Mechanistic Insights into Cytokine Antagonist-Drug Interactions: A Physiologically Based Pharmacokinetic Modelling Approach with Tocilizumab as a Case Study.

Understanding interactions between cytokine antagonists and drugs is essential for effective medication management in inflammatory conditions. Recent regulatory authority guidelines emphasise a systematic, risk-based approach to evaluating these interactions, underscoring the need for mechanistic insight. Proinflammatory cytokines, such as interleukin-6 (IL-6), modulate cytochrome P450 (CYP) enzymes, reducing the metabolism of CYP substrates.

Physiologically based pharmacokinetic modeling of aldehyde oxidase drug-drug interactions mediated by erlotinib.

The propensity for aldehyde oxidase (AO) substrates to be implicated in drug-drug interactions (DDI) has remained largely uninterrogated due to the lack of a precipitant drug which elicits potent inhibition of AO in vivo. Recently, we characterized the epidermal growth factor receptor inhibitor erlotinib as a clinical AO inhibitor and proposed, through mechanistic metabolism studies and static modeling, that AO inhibition was responsible for its observed DDI with the investigational drug OSI-930. However, as erlotinib also inhibits the organic anion transporting polypeptide 2B1 transporter in the liver and gut at clinically relevant concentrations, the potential contribution of transporter-mediated interactions to the observed clinical DDI with OSI-930 remained unclear.

Development and Verification of Virtual Population Models for Predicting Drug Pharmacokinetics in Ethnic North American Populations.

Ethnic variabilities can affect the outcome of drug pharmacokinetics (PK) and drug-drug interactions (DDI). This work aimed to develop four North American (NA) sub-populations: White, African American, Asian American, and Hispanic_Latino suitable for physiologically based pharmacokinetic (PBPK) modeling and simulations. Demographic data and tissue weight/volume, blood flows, cardiac output, plasma protein levels, hematocrit, enzyme and transporter abundances/frequencies, serum creatinine, glomerular filtration rate, and gastrointestinal transit times for the different populations were collated.

Dietary Carnosine Supplementation in Healthy Human Volunteers: A Safety, Tolerability, Plasma and Brain Concentration Study.

Background: Carnosine is a multimodal pleotropic endogenous molecule that exhibits properties that make it a compelling therapeutic agent for further evaluation in a number of diseases. However, little data currently exists on its pharmacokinetic profile, maximum tolerated doses, side effects and whether oral administration can lead to elevated brain concentrations.

Method: To investigate this, sixteen healthy volunteers underwent a single dose-escalation study of oral carnosine to establish safety, tolerability, and pharmacokinetics.

The intracellular free concentration of endocrine disrupting chemicals enables translation between cell-free and cell-based estrogenic activity assays.

Many environmental toxicants can activate estrogen receptor α (ERα), disrupting normal endocrine function. While these activities are predicted across in silico, in vitro, and in vivo models, translating active concentrations between these systems remains challenging. We hypothesized that cellular uptake and the resulting free intracellular toxicant concentration could bridge this gap.

Cross-species translational modelling of targeted therapeutic oligonucleotides using physiologically based pharmacokinetics.

Oligonucleotide therapeutics hold promise for targeted gene silencing, yet achieving optimal tissue-specific delivery remains challenging. This study introduces a mechanistic whole-body physiologically based pharmacokinetic (PBPK) model to predict tissue uptake dynamics of both conjugated (targeted) and unconjugated oligonucleotides across species. The model incorporates two uptake pathways: a non-saturable nonspecific pathway for all oligonucleotides and receptor-mediated endocytosis (RME) specific to conjugated molecules.

Accelerating Biologics PBPK Modelling with Automated Model Building: A Tutorial.

Physiologically based pharmacokinetic (PBPK) modelling for biologics, such as monoclonal antibodies and therapeutic proteins, involves capturing complex processes, including target-mediated drug disposition (TMDD), FcRn-mediated recycling, and tissue-specific distribution. The Simcyp Designer Biologics PBPK Platform Model offers an intuitive and efficient platform for constructing mechanistic PBPK models with pre-defined templates and automated model assembly, reducing manual input and improving reproducibility. This tutorial provides a step-by-step guide to using the platform, highlighting features such as cross-species scaling, population variability simulations, and flexibility for model customization.

The physiological limits of bispecific monoclonal antibody tissue targeting specificity.

