Prediction of Drug-Drug Interactions After Esketamine Intranasal Administration Using a Physiologically Based Pharmacokinetic Model.

Background And Objective: A physiologically based pharmacokinetic (PBPK) modeling approach for esketamine and its metabolite noresketamine after esketamine intranasal administration was developed to aid the prediction of drug-drug interactions (DDIs) during the clinical development of esketamine nasal spray (SPRAVATO). This article describes the development of the PBPK model to predict esketamine and noresketamine kinetics after intranasal administration of esketamine and its verification and application in the prediction of prospective DDIs with esketamine using models of index perpetrator and victim drugs.

Methods: The intranasal PBPK (IN-PBPK) models for esketamine/noresketamine were constructed in Simcyp v14.

Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity.

The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome.

Apalutamide Absorption, Metabolism, and Excretion in Healthy Men, and Enzyme Reaction in Human Hepatocytes.

In this phase 1 study, the absolute bioavailability and absorption, metabolism, and excretion (AME) of apalutamide, a competitive inhibitor of the androgen receptor, were evaluated in 12 healthy men. Subjects received 240 mg of apalutamide orally plus a 15-minute intravenous infusion of 100 g of apalutamide containing 9.25 kBq (250 nCi) of C-apalutamide (2 hours postdose) for absolute bioavailability assessment or plus one 400-g capsule containing 37 kBq (1000 nCi) of C-apalutamide for AME assessment.

Dose- and Time-dependency of the Toxicity and Pharmacokinetic Profiles of Bedaquiline and Its N-desmethyl Metabolite in Dogs.

Bedaquiline (BDQ) is an antibiotic to treat pulmonary multidrug-resistant tuberculosis (MDR-TB). Studies up to 39 weeks were conducted orally in dogs to assess the toxicity and pharmacokinetics of BDQ and its N-desmethyl metabolite (D-BDQ). Phospholipidosis (PLD) seen in the monocytic phagocytic system was considered an adaptive change.

Synthesis, in vitro and in vivo small-animal SPECT evaluation of novel technetium labeled bile acid analogues to study (altered) hepatic transporter function.

Introduction: Hepatobiliary transport mechanisms are crucial for the excretion of substrate toxic compounds. Drugs can inhibit these transporters, which can lead to drug-drug interactions causing toxicity. Therefore, it is important to assess this early during the development of new drug candidates.

Strategies for Determining Correct Cytochrome P450 Contributions in Hepatic Clearance Predictions: In Vitro-In Vivo Extrapolation as Modelling Approach and Tramadol as Proof-of Concept Compound.

Background And Objective: Although the measurement of cytochrome P450 (CYP) contributions in metabolism assays is straightforward, determination of actual in vivo contributions might be challenging. How representative are in vitro for in vivo CYP contributions? This article proposes an improved strategy for the determination of in vivo CYP enzyme-specific metabolic contributions, based on in vitro data, using an in vitro-in vivo extrapolation (IVIVE) approach. Approaches are exemplified using tramadol as model compound, and CYP2D6 and CYP3A4 as involved enzymes.

Best practices for metabolite quantification in drug development: updated recommendation from the European Bioanalysis Forum.

Metabolite quantification and profiling continues to grow in importance in today's drug development. The guidance provided by the 2008 FDA Metabolites in Safety Testing Guidance and the subsequent ICH M3(R2) Guidance (2009) has led to a more streamlined process to assess metabolite exposures in preclinical and clinical studies in industry. In addition, the European Bioanalysis Forum (EBF) identified an opportunity to refine the strategies on metabolite quantification considering the experience to date with their recommendation paper on the subject dating from 2010 and integrating the recent discussions on the tiered approach to bioanalytical method validation with focus on metabolite quantification.

Evaluation of the Pharmacokinetics and Renal Excretion of Simeprevir in Subjects with Renal Impairment.

Background: Simeprevir is a N3/4 protease inhibitor approved for the treatment of hepatitis C virus (HCV) infection. HCV prevalence is higher in patients with chronic kidney disease compared with the general population; safe and efficacious therapies in renal impairment are needed.

