Physiologically based Pharmacokinetic Model Validated to Enable Predictions Of Multiple Drugs in a Long-acting Drug-combination Nano-Particles (DcNP): Confirmation with 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products.

Drug-Combination Nanoparticles (DcNP) are a novel drug delivery system designed for synchronized delivery of multiple drugs in a single, long-acting, and targeted dose. Unlike depot formulations, slowly releasing drug at the injection site into the blood, DcNP allows multiple-drug-in-combination to collectively distribute from the injection site into the lymphatic system. Two distinct classes of long-acting injectables products are proposed based on pharmacokinetic mechanisms.

Incorporating Uremic Solute-mediated Inhibition of OAT1/3 Improves PBPK Prediction of Tenofovir Renal and Systemic Disposition in Patients with Severe Kidney Disease.

Background: Dose modification of renally secreted drugs in patients with chronic kidney disease (CKD) has relied on serum creatinine concentration as a biomarker to estimate glomerular filtration (GFR) under the assumption that filtration and secretion decline in parallel. A discrepancy between actual renal clearance and predicted renal clearance based on GFR alone is observed in severe CKD patients with tenofovir, a compound secreted by renal OAT1/3. Uremic solutes that inhibit OAT1/3 may play a role in this divergence.

Co-consuming green tea with raloxifene decreases raloxifene systemic exposure in healthy adult participants.

Green tea is a popular beverage worldwide. The abundant green tea catechin (-)-epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP-glucuronosyltransferase (UGT) activity (K  ~2 μM). Co-consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure.

Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction.

The mitochondrial dysfunction characteristic of heart failure (HF) is associated with changes in intracellular nicotinamide adenine dinucleotide (NAD) and NADH levels. Raising NAD levels with the NAD precursor, nicotinamide riboside (NR), may represent a novel HF treatment. In this 30-participant trial of patients with clinically stable HF with reduced ejection fraction, NR, at a dose of 1,000 mg twice daily, appeared to be safe and well tolerated, and approximately doubled whole blood NAD levels.

Model-Based Analysis of the Influence of Alcohol Use and Age on Pharmacokinetics-Pharmacodynamics of Oral Oxycodone in Middle-Age and Older Community-Dwelling Adults.

Little is known about how opioid responses vary by age and in the presence of alcohol consumption. This model-based pharmacokinetic (PK)-pharmacodynamic (PD) analysis quantified the impact of age and alcohol use on pupillometry and cold pressor test (CPT) PD based on data from an open-label study of a single, immediate-release 10-mg oral oxycodone in middle-age and older adults (aged 35-85) without severe functional limitations. PK and pupillometry assessments were obtained on 11 occasions over 8 hours.

Elevated customary alcohol consumption attenuates opioid effects.

Background: Regular alcohol consumption is on the rise among older adults and has the potential of altering the subjective experience of pain and response to pain medications. This study examined the cognitive, analgesic and side effect response to oxycodone in middle age and older adults with elevated levels of customary alcohol consumption in a human laboratory setting.

Methods: After refraining from alcohol for one day, eligible participants underwent baseline assessment cognition and side effects by means of questionnaires that were repeated at three time points (90 min, 5 and 8 h) following administration of a 10 mg oral dose of oxycodone.

Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 2: Model for the Drug-combination Nanoparticles.

We previously developed a mechanism-based pharmacokinetic (MBPK) model to characterize the PK of a lymphocyte-targeted, long-acting 3 HIV drug-combination nanoparticle (DcNP) formulation of lopinavir, ritonavir, and tenofovir. MBPK describes time-courses of plasma drug concentration and has provided an initial hypothesis for the lymphatic PK of DcNP. Because anatomical and physiological interpretation of MBPK is limited, in this Part 2, we report the development of a Physiologically Based Pharmacokinetic (PBPK) model for a detailed evaluation of the systemic and lymphatic PK of drugs associated with DcNP.

Physiologically Based Pharmacokinetic Modeling of 3 HIV Drugs in Combination and the Role of Lymphatic System after Subcutaneous Dosing. Part 1: Model for the Free-Drug Mixture.