Bispecific monoclonal antibodies (bsmAbs) are expected to provide targeted drug delivery that overcomes the dose-limiting toxicities often accompanying antibody-drug conjugates (ADC) in clinical practice. Much attention has been paid in the past to target selection, mAb affinities and the payload linker design, but challenges remain. Here, we demonstrate, by physiologically based pharmacokinetic (PBPK) modeling and simulation, that the tissue-targeting accuracy of mono- and bispecific antibody therapeutics is substantially limited by normal physiological characteristics like organ volumes, blood flow rates, lymphatic circulation, and rates of extravasation.

Mechanistic Physiologically Based Pharmacokinetic Modeling of Dry Powder and Nebulized Formulations of Orally Inhaled TMEM16A Potentiator GDC-6988.

The orally inhaled route of administration for respiratory indications can maximize drug exposure to the site of action (lung) to increase efficacy while minimizing systemic exposure to achieve an improved safety profile. However, due to the difficulty of taking samples from different regions of the human lung, often only systemic pharmacokinetic (PK) samples are taken and assumed to be reflective of the lung PK of the compound, which may not always be the case. In this study, a mechanistic lung physiologically based pharmacokinetic (PBPK) model was built using a middle-out approach (i.

Improved identification of human hepatotoxic potential by summary variables of gene expression.

Prediction of hepatotoxicity in humans remains an unresolved challenge. Recently, an in vitro/in silico method was established to predict blood concentrations of test compounds with an increased risk of causing human hepatotoxicity. In the present study, we addressed the question whether gene expression data can improve the quality of hepatotoxicity prediction compared to cytotoxicity analysis alone.

Application of a Physiologically Based Pharmacokinetic Approach to Predict Tenofovir Pharmacokinetics During Pregnancy.

Pharmacotherapy during pregnancy requires a better understanding of the impact of changes in maternal physiology on the maternal and fetal drug exposure. The physiologically based pharmacokinetic (PBPK) modelling approach can be applied to predict maternal and fetal exposure. In vitro and in vivo PK data in non-pregnant individuals were compiled and used to develop and verify a PBPK model for tenofovir.

PBPK-Led Assessment of Antimalarial Drug Concentrations in Breastmilk: A Strategy for Optimal Use of Prediction Methods to Guide Decision Making in an Understudied Population.

Treatment of breastfeeding mothers with malaria is challenging due to the lack of information describing drug exposure in milk and the daily dose to the breastfed infant. Physiologically based pharmacokinetic (PBPK) modeling was used to predict milk-to-plasma (M/P) ratios, infant daily doses (IDD) and relative infant doses (RID) for five antimalarials with clinical lactation data (chloroquine, pyrimethamine, piperaquine, mefloquine and primaquine). In all cases, RID was correctly categorized as above or below the WHO proposed cut-off of 10% using two prediction models.

Development of a PBPK Model for Lamotrigine which Incorporates Metabolism by UGT2B10: Impact of UGT2B10 Poor Metabolizer Phenotype and Pregnancy.

An updated physiologically based pharmacokinetic (PBPK) model was developed for lamotrigine by incorporating a component of metabolism due to a UDP-glucuronyltransferase (UGT) 2B isozyme. This was assigned to UGT2B10 based on recent in vitro data in our laboratory demonstrating metabolism of lamotrigine by this isozyme (Tang et al. AAPS J 26:107, 2024).

Transcriptomic changes and mitochondrial toxicity in response to acute and repeat dose treatment with brequinar in human liver and kidney in vitro models.

The potent dihydroorotate dehydrogenase (DHODH) inhibitor brequinar has been investigated as an anticancer, immunosuppressive, and antiviral pharmaceutical agent. However, its toxicity is still poorly understood. We investigated the cellular responses of primary human hepatocytes (PHH) and telomerase-immortalised human renal proximal tubular epithelial cells (RPTEC/TERT1) after a single 24-h exposure up to 100 μM brequinar.

Cytokine Dynamics in Action: A Mechanistic Approach to Assess Interleukin 6 Related Therapeutic Protein-Drug-Disease Interactions.

