Effect of the Phosphate Binder Sevelamer Carbonate on the Bioavailability of Enarodustat, an Oral Erythropoiesis Stimulating Agent.

Enarodustat is an orally available hypoxia-inducible factor-prolyl hydroxylase inhibitor which can correct the erythropoietic capacity and improve anemia in chronic kidney disease. Sevelamer carbonate, a non-calcium-based polymeric resin, is one of the commonly prescribed agents for the management of hyperphosphatemia in patients undergoing hemodialysis. This was an open-label, crossover study in healthy male subjects (N = 12) that evaluated the effect of sevelamer carbonate (2400 mg) on the bioavailability of enarodustat (25 mg) when the 2 drugs were administered together (Treatment B) or when enarodustat was administered 3 hours after (Treatment C) or 1 hour before (Treatment D) sevelamer carbonate compared to enarodustat alone (Treatment A).

Evaluation of Drug-Drug Interaction Potential of Enarodustat (JTZ-951) Using a Cytochrome P450 Probe Cocktail.

The drug interaction potential of enarodustat (doses: 25, 50 mg) on the activity of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated after once-daily administration for 15 days in a phase 1 multiple-ascending-dose study in healthy subjects. Probe substrates specific for the enzymes, i.e.

Pharmacokinetics of Enarodustat in Non-Japanese and Japanese Healthy Subjects and in Patients With End-Stage Renal Disease on Hemodialysis.

The pharmacokinetics of enarodustat were elucidated in healthy subjects and in patients with end-stage renal disease (ESRD) on hemodialysis in phase 1 studies conducted in the United States and Japan. In healthy non-Japanese and Japanese subjects, following single oral administration up to 400 mg, enarodustat was rapidly absorbed. Maximum plasma concentration and area under the plasma concentration-time curve from the time of dosing to infinity were dose-dependent, renal excretion of unchanged enarodustat was substantial (on average ≈45% of dose), and mean t of <10 hours indicated negligible accumulation with once-daily dosing.

Evaluation of Hemoglobin Response to Treatment With Enarodustat Using Pharmacometric Approach in Japanese Anemic Patients With Chronic Kidney Disease.

Enarodustat (JTZ-951) is a hypoxia-inducible factor prolyl hydroxylase inhibitor that has been approved and marketed in Japan for patients with anemia with chronic kidney disease (CKD). The pharmacometric approach was applied to assess the relationship between plasma concentrations of enarodustat and hemoglobin (Hb) levels, and to provide information regarding the optimal use of enarodustat in clinical practice by simulations based on the pharmacokinetic and pharmacodynamic (PK/PD) model that was developed. The PK/PD data of enarodusat obtained from phase 2 and phase 3 studies in Japanese patients with CKD were well described by the models: a 1-compartment model with first-order absorption and elimination for PK, and a semimechanistic model based on transit compartment model for PD.

Thorough QT/QTc Evaluation of the Cardiac Safety of Enarodustat (JTZ-951), an Oral Erythropoiesis-Stimulating Agent, in Healthy Adults.

This study evaluated the effect of enarodustat on cardiac repolarization in healthy subjects. Enarodustat (20 and 150 mg [supratherapeutic dose]), placebo, and moxifloxacin (positive control, 400 mg) were administered orally to males and females (N = 54) in a crossover fashion. Continuous 12-lead Holter electrocardiogram (ECG) data were obtained before and after dosing, and blood samples were obtained for pharmacokinetic assessments of enarodustat, its circulating metabolite (R)-M2, and moxifloxacin.

Hemodialysis Clearance of Enarodustat (JTZ-951), an Oral Erythropoiesis Stimulating Agent, in Patients with End-Stage Renal Disease.

The dialysis clearance of enarodustat (JTZ-951) was determined in patients (N = 6) with end-stage renal disease on hemodialysis. Enarodustat (5 mg PO) was administered before (day 1) and after hemodialysis (day 8) with pharmacokinetic assessments on the 2 occasions. Dialysis clearance was based on plasma and dialysate enarodustat concentrations.

A Mass Balance Study of C-Labeled JTZ-951 (Enarodustat), a Novel Orally Available Erythropoiesis-Stimulating Agent, in Patients With End-Stage Renal Disease on Hemodialysis.

