Physiologically-based pharmacokinetic model for predicting drug-drug interactions perpetrated by posaconazole in healthy subjects with normal weight and obesity: Concomitant use and washout.

Posaconazole is an effective broad-spectrum triazole antifungal used as prophylaxis or to treat invasive Aspergillus and Candida infections in adults and pediatric patients. Posaconazole is a known strong inhibitor of cytochrome P4503A4 (CYP3A4) and substrate of P-glycoprotein (P-gp), which may lead to drug-drug interactions (DDIs) when co-administered with CYP3A4-sensitive substrates and warrants modified dosing of sensitive drugs when administered concomitantly with posaconazole. Given the long elimination half-life of posaconazole (26-35 h), there is the potential for DDIs caused by posaconazole after discontinuing the antifungal.

Incomplete Data and Potential Risks of Drugs in People with Obesity.

Purpose Of Review: To provide examples of knowledge gaps in current pharmaceutical treatments for people with obesity and call for changes to regulatory and pharmaceutical clinical research requirements during the drug discovery and development process.

Recent Findings: Treatment of obesity and its comorbidities often require the use of prescription drugs, many of which have not been fully evaluated in people with obesity. Despite a growing body of research on this topic, the impact of obesity on the pharmacokinetics and pharmacodynamics of drugs is often under-studied by drug sponsors and regulators, and subsequently underappreciated by clinicians and caretakers.

Clinical Consequences of Altered Drug Disposition in Obesity: Call for Change.

Obesity is a serious condition with many known comorbid conditions and other health risks. Despite the rising global rates of obesity, drug disposition in this population is typically understudied, which results in limited information guiding the use of drugs in patients with obesity. Presently, dosing adjustments for patients with obesity typically focus on addressing altered drug clearance with body size and are therefore limited to chronic dosing recommendations.

Estimation of Absolute and Relative Body Fat Content Using Noninvasive Surrogates: Can DXA Be Bypassed?

Dual-energy x-ray absorptiometry (DXA) scanning is used for objective determination of body composition, but instrumentation is expensive and not generally available in customary clinical practice. Anthropometric surrogates are often substituted as anticipated correlates of absolute and relative body fat content in the clinical management of obesity and its associated medical risks. DXA and anthropometric data from a cohort of 9230 randomly selected American subjects, available through the ongoing National Health and Nutrition Examination Survey, was used to evaluate combinations of surrogates (age, height, total weight, waist circumference) as predictors of DXA-determined absolute and relative body fat content.

Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies.

Background: Progressive multifocal leukoencephalopathy (PML) is a rare and often lethal brain disorder caused by the common, typically benign polyomavirus 2, also known as JC virus (JCV). In a small percentage of immunosuppressed individuals, JCV is reactivated and infects the brain, causing devastating neurological defects. A wide range of immunosuppressed groups can develop PML, such as patients with: HIV/AIDS, hematological malignancies (e.

Drug Disposition in Subjects With Obesity: The Research Work of Darrell R. Abernethy.

In 1979, the late Dr. Darrell R. Abernethy and colleagues began a series of clinical studies aimed at understanding the pertinent determinants of drug distribution, elimination, and clearance in obesity, and how those variables are interconnected.

Impact of Obesity on Brexpiprazole Pharmacokinetics: Proposal for Improved Initiation of Treatment.

Brexpiprazole is an oral antipsychotic agent indicated for use in patients with schizophrenia or as adjunctive treatment for major depressive disorder. As obesity (body mass index ≥35 kg/m ) has the potential to affect drug pharmacokinetics and is a common comorbidity of both schizophrenia and major depressive disorder, it is important to understand changes in brexpiprazole disposition in this population. This study uses a whole-body physiologically based pharmacokinetic model to compare the pharmacokinetics of brexpiprazole in obese and normal-weight (body mass index 18-25 kg/m ) individuals known to be cytochrome P450 2D6 extensive metabolizers (EMs) and poor metabolizers (PMs).

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).

Effect of lipophilicity on drug distribution and elimination: Influence of obesity.

Aims: For a given passively-distributed lipophilic drug, the extent of in vivo distribution (pharmacokinetic volume of distribution, V ) in obese individuals increases in relation to the degree of obesity. The present study had the objective of evaluating drug distribution in relation to in vitro lipophilicity, and the relative increase in V associated with obesity across a series of drugs.

Methods: Cohorts of normal-weight control and obese subjects received single doses of drugs ranging from hydrophilic (acetaminophen, salicylate) to lipophilic (imipramine, verapamil).

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the brain caused by reactivation of the JC virus (JCV), a polyomavirus that infects at least 60% of the population but is asymptomatic or results in benign symptoms in most people. PML occurs as a secondary disease in a variety of disorders or as a serious adverse event from immunosuppressant agents, but is mainly found in three groups: HIV-infected patients, patients with hematological malignancies, or multiple sclerosis (MS) patients on the immunosuppressant therapy natalizumab. It is severely debilitating and is deadly in ~50% HIV cases, ~90% of hematological malignancy cases, and ~24% of MS-natalizumab cases.

HLA associations with infliximab-induced liver injury.

Biomarkers that are able to identify patients at risk of drug-induced liver injury (DILI) after treatment with infliximab could be important in increasing the safety of infliximab use. We performed a genetic analysis to identify possible human leukocyte antigen (HLA) associations with DILI in European Caucasian users of infliximab in a retrospective study of 16 infliximab-DILI patients and 60 matched controls. In infliximab-associated liver injury, multiple potentially causal individual HLA associations were observed, as well as possible haplotypes.