Objectives: To evaluate simeprevir renal excretion in healthy subjects and to compare the simeprevir steady-state pharmacokinetics between subjects with severe renal impairment and healthy subjects.

Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation.

This paper focuses on the retrospective evaluation of physiologically based pharmacokinetic (PBPK) techniques used to mechanistically predict clearance throughout pediatric life. An intravenous tramadol retrograde PBPK model was set up in Simcyp® using adult clearance values, qualified for CYP2D6, CYP3A4, CYP2B6, and renal contributions. Subsequently, the model was evaluated for mechanistic prediction of total, CYP2D6-related, and renal clearance predictions in very early life.

Absorption, metabolism, and excretion of oral ¹⁴C radiolabeled ibrutinib: an open-label, phase I, single-dose study in healthy men.

The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of ¹⁴C-labeled ibrutinib. The mean (S.D.

Physiology-based IVIVE predictions of tramadol from in vitro metabolism data.

Purpose: To predict the tramadol in vivo pharmacokinetics in adults by using in vitro metabolism data and an in vitro-in vivo extrapolation (IVIVE)-linked physiologically-based pharmacokinetic (PBPK) modeling and simulation approach (Simcyp®).

Methods: Tramadol metabolism data was gathered using metabolite formation in human liver microsomes (HLM) and recombinant enzyme systems (rCYP). Hepatic intrinsic clearance (CLintH) was (i) estimated from HLM corrected for specific CYP450 contributions from a chemical inhibition assay (model 1); (ii) obtained in rCYP and corrected for specific CYP450 contributions by study-specific intersystem extrapolation factor (ISEF) values (model 2); and (iii) scaled back from in vivo observed clearance values (model 3).

In vivo visualization and quantification of (Disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of 99mTc-mebrofenin in mice.

Unlabelled: Hepatic transport of (99m)Tc-mebrofenin through organic anion transport protein 1a and 1b (Oatp1a/1b) and multidrug resistance protein 2 (Mrp2) was investigated by small-animal SPECT. On the basis of the results, a noninvasive method to visualize and quantify disturbances in hepatic transport is proposed.

Methods: Friend virus B wild-type mice (untreated, bile duct-ligated, vehicle- or rifampicin-treated) and strain-matched knockout mice unable to express the uptake transporters Oatp1a/1b (Slco1a/1b(-/-)/(-/-)) or the efflux transporter Mrp2 (Abcc2(-/-)) were intravenously injected with (99m)Tc-mebrofenin (n = 3 per group).

A phase I, open-label, single-dose, mass balance study of 14C-labeled abiraterone acetate in healthy male subjects.

1. Metabolic disposition of (14)C-abiraterone acetate (AA), a prodrug of abiraterone was assessed in a phase I, open-label, single-dose (1000 mg, approximately 100 μCi) study in healthy males (18-55 years, N = 8). Blood, urine, and faecal samples were obtained at specified timepoints for determination of abiraterone concentrations in the plasma, total radioactivity (TR), and the metabolite profile.

Pharmacokinetics, metabolism and excretion of 14C-monoethyl phthalate (MEP) and 14C-diethyl phthalate (DEP) after single oral and IV administration in the juvenile dog.

The pharmacokinetics, metabolism and excretion of monoethyl phthalate (MEP) and diethyl phthalate (DEP) were compared after intravenous or oral administration of [(14)C]MEP or [(14)C]DEP in juvenile beagle dogs. Four male juvenile beagle dogs were treated with a single oral or bolus intravenous dose of either [(14)C]MEP or [(14)C]DEP (164 μg/kg). The absorption, metabolism, excretion and pharmacokinetics of [(14)C]MEP and [(14)C]DEP were nearly identical.

Clinical pharmacology of alcaftadine, a novel antihistamine for the prevention of allergic conjunctivitis.

Purpose: In this report, we characterize the in vitro pharmacokinetic properties of a new antihistamine, alcaftadine. In addition, we report results from phase 1 studies of several ophthalmic formulations of alcaftadine and examine the pharmacokinetic properties of one formulation in detail.

Methods: In vitro pharmacology employed a human liver microsome assay combined with index substrates or inhibitors for specific cytochromes.

