A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice

Varkhede, Ninad; Patel, Nita; Chang, William Y.; Ruterbories, Kenneth J.; Forrest, M. Laird

doi:10.1007/s11095-018-2447-9

Cited by 7 publications

(5 citation statements)

References 46 publications

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“…Similar disease-drug interactions were confirmed for simvastatin and cyclosporine through physiologically based pharmacokinetic simulations [ 49 ]. Metabolism of midazolam, a CYP3A probe substrate, was decreased 12 h after inducing inflammatory conditions with glucose-6-phosphate-isomerase as measured by increased serum IL-6 and TNFα levels and suppression of CYP3A mRNA [ 50 ]. CYP1A2-mediated hepatic clearance of theophylline is decreased by adenovirus or influenza virus [ 46 ].…”

Section: Effect Of Inflammation On Cytochrome P450 Enzyme Expression mentioning

confidence: 99%

Potential Effects of COVID-19 on Cytochrome P450-Mediated Drug Metabolism and Disposition in Infected Patients

Deb

Arrighi

2021

Eur J Drug Metab Pharmacokinet

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Coronavirus Disease 2019 (COVID-19) has been a global health crisis since it was first identified in December 2019. In addition to fever, cough, headache, and shortness of breath, an intense increase in immune response-based inflammation has been the hallmark of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) virus infection. This narrative review summarizes and critiques pathophysiology of COVID-19 and its plausible effects on drug metabolism and disposition. The release of inflammatory cytokines (e.g., interleukins, tumor necrosis factor α), also known as ‘cytokine storm’, leads to altered molecular pathophysiology and eventually organ damage in the lung, heart, and liver. The laboratory values for various liver function tests (e.g., alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin) have indicated potential hepatocellular injury in COVID-19 patients. Since the liver is the powerhouse of protein synthesis and the primary site of cytochrome P450 (CYP)-mediated drug metabolism, even a minor change in the liver function status has the potential to affect the hepatic clearance of xenobiotics. It has now been well established that extreme increases in cytokine levels are common in COVID-19 patients, and previous studies with patients infected with non-SARS-CoV-2 virus have shown that CYP enzymes can be suppressed by an infection-related cytokine increase and inflammation. Alongside the investigational COVID-19 drugs, the patients may also be on therapeutics for comorbidities; especially epidemiological studies have indicated that individuals with hypertension, hyperglycemia, and obesity are more vulnerable to COVID-19 than the average population. This complicates the drug-disease interaction profile of the patients as both the investigational drugs (e.g., remdesivir, dexamethasone) and the agents for comorbidities can be affected by compromised CYP-mediated hepatic metabolism. Overall, it is imperative that healthcare professionals pay attention to the COVID-19 and CYP-driven drug metabolism interactions with the goal to adjust the dose or discontinue the affected drugs as appropriate.

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Section: Effect Of Inflammation On Cytochrome P450 Enzyme Expression mentioning

confidence: 99%

Potential Effects of COVID-19 on Cytochrome P450-Mediated Drug Metabolism and Disposition in Infected Patients

Deb

Arrighi

2021

Eur J Drug Metab Pharmacokinet

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“…The metabolism of small-molecule drugs (SMDs) in the liver and other organs has been extensively studied using in vitro systems to obtain quantitative data. 68 Furthermore, these in vitro data are commonly used in the physiologically based pharmacokinetic (PBPK) models to predict PK of SMDs. 69 However, similar quantitative information about the metabolic processes of TPs in the SC or ID injection sites and lymphatic system is not available.…”

Section: Key Points and Unknownsmentioning

confidence: 99%

Proteolysis and Oxidation of Therapeutic Proteins After Intradermal or Subcutaneous Administration

