A5053997698- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Pharmacological Effects and Toxicity Studies
- Pregnancy and Medication Impact
- Analytical Methods in Pharmaceuticals
- Pharmaceutical studies and practices
- Antibiotics Pharmacokinetics and Efficacy
- Multiple Myeloma Research and Treatments
- Chronic Lymphocytic Leukemia Research
- Innovative Microfluidic and Catalytic Techniques Innovation
- Schizophrenia research and treatment
- Pregnancy and preeclampsia studies
- Neonatal Respiratory Health Research
- HIV/AIDS drug development and treatment
- Blood Pressure and Hypertension Studies
- Protein Degradation and Inhibitors
- Pediatric Hepatobiliary Diseases and Treatments
- Neutropenia and Cancer Infections
- Inflammatory mediators and NSAID effects
- Peroxisome Proliferator-Activated Receptors
- Pancreatic function and diabetes
- Pharmacological Effects and Assays
- Birth, Development, and Health
- Plant-based Medicinal Research
- Sleep and related disorders
Certara (United States)
2015-2024
Simcyp (United Kingdom)
2013-2023
Integra LifeSciences (United States)
2017-2021
Research and Studies Telecommunications Centre
2020
University of Florida
2018
Columbus Oncology and Hematology Associates
2018
Eli Lilly (United States)
2013-2015
Research Triangle Park Foundation
2015
GlaxoSmithKline (United States)
2015
University of Washington
2013
Conducting PK studies in pregnant women is challenging. Therefore, we asked if a physiologically-based pharmacokinetic (PBPK) model could be used to predict the disposition of drugs cleared by multiple CYP enzymes.We expanded and verified our previously published pregnancy PBPK incorporating hepatic CYP2B6 induction (based on vitro data), CYP2C9 phenytoin PK) CYP2C19 suppression proguanil PK), into model. This accounted for gestational age-dependent changes maternal physiology CYP3A, CYP1A2...
Although organic anion transporting polypeptide (OATP)–mediated hepatic uptake is generally conserved between rodents and humans at a gross pharmacokinetic level, the presence of three major OATPs with broad overlap in substrate inhibitor affinity, absence rodent-human orthologs preclude clinical translation single-gene knockout/knockin findings. At present, changes pharmacokinetics tissue distribution pravastatin, atorvastatin, simvastatin, carboxydichlorofluorescein were studied...
Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based (PBPK) model could be used to evaluate different dosing regimens for women. We refined and verified our previously published pregnancy PBPK by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) CYP2D6 induction metoprolol into the model. This accounts gestational age–dependent changes maternal physiology hepatic CYP3A activity. For verification,...
High-dose ketoconazole (400 mg q.d. for ≥5 days) has been the gold-standard strong cytochrome P450 3A (CYP3A) inhibitor in drug development drug–drug interaction (DDI) studies. In 2013, US Food and Drug Administration (FDA) European Medicines Agency (EMA) advised against using this regimen following review of clinical safety reports. We systematically evaluated 19 CYP3A inhibitors from regulatory guidances a literature database to identify itraconazole (200 b.i.d. on day 1, days 2–6)...
In this study, we present efavirenz physiologically based pharmacokinetic (PBPK) model development as an example of our best practice approach that uses a stepwise to verify the different components model. First, PBPK for incorporating in vitro and clinical (PK) data was developed predict exposure following multiple dosing (600 mg q.d.). Alfentanil i.v. p.o. drug‐drug interaction (DDI) studies were utilized evaluate refine CYP3A4 induction component liver gut. Next, independent DDI with...
Abstract Physiologically‐based pharmacokinetic (PBPK) modeling is being increasingly used in drug development to avoid unnecessary clinical drug–drug interaction (DDI) studies and inform labels. Thus, regulatory agencies are recommending, or indeed requesting, more rigorous demonstration of the prediction accuracy PBPK platforms area their intended use. We describe a framework for qualification Simcyp Simulator with respect competitive mechanism‐based inhibition (MBI) CYP1A2, CYP2D6, CYP2C8,...
We use a mechanistic lung model to demonstrate that accumulation of chloroquine (CQ), hydroxychloroquine (HCQ), and azithromycin (AZ) in the lungs is sensitive changes pH, parameter can be affected patients with coronavirus disease 2019 (COVID-19). A reduction pH from 6.7 6 lungs, as observed respiratory disease, led 20-fold, 4.0-fold, 2.7-fold increases exposure CQ, HCQ, AZ, respectively. Simulations indicated relatively high concentrations CQ HCQ tissue were sustained long after...
Ivosidenib is a potent, targeted, orally active, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) that has been approved in the United States for treatment adults with newly diagnosed acute myeloid leukemia (AML) who are greater than or equal to 75 years age ineligible intensive chemotherapy, and those relapsed refractory AML, susceptible IDH1 mutation. an inducer CYP2B6, CYP2C8, CYP2C9, CYP3A4 P-glycoprotein (P-gp), organic anion transporting polypeptide-1B1/1B3...
At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to metabolism. However, at higher than clinical was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated effect of strong inhibitors ketoconazole and clarithromycin inducer rifampin on pharmacokinetics...
