Elucidation of Metabolic and Disposition Pathways for Maribavir in Nonhuman Primates through Mass Balance and Semi-Physiologically Based Modeling Approaches.

Maribavir is in phase 3 clinical development for treatment of cytomegalovirus infection/disease in transplant recipients. Previous research conducted using only intact cynomolgus monkeys indicated biliary secretion as the primary elimination pathway for maribavir and that maribavir undergoes enterohepatic recirculation (EHR). To clarify the exact mechanisms of maribavir's EHR behavior, we studied its clearance pathways using intravenously administered C-labeled maribavir in intact and bile duct-cannulated (BDC) monkeys and constructed a semi-physiologically based pharmacokinetic (PBPK) model.

Leveraging Quantitative Systems Pharmacology Approach into Development of Human Recombinant Follistatin Fusion Protein for Duchenne Muscular Dystrophy.

Quantitative understanding about the dynamics of drug-target interactions in biological systems is essential, especially in rare disease programs with small patient populations. Follistatin, by antagonism of myostatin and activin, which are negative regulators of skeletal muscle and inflammatory response, is a promising therapeutic target for Duchenne Muscular Dystrophy. In this study, we constructed a quantitative systems pharmacology model for FS-EEE-Fc, a follistatin recombinant protein to investigate its efficacy from dual target binding, and, subsequently, to project its human efficacious dose.

Correction to: Development of Guanfacine Extended-Release Dosing Strategies in Children and Adolescents with ADHD Using a Physiologically Based Pharmacokinetic Model to Predict Drug-Drug Interactions with Moderate CYP3A4 Inhibitors or Inducers.

The article "Development of Guanfacine Extended-Release Dosing Strategies in Children and Adolescents with ADHD Using a PhysiologicallyBased Pharmacokinetic Model to Predict Drug-Drug Interactions with Moderate CYP3A4 Inhibitors or Inducers", written by Aiqun Li, Karen Yeo, Devin Welty, Haojing Rong, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 02nd November, 2017 without open access.

Ocular Distribution and Pharmacokinetics of Lifitegrast in Pigmented Rabbits and Mass Balance in Beagle Dogs.

Purpose: Lifitegrast is approved in the United States for the treatment of dry eye disease (DED). We assessed lifitegrast's ocular distribution/pharmacokinetic profile in rabbits, and C-lifitegrast mass balance/excretion in dogs.

Methods: Female pigmented rabbits received a single topical ocular dose of lifitegrast (Formulation No.

Development of Guanfacine Extended-Release Dosing Strategies in Children and Adolescents with ADHD Using a Physiologically Based Pharmacokinetic Model to Predict Drug-Drug Interactions with Moderate CYP3A4 Inhibitors or Inducers.

Background: Guanfacine extended-release (GXR) is an orally administered, non-stimulant treatment for children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and is primarily metabolized by the 3A4 isozyme of cytochrome P450 (CYP3A4). The results of clinical pharmacokinetic (PK) studies indicate that guanfacine is sensitive to drug-drug interactions (DDIs) perpetrated by strong inhibitors and inducers of CYP3A4.

Objective: The aim was to provide guidance on the possible requirement for GXR dose adjustment in children and adolescents with ADHD by predicting DDIs following co-administration with moderate CYP3A4 inhibitors and inducers.

In vitro drug-drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes.

1. Budesonide is a glucocorticoid used in the treatment of several respiratory and gastrointestinal inflammatory diseases. Glucocorticoids have been demonstrated to induce cytochrome P450 (CYP) 3A and the efflux transporter P-glycoprotein (P-gp).

Continuous infusion of the α7 nicotinic acetylcholine receptor agonist EVP-6124 produces no signs of tolerance at memory-enhancing doses in rats: a pharmacokinetic and behavioral study.

We investigated whether the effects of acutely administered EVP-6124, an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, on cognition were maintained after 6-day continuous minipump administration. Performance in a delay-dependent forgetting test was measured in the object recognition task after single-oral doses of 0.3 or 1 mg/kg, or at plasma steady-state concentrations (Css) of 0.

Neuropharmacokinetics of two investigational compounds in rats: divergent temporal profiles in the brain and cerebrospinal fluid.