Drug-combination nanoparticles (DcNP) allow the formulation of multiple HIV drugs in one injectable. In nonhuman primates (NHP), all drugs in DcNP have demonstrated long-acting pharmacokinetics (PK) in the blood and lymph nodes, rendering it suitable for a Targeted Long-acting Antiretroviral Therapy (TLC-ART). To support the translation of TLC-ART into the clinic, the objective is to present a physiologically based PK (PBPK) model tool to control mechanisms affecting the rather complex DcNP-drug PK.

Predicting Maternal-Fetal Disposition of Fentanyl Following Intravenous and Epidural Administration Using Physiologically Based Pharmacokinetic Modeling.

Fentanyl is an opioid analgesic used to treat obstetrical pain in parturient women through epidural or intravenous route, and unfortunately can also be abused by pregnant women. Fentanyl is known to cross the placental barrier, but how the route of administration and time after dosing affects maternal-fetal disposition kinetics at different stages of pregnancy is not well characterized. To address this knowledge gap, we developed a maternal-fetal physiologically based pharmacokinetic (mf-PBPK) model for fentanyl to evaluate the feasibility to predict the maternal and fetal plasma concentration-time profiles of fentanyl after various dosing regimens.

Relationship of Phosphatidylethanol Biomarker to Self-Reported Alcohol Drinking Patterns in Older and Middle-Age Adults.

Background: Risky alcohol consumption is on the rise among older adults. Biomarkers such as phosphatidylethanol (PEth) have been used to evaluate the correspondence between an objective, laboratory-based biomarker and self-report of alcohol consumption. This study examined the relationship between PEth, self-report of alcohol consumption, and health indices in a sample of community-dwelling older to middle-age adults (aged 35 to 89) with healthy and risky levels of alcohol consumption.

Novel Long-Acting Drug Combination Nanoparticles Composed of Gemcitabine and Paclitaxel Enhance Localization of Both Drugs in Metastatic Breast Cancer Nodules.

Purpose: To develop drug-combination nanoparticles (DcNPs) composed of hydrophilic gemcitabine (G) and hydrophobic paclitaxel (T) and deliver both drugs to metastatic cancer cells.

Methods: GT DcNPs were evaluated based on particle size and drug association efficiency (AE%). The effect of DcNP on GT plasma time-course and tissue distribution was characterized in mice and a pharmacokinetic model was developed.

An Improved Vascularized, Dual-Channel Microphysiological System Facilitates Modeling of Proximal Tubular Solute Secretion.

A vascularized human proximal tubule model in a dual-channel microphysiological system (VPT-MPS) was developed, representing an advance over previous, single-cell-type kidney microphysiological systems. Human proximal tubule epithelial cells (PTECs) and human umbilical vein endothelial cells (HUVECs) were cocultured in side-by-side channels. Over 24 h of coculturing, PTECs maintained polarized expression of Na/K ATPase, tight junctions (ZO-1), and OAT1.

Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.

Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ≥36 weeks' gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6 h rewarming period.

Integration of Computational and Experimental Approaches to Elucidate Mechanisms of First-Pass Lymphatic Drug Sequestration and Long-Acting Pharmacokinetics of the Injectable Triple-HIV Drug Combination TLC-ART 101.

TLC-ART101 is a long-acting triple-HIV drug combination of lopinavir-ritonavir-tenofovir in one nanosuspension intended for subcutaneous injection. After a single TLC-ART 101 administration in nonhuman primates, drug concentrations in both plasma and HIV-target lymph node mononuclear cells were sustained for 2 weeks. Nevertheless, the mechanisms leading to the targeted long-acting pharmacokinetics remain elusive.

The Impact of Proximal Roux-en-Y Gastric Bypass Surgery on Acetaminophen Absorption and Metabolism.

Background: Roux-en-Y gastric bypass (RYGBS), a surgery that creates a smaller stomach pouch and reduces the length of small intestine, is one of the most common medical interventions for the treatment of obesity.

Aim: The aim of this study was to determine how RYGBS affects the absorption and metabolism of acetaminophen.

Materials And Methods: Ten morbidly obese patients received 1.

Influence of St. John's Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects: A Randomized Clinical Trial.

Background: Patients often use complementary and alternative herbal medicines, hence, potential exists for adverse herb-drug interactions. Fentanyl is metabolized by hepatic CYP3A4 and considered transported by blood-brain barrier P-glycoprotein. Both disposition processes could be upregulated by the herbal St.