In vitro studies on the metabolism of trabectedin (YONDELIS) in monkey and man, including human CYP reaction phenotyping.

Trabectedin (YONDELIS) is a potent anticancer agent which was recently approved in Europe for the treatment of soft tissue sarcoma. The drug is currently also in clinical development for the treatment of ovarian carcinoma. In vitro experiments were conducted to investigate the hepatic metabolism of [(14)C]trabectedin in Cynomolgus monkey and human liver subcellular fractions.

Which human metabolites have we MIST? Retrospective analysis, practical aspects, and perspectives for metabolite identification and quantification in pharmaceutical development.

With the recent publication of the FDA guidance on metabolites in safety testing (MIST), a reflection is provided that describes the impact of this guidance on the processes of drug metabolite identification and quantification at various stages of drug development. First, a retrospective analysis is described that was conducted on 12 human absorption, metabolism, and excretion (AME) trials with the application of these MIST criteria. This analysis showed that the number of metabolites requiring identification, (semi)-quantification, and coverage in the toxicology species would substantially increase.

Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjects.

Absorption, metabolism, and excretion of darunavir, an inhibitor of human immunodeficiency virus protease, was studied in eight healthy male subjects after a single oral dose of 400 mg of [(14)C]darunavir given alone (unboosted subjects) or with ritonavir [100 mg b.i.d.

The ontogeny of drug metabolizing enzymes and transporters in the rat.

Knowledge of the ontogeny of the various systems involved in distribution and elimination of drugs is important for adequate interpretation of the findings during safety studies in juvenile animals. The present study was designed to collect information on plasma concentrations of total protein and albumin, enzyme activity and mRNA expression of cytochrome P450 isoenzymes (CYP1A1/2, CYP2B1/2, CYP2E1, CYP3A1/2, and CYP4A1), carboxylesterase and thyroxin glucuronidation (T4-GT) activity in liver microsomes, and mRNA expression of transporters (Mdr1a/b, Mrp1-3 and 6, Bsep and Bcrp, Oct1-2, Oat1-3 and Oatp1a4) in liver, kidney and brain tissue during development in Sprague-Dawley rats. Enzyme activities were determined by measuring the metabolism of marker substrates; expression of mRNAs was assessed using RTq-PCR.

Disposition, metabolism, and excretion of [14C]doripenem after a single 500-milligram intravenous infusion in healthy men.

In this open-label, single-center study, eight healthy men each received a single 500-mg dose of [(14)C]doripenem, containing 50 microCi of [(14)C]doripenem, administered as a 1-h intravenous infusion. The concentrations of unchanged doripenem and its primary metabolite (doripenem-M-1) resulting from beta-lactam ring opening were measured in plasma and urine by a validated liquid chromatography method coupled to a tandem mass spectrometry assay. Total radioactivity was measured in blood, plasma, urine, and feces by liquid scintillation counting.

Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans.

Absorption, metabolism, and excretion of paliperidone, an atypical antipsychotic, was studied in five healthy male subjects after a single dose of 1 mg of [(14)C]paliperidone oral solution ( approximately 16 microCi/subject). One week after dosing, 88.4 to 93.

Metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-] in mice, rats, rabbits, and dogs.

The in vivo metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-], a novel neuromodulator, were investigated in mice, rats, rabbits, and dogs after oral administration of (14)C-RWJ-333369. Plasma, urine, and feces samples were collected, assayed for radioactivity, and profiled for metabolites. In almost all species, the administered radioactive dose was predominantly excreted in urine (>85%) with less than 10% in feces.

Cell-based models to study hepatic drug metabolism and enzyme induction in humans.

Cell-based in vitro models are invaluable tools in elucidating the pharmacokinetic profile of a drug candidate during its drug discovery and development process. As biotransformation is one of the key determinants of a drug's disposition in the body, many in vitro models to study drug metabolism have been established, and others are still being developed and validated. This review is aimed at providing the reader with a concise overview of the characteristics and optimal application of established and emerging in vitro cell-based models to study human drug metabolism and induction of drug metabolising enzymes in the liver.