Drug-Drug Interaction Potential of Mavacamten with Midazolam: Combined Results from Clinical and Model-Based Studies.

Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and could reduce the effectiveness of concomitant drugs that are metabolized by CYP3A4, such as midazolam. This study aimed to determine if repeat doses of mavacamten achieving clinically relevant exposures affected midazolam exposure. This was a single-center, open-label study in healthy participants.

A close examination of BCRP's role in lactation and methods for predicting drug distribution into milk.

Breastfeeding is the most complete nutritional method of feeding infants, but several impediments affect the decision to breastfeed, including questions of drug safety for medications needed during lactation. Despite recent FDA guidance, few labels provide clear dosing advice during lactation. Physiologically based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms to fill gaps in the absence of extensive clinical studies and complement existing real-world data.

Effect of Activated Charcoal on Mavacamten Pharmacokinetics in Healthy Participants.

Objective: To assess the effect of activated charcoal on the single-dose pharmacokinetics of mavacamten when administered 2 h or 6 h after mavacamten dosing.

Methods: In this open-label, randomized, parallel-group study, healthy adults were randomized into three groups to receive mavacamten 15 mg alone or mavacamten 15 mg plus activated charcoal 50 g administered either 2 h or 6 h after mavacamten dosing. Pharmacokinetic parameters were derived from plasma concentration-time data using noncompartmental methods.

The Interplay of Permeability, Metabolism, Transporters, and Dosing in Determining the Dynamics of the Tissue/Plasma Partition Coefficient and Volume of Distribution-A Theoretical Investigation Using Permeability-Limited, Physiologically Based Pharmacokinetic Modeling.

A permeability-limited physiologically based pharmacokinetic (PBPK) model featuring four subcompartments (corresponding to the intracellular and extracellular water of the tissue, the residual plasma, and blood cells) for each tissue has been developed in MATLAB/SimBiology and applied to various what-if scenario simulations. This model allowed us to explore the complex interplay of passive permeability, metabolism in tissue or residual blood, active uptake or efflux transporters, and different dosing routes (intravenous (IV) or oral (PO)) in determining the dynamics of the tissue/plasma partition coefficient (Kp) and volume of distribution (Vd) within a realistic pseudo-steady state. Based on the modeling exercise, the permeability, metabolism, and transporters demonstrated significant effects on the dynamics of the Kp and Vd for IV bolus administration and PO fast absorption, but these effects were not as pronounced for IV infusion or PO slow absorption.

Physiologically Based Pharmacokinetic Modeling and Simulation of Mavacamten Exposure with Drug-Drug Interactions from CYP Inducers and Inhibitors by CYP2C19 Phenotype.

Mavacamten is a first-in-class, oral, selective, allosteric, reversible cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association functional class II-III obstructive hypertrophic cardiomyopathy. Mavacamten is metabolized in the liver, predominantly via cytochrome P450 (CYP) enzymes CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). A physiologically-based pharmacokinetic (PBPK) model was developed using Simcyp version 19 (Certara, Princeton, NJ).

Drug-Drug Interaction Potential of Mavacamten with Oral Contraceptives: Results from a Clinical Pharmacokinetic Study and a Physiologically Based Pharmacokinetic Model.

Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and, as such, could reduce the exposure of the active components of oral contraceptives, ethinyl estradiol (EE) and norethindrone (NOR), where CYP3A4 is involved in metabolism. This study assessed if repeat doses of mavacamten led to a drug-drug interaction with EE and/or NOR. This was an open-label study in healthy women.

Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21.

Physiologically based pharmacokinetic (PBPK) modeling has a number of applications, including assessing drug−drug interactions (DDIs) in polymorphic populations, and should be iteratively refined as science progresses. The Simcyp Simulator is annually updated and version 21 included updates to hepatic and intestinal CYP2C19 enzyme abundance, including addition of intermediate and rapid metabolizer phenotypes and changes to the ultra-rapid metabolizer enzyme abundance, with implications for population clearance and DDI predictions. This work details verification of the updates with sensitive CYP2C19 substrates, omeprazole and lansoprazole, using available clinical data from literature.