Pharmacodynamics of Metformin in Pregnant Women With Gestational Diabetes Mellitus and Nonpregnant Women With Type 2 Diabetes Mellitus.

Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, β-cell responsivity, and disposition index following a mixed-meal tolerance test utilizing a minimal model of glucose, insulin, and C-peptide kinetics before and during treatment with metformin.

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6-Mediated Metabolic Activity.

The cytochrome P450 2D6 (CYP2D6) gene locus is challenging to accurately genotype due to numerous single nucleotide variants and complex structural variation. Our goal was to determine whether the CYP2D6 genotype-phenotype correlation is improved when diplotype assignments incorporate structural variation, identified by the bioinformatics tool Stargazer, with next-generation sequencing data. Using CYP2D6 activity measured with substrates dextromethorphan and metoprolol, activity score explained 40% and 34% of variability in metabolite formation rates, respectively, when diplotype calls incorporated structural variation, increasing from 36% and 31%, respectively, when diplotypes did not incorporate structural variation.

Effect of N-Acetyltransferase 2 Genotype on the Pharmacokinetics of Hydralazine During Pregnancy.

Hydralazine, an antihypertensive agent used during pregnancy, undergoes N-acetylation primarily via N-acetyltransferase 2 (NAT2) to form 3-methyl-1,2,4-triazolo[3,4-a]phthalazine (MTP). To characterize the steady-state pharmacokinetics (PK) of hydralazine during pregnancy and evaluate the effects of NAT2 genotype on hydralazine and MTP PK during pregnancy, 12 pregnant subjects received oral hydralazine (5-25 mg every 6 hours) in mid- (n = 5) and/or late pregnancy (n = 8). Serial blood samples were collected over 1 dosing interval, and steady-state noncompartmental PK parameters were estimated.

Gut Microbiota Modulates Interactions Between Polychlorinated Biphenyls and Bile Acid Homeostasis.

The gut microbiome is increasingly recognized as a second genome that contributes to the health and diseases of the host. A major function of the gut microbiota is to convert primary bile acids (BAs) produced from cholesterol in the liver into secondary BAs that activate distinct host receptors to modulate xenobiotic metabolism and energy homeostasis. The goal of this study was to investigate to what extent oral exposure to an environmentally relevant polychlorinated biphenyl (PCBs mixture), namely the Fox River mixture, impacts gut microbiome and BA homeostasis.

Three HIV Drugs, Atazanavir, Ritonavir, and Tenofovir, Coformulated in Drug-Combination Nanoparticles Exhibit Long-Acting and Lymphocyte-Targeting Properties in Nonhuman Primates.

Drug-combination nanoparticles (DcNPs) administered subcutaneously represent a potential long-acting lymphatic-targeting treatment for HIV infection. The DcNP containing lopinavir (LPV)-ritonavir (RTV)-tenofovir (TFV), Targeted-Long-Acting-Antiretroviral-Therapy product candidate 101 (TLC-ART 101), has shown to provide long-acting lymphocyte-targeting performance in nonhuman primates. To extend the TLC-ART platform, we replaced TLC-ART 101 LPV with second-generation protease inhibitor, atazanavir (ATV).

Reevaluating the role of megalin in renal vitamin D homeostasis using a human cell-derived microphysiological system.

The role of megalin in the regulation of renal vitamin D homeostasis has previously been evaluated in megalin-knockout mice and rat proximal tubule epithelial cells. We revisited these hypotheses that were previously tested solely in rodent models, this time using a 3-dimensional proximal tubule microphysiological system incorporating primary human proximal tubule epithelial cells. Using this human cell-derived model, we confirmed that 25OHD3 is transported into the human proximal tubule epithelium via megalin-mediated endocytosis while bound to vitamin D binding protein.

Disposition of Methamphetamine and Major Metabolites in Mice: Role of Organic Cation Transporter 3 in Tissue-Selective Accumulation of -Hydroxymethamphetamine.

Methamphetamine is one of the most widely abused illicit drugs. Although human intoxication and multiple tissue toxicities frequently occur in abusers, little is known about the distribution of methamphetamine or its primary metabolites, amphetamine and -hydroxymethamphetamine (-OHMA), to their sites of toxicity. This study determined the pharmacokinetics, tissue exposure, and partition ratios of methamphetamine and major metabolites in various mouse tissues and investigated the impact of organic cation transporter 3 (Oct3) following i.