The mass balance, pharmacokinetics, and biotransformation of JTZ-951 (enarodustat), a novel hypoxia-inducible factor prolyl hydroxylase inhibitor, were characterized in patients (N = 6) with end-stage renal disease on hemodialysis. Following a 10-mg (100 µCi) oral dose of C-JTZ-951, whole blood, feces, dialysate, and, if feasible, urine were obtained for pharmacokinetic assessments and for metabolite profiling and identification in appropriate matrices. Fecal excretion was the major route of elimination of radioactivity, and urinary excretion a minor route, with mean (coefficient of variation [%CV]) recovery of 77.

Pharmacokinetics of Lapatinib, a Nonrenally Cleared Drug, in Patients With End-Stage Renal Disease on Maintenance Hemodialysis.

Lapatinib, a tyrosine kinase inhibitor, is approved for the treatment of breast cancer. The literature shows that it is metabolized by CYP3A4 and eliminated predominantly (>90%) by the fecal route, with minimal (<2%) renal elimination in healthy subjects (dose of 250 mg); in cancer patients, renal elimination is minimal at therapeutic doses. For nonrenally cleared drugs, while there is ample evidence of pharmacokinetic alterations secondary to renal impairment-induced effects on drug metabolizing enzymes and/or transporters, the effect of end-stage renal disease (ESRD) on lapatinib pharmacokinetics has not been determined.

Pharmacokinetics, Food Effect, Ketoconazole Interaction, and Safety of JTK-853, a Novel Nonnucleoside HCV Polymerase Inhibitor, After Ascending Single and Multiple Doses in Healthy Subjects.

Pharmacokinetics, safety, and tolerability of JTK-853, a novel HCV polymerase inhibitor, were evaluated in single and multiple ascending dose (SAD, MAD) studies, with food- and ketoconazole-related effects on exposure to JTK-853 and its active (CYP3A4 mediated) metabolite M2. JTK-853 was safe and well tolerated in both studies. In the SAD study, at doses >1600 mg (with standard breakfast [SBF]), JTK-853 exposure did not increase further, was substantially higher (AUC increase: 3- to 8-fold) with SBF (vs fasted), with a moderate increase in AUC (approximately 1.

A semimechanistic model of the time-course of release of PTH into plasma following administration of the calcilytic JTT-305/MK-5442 in humans.

JTT-305/MK-5442 is a calcium-sensing receptor (CaSR) allosteric antagonist being investigated for the treatment of osteoporosis. JTT-305/MK-5442 binds to CaSRs, thus preventing receptor activation by Ca(2+) . In the parathyroid gland, this results in the release of parathyroid hormone (PTH).

Population pharmacodynamic parameter estimation from sparse sampling: effect of sigmoidicity on parameter estimates.

The objective of this stimulation study was to evaluate effect of simoidicity of the concentration-effect (C-E) relationship on the efficiency of population parameter estimation from sparse sampling and is a continuation of previous work that addressed the effect of sample size and number of samples on parameters estimation from sparse sampling for drugs with C-E relationship characterized by high sigmoidicity (gamma > 5). The findings are based on observed C-E relationships for two drugs, octreotide and remifentanil, characterized by simple E (max) and sigmoid E (max) models (gamma = ~2.5), respectively.

An improved LC-ESI-MS-MS method for simultaneous quantitation of rosiglitazone and N-desmethyl rosiglitazone in human plasma.

A fast, sensitive, and selective method for the simultaneous quantitation of rosiglitazone and N-desmethyl rosiglitazone in human plasma, using rosiglitazone-d(4) and N-desmethyl rosiglitazone-d(4) as the respective internal standards, has been developed and validated. The analytes in human plasma (50 microL sample aliquot) were isolated through supported liquid/liquid extraction (SLE) and separated by isocratic HPLC over a 3-min period. The precursor and product ions were detected by ESI-MS-MS with multiple reaction monitoring (MRM) in a triple quadrupole mass spectrometer.

Pharmacodynamic parameter estimation: population size versus number of samples.

The purpose of this study was to evaluate the effects of population size, number of samples per individual, and level of interindividual variability (IIV) on the accuracy and precision of pharmacodynamic (PD) parameter estimates. Response data were simulated from concentration input data for an inhibitory sigmoid drug efficacy (E(max)) model using Nonlinear Mixed Effect Modeling, version 5 (NONMEM). Seven designs were investigated using different concentration sampling windows ranging from 0 to 3 EC(50) (EC(50) is the drug concentration at 50% of the E(max)) units.