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.

Postpartum changes in maternal physiology and milk composition: a comprehensive database for developing lactation physiologically-based pharmacokinetic models.

Introduction: Pharmacotherapy during lactation often lacks reliable drug safety data, resulting in delayed treatment or early cessation of breastfeeding. tools, such as physiologically-based pharmacokinetic (PBPK) models, can help to bridge this knowledge gap. To increase the accuracy of these models, it is essential to account for the physiological changes that occur throughout the postpartum period.

Physiologically Based Pharmacokinetic Modeling of Cannabidiol, Delta-9-Tetrahydrocannabinol, and Their Metabolites in Healthy Adults After Administration by Multiple Routes.

The two most extensively studied cannabinoids, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), are used for myriad conditions. THC is predominantly eliminated via the cytochromes P450 (CYPs), whereas CBD is eliminated through both CYPs and UDP-glucuronosyltransferases (UGTs). The fractional contributions of these enzymes to cannabinoid metabolism have shown conflicting results among studies.

Combining data on the bioavailability of midazolam and physiologically-based pharmacokinetic modeling to investigate intestinal CYP3A4 ontogeny.

Pediatric physiologically-based modeling in drug development has grown in the past decade and optimizing the underlying systems parameters is important in relation to overall performance. In this study, variation of clinical oral bioavailability of midazolam as a function of age is used to assess the underlying ontogeny models for intestinal CYP3A4. Data on midazolam bioavailability in adults and children and different ontogeny patterns for intestinal CYP3A4 were first collected from the literature.

Prediction of Pediatric Pharmacokinetics for CYP3A4 Metabolized Drugs: Comparison of the Performance of Two Hepatic Ontogeny Within a Physiologically Based Pharmacokinetic Model.

The rapid growth in the use of pediatric physiologically based pharmacokinetic (PBPK) models, particularly for regulatory applications, has focused emphasis on model verification and ensuring system parameters are robust, including how these change with age. Uncertainty remains regarding the ontogeny of some enzymes and transporters, in this study 2 published ontogeny profiles for hepatic CYP3A4 were compared. Clinical pharmacokinetic data on 4 intravenously administered CYP3A4 substrates (alfentanil, fentanyl, midazolam, and sildenafil) used across the pediatric age range was collected from the literature.

Physiologically Based Pharmacokinetics Modeling in the Neonatal Population-Current Advances, Challenges, and Opportunities.

Physiologically based pharmacokinetic (PBPK) modeling is an approach to predicting drug pharmacokinetics, using knowledge of the human physiology involved and drug physiochemical properties. This approach is useful when predicting drug pharmacokinetics in under-studied populations, such as pediatrics. PBPK modeling is a particularly important tool for dose optimization for the neonatal population, given that clinical trials rarely include this patient population.

Impact of CYP2C:TG Haplotype on CYP2C19 Substrates Clearance In Vivo, Protein Content, and In Vitro Activity.

A novel haplotype composed of two non-coding variants, CYP2C18 NM_000772.3:c.*31T (rs2860840) and NM_000772.

Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and Degradation.

CYP2J2 is the main epoxygenase in the heart that is responsible for oxidizing arachidonic acid to -epoxyeicosatrienoic acids (EETs). Once formed, EETs can then be hydrolyzed by soluble epoxide hydrolase (sEH, encoded by ) or re-esterified back to the membrane. EETs have several cardioprotective properties and higher levels are usually associated with better cardiac outcomes/prognosis.

Selective deuteration of bupropion slows epimerization and reduces metabolism.

Strategically replacing hydrogen with deuterium at sites of metabolism in small molecule drugs can significantly alter clearance and potentially enhance clinical safety. Bupropion is an antidepressant and smoking cessation medication with the potential to cause seizures. We hypothesized that incorporating deuterium at specific sites in bupropion may greatly reduce epimerization, potentially slow metabolism, and reduce the formation of toxic metabolites, namely hydroxybupropion which has been associated with bupropion's toxicity.

The Impact of the CYP2D6 "Enhancer" Single Nucleotide Polymorphism on CYP2D6 Activity.

rs5758550 has been associated with enhanced transcription and suggested to be a useful marker of CYP2D6 activity. As there are limited and inconsistent data regarding the utility of this distant "enhancer" single nucleotide polymorphism (SNP), our goal was to further assess the impact of rs5758550 on CYP2D6 activity toward two probe substrates, atomoxetine (ATX) and dextromethorphan (DM), using in vivo urinary metabolite (DM; n = 188) and pharmacokinetic (ATX; n = 70) and in vitro metabolite formation (ATX and DM; n = 166) data. All subjects and tissues were extensively genotyped, the "enhancer" SNP phased with established CYP2D6 haplotypes either computationally or experimentally, and the impact on CYP2D6 activity investigated using several linear models of varying complexity to determine the proportion of variability in CYP2D6 activity captured by each model.