Varkhede

Bommana

Schöneich

et al. 2020

Journal of Pharmaceutical Sciences

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Keywords:intradermal subcutaneous therapeutic proteins PBPK modeling reactive oxygen species proteolysis oxidation lymphatic system a b s t r a c tThe intradermal (ID) and subcutaneous (SC) routes are commonly used for therapeutic proteins (TPs) and vaccines; however, the bioavailability of TPs is typically less than small molecule drugs given via the same routes. Proteolytic enzymes in the dermal, SC, and lymphatic tissues may be responsible for the loss of TPs. In addition, the TPs may be exposed to reactive oxygen species generated in the SC tissue and the lymphatic system in response to injection-related trauma and impurities within the formulation. The reactive oxygen species can oxidize TPs to alter their efficacy and immunogenicity potential. Mechanistic understandings of the dominant proteolysis and oxidative routes are useful in the drug discovery process, formulation development, and to assess the potential for immunogenicity and altered pharmacokinetics (PK). Furthermore, in vitro tools representing the ID or SC and lymphatic system can be used to evaluate the extent of proteolysis of the TPs after the injection and before systemic entry. The in vitro clearance data may be included in physiologically based pharmacokinetic models for improved PK predictions. In this review, we have summarized various physiological factors responsible for proteolysis and oxidation of TPs after ID and SC administration.

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“…Only in one-compartment model where drug distribution rapidly reaches equilibrium in the whole body can the effect of the distribution on the plasma drug profile be neglected. However, MDZ is a typical two-compartment model ( 19 ), resulting in poor correlations between single point plasma concentrations and AUC. (II) If urinary excretion is the main contributor to drug elimination, urinary excretion of the parent drug may be positively correlated with CL.…”

Section: Discussionmentioning

confidence: 99%

An exploration on retro-construction of plasma drug concentration-time curves from corresponding urine excretion data and single-point plasma concentrations using a simplified and idealized method

Li¹,

Zhang²,

Zhang³

et al. 2023

Transl Pediatr

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Background: Despite the availability of various tools of modeling and simulation, clinical pediatric pharmacokinetic (PK) studies remain far less efficient than those on adults due to ethical constraints. One of the optimal solutions is to substitute urine to blood sampling based on explicit mathematic relationships between them. However, this idea is limited by three main knowledge gaps associated with urine data, i.e., complicated excretion equations with excessive parameters, insufficient frequency that is hard to fit, and the mere expression of amounts with no in vivo distribution volume information involved.Methods: To overcome these obstacles, we sacrificed the precision from mechanistic PK models with complex excretion equations to expediency of compartmental model in which a constant k e is used to cover all the internal parameters. And the total cumulative amounts of urinary drug excretion ( ) u X ∞ were estimated and introduced to the excretion equation so that urine data were likely to be fitted using a semi-log-terminal linear regression method. In addition, urinary excretion clearance (CL r ) could be calculated by single point plasma data to anchor the plasma concentration-time (C-t) curve based on the assumption that CL r was kept constant throughout the PK process.Results: After sensitivity analysis of two subjective judgements (the selection of the compartmental model and the selection of plasma time point to calculate CL r ), the performance of the optimized models was assessed using desloratadine or busulfan as model drugs in a variety of PK scenarios, from i.v. bolus/infusion to p.o. administration, from a single dose to multiple doses, and from rats to children. The fitting plasma drug concentrations of the optimal model were close to the observed value. Meanwhile, the drawbacks inherent to the simplified and idealized modeling strategy were fully identified. Conclusions:The method proposed by this tentative proof-of-principle study was able to deliver acceptable plasma exposure curves and shed light on the future refinements.

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A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered Metabolism of Midazolam Due to Inflammation in Mice

Abstract: The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs.

Cited by 7 publications

References 46 publications

Potential Effects of COVID-19 on Cytochrome P450-Mediated Drug Metabolism and Disposition in Infected Patients

Potential Effects of COVID-19 on Cytochrome P450-Mediated Drug Metabolism and Disposition in Infected Patients

Proteolysis and Oxidation of Therapeutic Proteins After Intradermal or Subcutaneous Administration

An exploration on retro-construction of plasma drug concentration-time curves from corresponding urine excretion data and single-point plasma concentrations using a simplified and idealized method

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