A perspective on the current use of the phase distribution model for predicting milk-to-plasma drug concentration ratio.

The phase distribution model, proposed by Atkinson and Begg in 1990, has been widely used for predicting breastmilk-to-plasma drug concentration ratio. However, misrepresentations of the equations have been noted in recent publications. In this perspective, we revisit the derivation of the equations and provide an R/Shiny interface for the model with a view to helping scientists in this field acquire in-depth understanding of the theoretical background and implementation of the model.

When special populations intersect with drug-drug interactions: Application of physiologically-based pharmacokinetic modeling in pregnant populations.

Pregnancy results in significant physiological changes that vary across trimesters and into the postpartum period, and may result in altered disposition of endogenous substances and drug pharmacokinetics. Pregnancy represents a unique special population where physiologically-based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms without subjecting pregnant women or their fetuses to extensive clinical studies. A critical review of applications of pregnancy PBPK models (pPBPK) was conducted to understand its current status for prediction of drug exposure in pregnant populations and to identify areas of further expansion.

Intact mAb LC-MS for drug concentration from pre-clinical studies: bioanalytical method performance and in-life samples.

Antibody biotherapeutic measurement from pharmacokinetic studies has not been traditionally based on intact molecular mass as is the case for small molecules. However, recent advancements in protein capture and mass spectrometer technology have enabled intact mass detection and quantitation for dosed biotherapeutics. A bioanalytical method validation is part of the regulatory requirement for sample analysis to determine drug concentration from in-life study samples.

Antibody Subunit LC-MS Analysis for Pharmacokinetic and Biotransformation Determination from In-Life Studies for Complex Biotherapeutics.

Complex biotherapeutics present challenges from drug discovery, screening, and development perspectives. While monoclonal antibody drugs are not monitored for metabolites in the same manner as small molecules, biotherapeutics such as fusion proteins, antibody-drug conjugates, or bispecific antibodies may undergo biotransformation (such as clipping, deamidation, or oxidation) in vivo, resulting in catabolites that can have a direct impact on drug safety or efficacy. Here antibody subunit LC-MS is utilized for evaluation of two classes of complex biotherapeutics: an antibody-drug conjugate and a mAb-fusion biotherapeutic.

Hepatobiliary Disposition of Atovaquone: A Case of Mechanistically Unusual Biliary Clearance.

Atovaquone, an antiprotozoal and antipneumocystic agent, is predominantly cleared by biliary excretion of unchanged parent drug. Atovaquone is ≥10,000-fold concentrated in human bile relative to unbound plasma. Even after correcting for apparent nonspecific binding and incomplete solubility in bile, atovaquone is still concentrated ≥100-fold in bile, consistent with active biliary excretion.

Single ocular injection of a sustained-release anti-VEGF delivers 6months pharmacokinetics and efficacy in a primate laser CNV model.

A potent anti-vascular endothelial growth factor (VEGF) biologic and a compatible delivery system were co-evaluated for protection against wet age-related macular degeneration (AMD) over a 6month period following a single intravitreal (IVT) injection. The anti-VEGF molecule is dimeric, containing two different anti-VEGF domain antibodies (dAb) attached to a human IgG1 Fc region: a dual dAb. The delivery system is based on microparticles of PolyActive™ hydrogel co-polymer.

Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules.

The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding.

Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer.

1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. 2.

Assessing a novel depot delivery strategy for noninvasive administration of VEGF/PDGF RTK inhibitors for ocular neovascular disease.

Purpose: Two noninvasive delivery strategies for VEGF/PDGF receptor tyrosine kinase inhibitors (RTKI) were explored that exploited uveal retention as a means for establishing an ocular drug depot: a single oral "loading" dose and topical administration.

Methods: Melanin binding was confirmed by centrifugation and mass spectrometry. Ocular retention was examined in pigmented and albino rats.

Investigations of hydrazine cleavage of eltrombopag in humans.

After oral administration to humans, eltrombopag undergoes extensive cleavage of its hydrazine linkage to metabolites, which are exclusively eliminated in urine. In vitro, the cleavage pathway was not detected in systems using cytochrome P450 enzymes, renal or hepatic microsomes, or hepatocytes but was readily evident after anaerobic incubation with rodent cecal contents or human fecal homogenate. Antibiotic treatment in vitro and in vivo inhibited eltrombopag cleavage, further indicating that cleavage is via gut microbes.