Betamethasone and dexamethasone are the most widely studied antenatal corticosteroids ( ACS ) administered to pregnant women, just prior birth of a preterm neonate, accelerate fetal lung maturation. Although betamethasone, predominantly used in developed countries, has been shown be an effective safe intervention for reducing neonatal mortality, choice optimal dosing low middle income countries LMIC s) remains unclear. This is primarily because exposure–response relationships have not...
e15127 Background: Debio 0123 is an oral, brain-penetrant, highly selective WEE1 kinase inhibitor currently being investigated in several clinical trials patients with advanced solid tumors both as monotherapy and combination. In vitro , can inhibit induce cytochrome P450 (CYP) 3A4 P-gp. Methods: A physiologically-based pharmacokinetic (PBPK) model using Simcyp Population Based Simulator was developed for to evaluate its perpetrator effect on sensitive substrates of CYP3A4 second etoposide...
Through PET imaging, our laboratory has studied the dynamic biodistribution of <sup>11</sup>C-verapamil, a P-gp substrate, in nonhuman primate <i>Macaca nemestrina</i>. To gain detailed insight into kinetics verapamil transport across blood–brain barrier (BBB) and blood–placental (BPB), we analyzed these data by compartmental modeling. <b>Methods:</b> Thirteen pregnant macaques (gestational age, 71–159 d; term, ∼172 d) underwent imaging with <sup>11</sup>C-verapamil before during infusion...
The glycogen synthase kinase-3 inhibitor LY2090314 specifically impaired CYP2B6 activity during in vitro evaluation of cytochrome P450 (P450) enzyme induction human hepatocytes. catalytic was significantly decreased following 3-day incubation with 0.1–10 <i>μ</i>M LY2090314, on average by 64.3% ± 5.0% at 10 <i>μ</i>M. These levels exposure were not cytotoxic to hepatocytes and did reduce CYP1A2 CYP3A activities. a time-dependent inhibitor, otherwise inhibit concentrations ≤10 <i>μ</i>M,...
Abstract Trazodone is approved for the treatment of major depressive disorders, marketed as immediate release (IR), prolonged release, and once a day (OAD) formulation. The different formulations allow administration schedules may be useful to facilitate patients’ compliance antidepressant treatment. A previously verified physiologically‐based pharmacokinetic model based on in vitro vivo information trazodone pharmacokinetics was applied, aiming at predicting brain receptor occupancy (RO)...
Abstract Lefamulin is being evaluated as a treatment for bacterial exacerbations in cystic fibrosis (CF). Ivacaftor approved the of patients with CF. moderate CYP3A inhibitor and co‐administration ivacaftor may result drug–drug interaction (DDI). A CF population was built based on literature using Simcyp Simulator. previously developed validated physiologically‐based pharmacokinetic (PBPK) model used. PBPK lefamulin verified. Predicted concentrations (PK) parameters both healthy subjects...
Leriglitazone is a unique peroxisome proliferator-activated receptor-gamma (PPARγ) agonist that crosses the blood-brain barrier in humans and clinical trials have shown evidence of efficacy neurodegenerative diseases. At doses which are well-tolerated, leriglitazone reaches target central nervous system (CNS) concentrations needed for PPARγ engagement efficacy; also supported by anti-inflammatory biomarker changes Cerebrospinal fluid CNS. Plasma pharmacokinetics (PK) were determined phase 1...
Ketoconazole is no longer available for clinical determination of worst-case victim drug-drug interaction (DDI) potential cytochrome P450 3A (CYP3A)-substrate drugs; clarithromycin and itraconazole are the proposed replacements. DDIs described by unbound systemic exposures due to absence carrier-facilitated hepatic uptake, but this aspect disposition has not been investigated. At present, transport clarithromycin, itraconazole, hydroxyitraconazole organic anion transporting polypeptides...
Blood cells are considered an important distributional compartment for metformin based on the high blood-to-plasma partition ratio (B/P) in humans (>10 at <i>C</i><sub>min</sub>). However, literature reports of metformin9s intrinsic vitro B/P values lacking. At present, extent and rate cellular partitioning was determined incubations fresh human rat blood with [<sup>14</sup>C]metformin up to 1 week concentrations spanning steady-state plasma <i>C</i><sub>min</sub>, <i>C</i><sub>max</sub>,...
Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, has been reported to have longer elimination half-life after treatment. Two pharmacokinetic model-based approaches were used assess whether evacetrapib, another CETP could behave similarly. Using population (PopPK) modeling, evacetrapib and anacetrapib pharmacokinetics characterized using available concentration-time data, steady-state conditions simulated. Published 2-compartment models for each compound adapted include...
There is a paucity of clinical trials for the treatment pediatric insomnia. This study was designed to predict doses trazodone guide dosing in trial insomnia using physiologically-based pharmacokinetic (PBPK) modeling. Data on pharmacokinetics children are currently lacking. The interaction potential between and atomoxetine also predicted. Doses predicted following age groups, with exposures corresponding adult dosages 30, 75, 150 mg once day (q.d.), respectively, were: (i) 2- 6-year-old...