Understanding cytokine-related therapeutic protein-drug interactions (TP-DI) is crucial for effective medication management in conditions characterized by elevated inflammatory responses. Recent FDA and ICH guidelines highlight a systematic, risk-based approach for evaluating these interactions, emphasizing the need for a thorough mechanistic understanding of TP-DIs. This study integrates the physiologically based pharmacokinetic (PBPK) model for TP (specifically interleukin-6, IL-6) with small-molecule drug PBPK models to elucidate cytokine-related TP-DI mechanistically.

Inhibition of Neural Crest Cell Migration by Strobilurin Fungicides and Other Mitochondrial Toxicants.

Cell-based test methods with a phenotypic readout are frequently used for toxicity screening. However, guidance on how to validate the hits and how to integrate this information with other data for purposes of risk assessment is missing. We present here such a procedure and exemplify it with a case study on neural crest cell (NCC)-based developmental toxicity of picoxystrobin.

Static Versus Dynamic Model Predictions of Competitive Inhibitory Metabolic Drug-Drug Interactions via Cytochromes P450: One Step Forward and Two Steps Backwards.

Background: Predicting metabolic drug-drug interactions (DDIs) via cytochrome P450 enzymes (CYP) is essential in drug development, but controversy has reemerged recently about whether in vitro-in vivo extrapolation (IVIVE) using static models can replace dynamic models for some regulatory filings and label recommendations.

Objective: The aim of this study was to determine if static and dynamic models are equivalent for the quantitative prediction of metabolic DDIs arising from competitive CYP inhibition.

Methods: Drug parameter spaces were varied to simulate 30,000 DDIs between hypothetical substrates and inhibitors of CYP3A4.

Limitations of acetaminophen as a reference hepatotoxin for the evaluation of in vitro liver models.

Acetaminophen is commonly used as a reference hepatotoxin to demonstrate that in vitro human liver platforms can emulate features of clinical drug-induced liver injury. However, the induction of substantial cell death in these models typically requires acetaminophen concentrations (∼10 mM) far higher than blood concentrations of the drug associated with clinical hepatotoxicity (∼1 mM). Using the cytochrome P450 inhibitor 1-aminobenzotriazole, we show that acetaminophen toxicity in cultured human, mouse, and rat hepatocytes is not dependent on N-acetyl-p-benzoquinonimine formation, unlike the in vivo setting.

Metabolite Measurement in Index Substrate Drug Interaction Studies: A Review of the Literature and Recent New Drug Application Reviews.

Background/objectives: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug-drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 ((S)-warfarin, flurbiprofen), CYP2C19 (omeprazole), CYP2D6 (desipramine, dextromethorphan, nebivolol), and CYP3A (midazolam, triazolam).

Methods: All data used in this evaluation were obtained from the Certara Drug Interaction Database.

Application of Physiologically Based Pharmacokinetic Model to Delineate the Impact of Aging and Renal Impairment on Ceftazidime Clearance.

The impact of physiological changes during aging on drug disposition has not always been thoroughly assessed in clinical studies. This has left an open question such as how and to what extent patho- and physiological changes in renal function can affect pharmacokinetics in the geriatric population. The objective of this work was to use a physiologically based pharmacokinetic (PBPK) model to quantify the impact of aging and renal impairment (RI) separately and together on ceftazidime pharmacokinetics (PK).

A Physiologically Based Pharmacokinetic Model Relates the Subcutaneous Bioavailability of Monoclonal Antibodies to the Saturation of FcRn-Mediated Recycling in Injection-Site-Draining Lymph Nodes.

The bioavailability of a monoclonal antibody (mAb) or another therapeutic protein after subcutaneous (SC) dosing is challenging to predict from first principles, even if the impact of injection site physiology and drug properties on mAb bioavailability is generally understood. We used a physiologically based pharmacokinetic model to predict pre-systemic clearance after SC administration mechanistically by incorporating the FcRn salvage pathway in antigen-presenting cells (APCs) in peripheral lymph nodes, draining the injection site. Clinically observed data of the removal rate of IgG from the arm as well as its plasma concentration after SC dosing were mostly predicted within the 95% confidence interval.

An Application of a Physiologically Based Pharmacokinetic Approach to Predict Ceftazidime Pharmacokinetics in a Pregnant Population.

Physiological changes during pregnancy can alter maternal and fetal drug exposure. The objective of this work was to predict maternal and umbilical ceftazidime pharmacokinetics during pregnancy. Ceftazidime transplacental permeability was predicted from its physicochemical properties and incorporated into the model.