Comparison of CT, MRI, and radiographs in assessing pelvic osteolysis: a cadaveric study.

In this study, we compared the accuracy of radiography, computed tomography, and magnetic resonance imaging in assessing periacetabular osteolytic lesions. Using a previously published cadaver model, we created 87 lesions in pelves implanted with total hip replacement components. The sensitivity for detecting lesions was 51.

Magnetic resonance imaging in the evaluation of periprosthetic acetabular osteolysis: a cadaveric study.

Periprosthetic osteolysis is a well recognized complication of total hip arthroplasty that leads to implant failure. The ability to accurately assess and visualize the position and volume of periacetabular bone defects is paramount for clinical observation and medical treatment, as well as pre-operative planning of revision surgery. We have developed a modified magnetic resonance imaging (MRI) protocol that is useful in detection and quantification of periacetabular bone loss.

Conventional ultra-high molecular weight polyethylene: a gold standard of sorts.

Data from a series of four recent studies showed that conventional polyethylene liners sterilized by gamma irradiation in air and coupled with second-generation acetabular components outperformed first-generation components with consistent average wear behavior below 0.1 mm/yr. It was found that liners sterilized by gamma irradiation in air outperformed liners sterilized by gas plasma, indicating that cross-linking induced by gamma irradiation sterilization, even if the component is radiated in an oxygen environment, is essential for keeping wear rates low.

The relationship between shelf life and in vivo wear for polyethylene acetabular liners.

Abstract: Although laboratory studies have correlated shelf life for gamma-irradiated-in-air polyethylene with material degradation, it is unknown whether this clinically affects wear. Therefore, we examined the relationship between shelf life and clinical wear for 152 gamma-irradiated-in-air acetabular liners. True wear rates were calculated from computer-assisted head penetration analyses of serial radiographs.

Computed tomography to assess pelvic lysis after total hip replacement.

To assess the accuracy of a computer-assisted computed tomography image analysis program in determining the location and volume of periacetabular osteolysis, we designed an osteolysis model by implanting bilateral total hip replacements in human pelvic cadavers and creating osteolytic lesions of varying sizes. The volumes of 48 defects were measured physically, and axial computed tomography scans were obtained. The computed tomography images were processed with streak artifact reduction and segmentation algorithms.

Sterilization and polyethylene wear: clinical studies to support laboratory data.

Background: Recently, in vitro studies have linked gamma radiation sterilization in air and subsequent oxidation to decreasing mechanical properties and rapid polyethylene wear. As a result of these studies, orthopaedic device manufacturers have developed alternate sterilization strategies designed to limit or to prevent oxidative degradation. We compared how the in vivo wear performance of conventional and highly-crystalline polyethylene acetabular liners was affected by two sterilization strategies (gas plasma sterilization and gamma radiation sterilization in vacuum-barrier packaging) as compared with gamma radiation sterilization in air.

Radiographic definition of pelvic osteolysis following total hip arthroplasty.

Background: Radiographs are the standard clinical tool used to monitor patients with pelvic osteolysis after total hip arthroplasty; however, previous reports have questioned the value and accuracy of this method. With use of a cadaveric model, we investigated the accuracy of radiographs in determining the location and size of periacetabular osteolysis.

Methods: We implanted total hip arthroplasty components in eight cadaveric hips and made four radiographs of each hip from different views.

Relationship between polyethylene wear and osteolysis in hips with a second-generation porous-coated cementless cup after seven years of follow-up.

Background: The development of osteolysis, a commonly reported complication after total hip arthroplasty without cement, is perceived to be related to the amount of polyethylene particles generated from the bearing surfaces. Although the literature has suggested that the prevalence of osteolysis increases with increasing rates of polyethylene wear, this relationship has never been quantified. The goals of this study were to quantify the relationship between the prevalence of osteolysis and both linear and volumetric wear and to evaluate the risk of osteolysis as a function of wear in a currently used, porous-coated cup design.