Two investigational compounds (FRM-1, (R)-7-fluoro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and FRM-2, (R)-7-cyano-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide) resided in rat brain longer than in systemic circulation. In Caco-2 directional transport studies, they both showed good intrinsic passive permeability but differed significantly in efflux susceptibility (efflux ratio of <2 and ∼7, respectively), largely attributed to P-glycoprotein (P-gp). Capitalizing on these interesting properties, we investigated how cerebrospinal fluid (CSF) concentration (CCSF) would be shaped by unbound plasma concentration (Cu,p) and unbound brain concentration (Cu,b) in disequilibrium conditions and at steady state.

A dynamic view to the modulation of phosphorylation and O-GlcNAcylation by inhibition of O-GlcNAcase.

Protein phosphorylation and O-GlcNAcylation are reciprocally regulated. As hyperphosphorylation is implicated in tau pathology, approaches have been exploited to reduce the magnitude of tau phosphorylation by increasing the level of tau O-GlcNAcylation. With mathematic models constructed to describe different kinetic scenarios, we analyzed the temporal change of an O-GlcNAcylated protein in contrast to that of the phosphorylated form upon inhibition of O-GlcNAcase (OGA).

Pharmacokinetics of a sustained-release dexamethasone intravitreal implant in vitrectomized and nonvitrectomized eyes.

Purpose: To evaluate dexamethasone pharmacokinetics after implantation of a sustained-release dexamethasone (DEX) intravitreal implant in nonvitrectomized and vitrectomized eyes.

Methods: The right eyes of 25 rabbits underwent vitrectomy; contralateral eyes served as nonvitrectomy controls. The 0.

Ocular pharmacokinetics of 0.45% ketorolac tromethamine.

Purpose: A new carboxymethylcellulose (CMC)-containing ophthalmic formulation of 0.45% ketorolac, pH 6.8 (Acuvail(®)) was recently developed for treatment of inflammation and pain after cataract surgery.

Sensitivity and proportionality assessment of metabolites from microdose to high dose in rats using LC-MS/MS.

Background: The objective of this study was to evaluate the sensitivity requirement for LC-MS/MS as an analytical tool to characterize metabolites in plasma and urine at microdoses in rats and to investigate proportionality of metabolite exposure from a microdose of 1.67 µg/kg to a high dose of 5000 µg/kg for atorvastatin, ofloxacin, omeprazole and tamoxifen.

Results: Only the glucuronide metabolite of ofloxacin, the hydroxylation metabolite of omeprazole and the hydration metabolite of tamoxifen were characterized in rat plasma at microdose by LC-MS/MS.

Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant.

Purpose: To determine the pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc.).

Methods: Thirty-four male monkeys (Macaca fascicularis) received bilateral 0.

Microdosing assessment to evaluate pharmacokinetics and drug metabolism in rats using liquid chromatography-tandem mass spectrometry.

Purpose: To evaluate the sensitivity requirement for LC-MS/MS as an analytical tool to support human microdosing study with sub-pharmacological dose, investigate proportionality of pharmacokinetics from the microdose to therapeutic human equivalent doses in rats and characterize circulating metabolites in rats administered with the microdose.

Materials And Methods: Five drugs of antipyrine, metoprolol, carbamazepine, digoxin and atenolol were administered orally to male Sprague-Dawley rats at 0.167, 1.

AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives.

Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment.

Effects of the preservative purite on the bioavailability of brimonidine in the aqueous humor of rabbits.

Purpose: To determine aqueous humor concentrations of brimonidine given the following ophthalmic formulations in female New Zealand White Rabbits: (1) BAK-preserved brimonidine tartrate 0.20% at a pH of 6.4; (2) BAK-preserved brimonidine tartrate 0.

Evaluation of an immortalized retinal endothelial cell line as an in vitro model for drug transport studies across the blood-retinal barrier.

Purpose: To evaluate the growth and barrier properties of an immortalized rat retinal endothelial cell line (TR-iBRB) maintained on permeable membrane for drug transport studies.

Methods: TR-iBRB cells were grown on permeable membrane filters. The effect of coating material on cell growth was investigated.

Formulation effects on ocular absorption of brimonidine in rabbit eyes.

Purite (stabilized oxychloro complex) and benzalkonium chloride (BAK) are preservatives. We investigated formulation effects on ocular absorption of brimonidine in rabbit eyes. The formulations compared were: Alphagan (0.