to exposure under chronic use conditions in patients, particularly given that phenytoin has a narrow therapeutic index. The objective of this study was to quantitatively evaluate the appropriateness of single-dose PK BE through simulations for the phenytoin extended-capsule products.

A pre-clinical quantitative model predicts the pharmacokinetics/pharmacodynamics of an anti-BDCA2 monoclonal antibody in humans.

BIIB059 is a novel humanized monoclonal antibody (mAb) that is currently under development for the treatment of Systemic Lupus Erythematosus and Cutaneous Lupus Erythematosus. BIIB059 is targeted against the blood dendritic cell antigen 2 (BDCA2), a receptor exclusively expressed on the surface of plasmacytoid dendritic cells (pDCs). Herein, we utilized pre-clinical pharmacokinetic (PK) and pharmacodynamic (PD) data to develop a non-human primate (NHP) model and to address whether the NHP model can be successfully scaled to predict the human PK/PD.