Ontogeny of Scaling Factors for Pediatric Physiology-Based Pharmacokinetic Modeling and Simulation: Microsomal Protein Per Gram of Liver.

Microsomal protein per gram of liver (MPPGL) is an important scaling factor for bottom-up physiology-based pharmacokinetic modeling and simulation, but data in pediatrics are limited. Therefore, MPPGL was determined in 160 liver samples from pediatric ( = 129) and adult ( = 31) donors obtained from four sources: the University of Maryland Brain and Tissue Bank (UMBTB), tissue retrieval services at the University of Minnesota and University of Pittsburgh, and Sekisui-Xenotech. Tissues were homogenized and subjected to differential centrifugation to prepare microsomes, and cytochrome reductase activities in tissue homogenates and microsomes were used to estimate cytochrome P450 reductase (POR) activity as a marker of microsomal recovery; microsomal POR content was also assessed by quantitative proteomics.

The Respective Roles of CYP3A4 and CYP2D6 in the Metabolism of Pimozide to Established and Novel Metabolites.

Pimozide is a dopamine receptor antagonist indicated for the treatment of Tourette syndrome. Prior in vitro studies characterized dealkylation of pimozide to 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI) via CYP3A4 and, to a lesser extent, CYP1A2 as the only notable routes of pimozide biotransformation. However, drug-drug interactions between pimozide and CYP2D6 inhibitors and genotype-dependent effects have since been observed.

Pediatric Clinical Endpoint and Pharmacodynamic Biomarkers: Limitations and Opportunities.

Medical research in children typically lags behind that of adult research in both quantity and quality. The conduct of rigorous clinical trials in children can raise ethical concerns because of children's status as a 'vulnerable' population. Moreover, carrying out studies in pediatrics also requires logistical considerations that rarely occur with adult clinical trials.

Description of an Innovative Pediatric Individualized Therapeutics Clinic: Working toward Precision Drug Therapy.

The GOLDILOKs (Genomic and Ontogeny-Linked Dose Individualization and cLinical Optimization for KidS) Clinic aims to provide families and physicians with data to make more informed decisions with regard to pharmacological therapy by using innovative therapy and genomic technologies. The objectives are two-fold: (1) To describe the utility of the GOLDILOKs Clinic to referring prescribers by evaluating the type of referrals made to the GOLDILOKs Clinic and (2) to assess the most often utilized technologies (e.g.

Clinical Pharmacogenetics Implementation Consortium Guideline for Cytochrome P450 (CYP)2D6 Genotype and Atomoxetine Therapy.

Atomoxetine is a nonstimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). Cytochrome P450 (CYP)2D6 polymorphisms influence the metabolism of atomoxetine thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for atomoxetine based on CYP2D6 genotype (updates at www.

Ten Years' Experience with the CYP2D6 Activity Score: A Perspective on Future Investigations to Improve Clinical Predictions for Precision Therapeutics.

The seminal paper on the CYP2D6 Activity Score (AS) was first published ten years ago and, since its introduction in 2008, it has been widely accepted in the field of pharmacogenetics. This scoring system facilitates the translation of highly complex diplotype data into a patient’s phenotype to guide drug therapy and is at the core of all gene/drug pair guidelines issued by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The AS, however, only explains a portion of the variability observed among individuals and ethnicities.

Characterization of Atomoxetine Biotransformation and Implications for Development of PBPK Models for Dose Individualization in Children.

Atomoxetine (ATX) is a second-line nonstimulant medication used to control symptoms of attention deficit hyperactivity disorder (ADHD). Inconsistent therapeutic efficacy has been reported with ATX, which may be related to variable CYP2D6-mediated drug clearance. We characterized ATX metabolism in a panel of human liver samples as a basis for a bottom-up PBPK model to aid in ATX exposure prediction and control.

Potential contribution of cytochrome P450 2B6 to hepatic 4-hydroxycyclophosphamide formation in vitro and in vivo.

Results from retrospective studies on the relationship between cytochrome P450 (P450) 2B6 (CYP2B6) genotype and cyclophosphamide (CY) efficacy and toxicity in adult cancer patients have been conflicting. We evaluated this relationship in children, who have faster CY clearance and receive different CY-based regimens than adults. These factors may influence the P450s metabolizing CY to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite.