Highly active and stable surface structure for oxygen evolution reaction originating from balanced dissolution and strong connectivity in BaIrO3 solid solutions.

Catalysts for the oxygen evolution reaction (OER) are receiving great interest since OER remains the bottleneck of water electrolyzers for hydrogen production. Especially, OER in acidic solutions is crucial since it produces high current densities and avoids precipitation of carbonates. However, even the acid stable iridates undergo severe dissolution during the OER. BaIrO3 has the strongest IrO6 connectivity and stable surface structure, yet it suffers from lattice collapse after OER cycling, making it difficult to improve the OER durability. In the present study, we have successfully developed an OER catalyst with both high intrinsic activity and stability under acidic conditions by preventing the lattice collapse after repeated OER cycling. Specifically, we find that the substitution of Ir-site with Mn for BaIrO3 in combination with OER cycling leads to a remarkable activity enhancement by a factor of 28 and an overall improvement in stability. This dual enhancement of OER performance was accomplished by the novel strategy of slightly increasing the Ir-dissolution and balancing the elemental dissolution in BaIr1-x Mn x O3 to reconstruct a rigid surface with BaIrO3-type structure. More importantly, the mass activity for BaIr0.8Mn0.2O3 reached ∼73 times of that for IrO2, making it a sustainable and promising OER catalyst for energy conversion technologies.

Novel Platform for Predicting Drug Effects in Patients with Acromegaly: Translational Exposure-Response Evaluation of Growth Hormone-Inhibitory Effect of Octreotide after Growth Hormone-Releasing Hormone Stimulation.

Acromegaly is a chronic systemic disease characterized by facial and peripheral changes caused by soft tissue overgrowth and is associated with multiple comorbidities. Despite available surgical and medical therapies, suitable treatments for acromegaly are still lacking. Efficient drug development requires an understanding of the exposure-response (E-R) relationship based on nonclinical and early clinical studies. We aimed to establish a platform to facilitate the development of novel drugs to treat acromegaly. We evaluated the E-R relationship of the growth hormone (GH)-inhibitory effect of the somatostatin analog octreotide under growth hormone-releasing hormone + arginine stimulation in healthy participants and compared the results with historical data for patients with acromegaly. This randomized five-way crossover study included two placebo and three active-treatment periods with different doses of octreotide acetate. GH secretion in the two placebo periods was comparable, which confirmed the reproducibility of the response with no carryover effect. GH secretion was inhibited by low-, medium-, and high-dose octreotide acetate in a dose-dependent manner. We also examined the E-R relationship in monkeys as a preclinical drug evaluation study and in rats as a more convenient and simple system for screening candidate drugs. The E-R relationships and EC50 values were similar among animals, healthy participants, and patients with acromegaly, which suggests that GH stimulation studies in early research and development allowed simulation of the drug response in patients with acromegaly. SIGNIFICANCE STATEMENT: This study demonstrated similar exposure-response relationships in terms of the growth hormone-inhibitory effect of octreotide after growth hormone-releasing hormone stimulation among healthy participants, monkeys, and rats. The research methods and analyses utilized in this study will be useful for simulating the dosages and therapeutic effects of drugs for acromegaly and will facilitate the research and development of novel therapeutic agents with similar modes of action.

Adiposity and the risk of rheumatoid arthritis: a systematic review and meta-analysis of cohort studies.

Several studies have investigated associations between overweight/obesity and risk of developing rheumatoid arthritis, however, the evidence is not entirely consistent, and previous meta-analyses mainly included case-control studies, which can be affected by various biases. We therefore conducted a systematic review and meta-analysis of cohort studies on adiposity and risk of rheumatoid arthritis. Relevant studies were identified by searching PubMed and Embase databases. Random effects models were used to estimate summary relative risks (RRs) and 95% confidence intervals (CIs) for rheumatoid arthritis in relation to different measures of adiposity. Thirteen cohort studies (10 publications) were included. The summary RR per 5 kg/m2 increase in body mass index (BMI) was 1.11 (95% CI 1.05-1.18, I2 = 50%), but the association was restricted to women (1.15, 95% CI 1.08-1.21, I2 = 17%) and not observed in men (0.89, 95% CI 0.73-1.09, I2 = 58%). The summary RR per 5 kg/m2 increment in BMI at age 18 years was 1.17 (95% CI 1.01-1.36, I2 = 26%, n = 3), and per 10 cm increase in waist circumference was 1.13 (95% CI 1.02-1.25, I2 = 44%, n = 2). Higher BMI in middle age, BMI at age 18 years, and waist circumference were associated with increased rheumatoid arthritis risk, suggesting adiposity could be targeted for primary prevention.

Pharmacokinetic-Pharmacodynamic-Efficacy Modeling of ONO-7579, a Novel Pan-Tropomyosin Receptor Kinase Inhibitor, in a Murine Xenograft Tumor Model.

The orally available and novel small molecule ONO-7579 (N-{2-[4-(2-amino-5-chloropyridin-3-yl)phenoxy]pyrimidin-5-yl}-N'-[2-(methanesulfonyl)-5-(trifluoromethyl)phenyl]urea) is a highly potent and selective pan-tropomyosin receptor kinase (TRK) inhibitor. The objective of the present study was to characterize the pharmacokinetic (PK), pharmacodynamic (PD), and antitumor efficacy relationships of ONO-7579 in mice xenografted with a human colorectal cancer cell line, KM12 (harboring the tropomyosin 3 (TPM3) -neurotrophic tyrosine receptor kinase 1 fusion gene), via a PK/PD modeling approach. Plasma and tumor concentrations of ONO-7579, tumor levels of phosphorylated TPM3-TRKA (pTRKA), and tumor volumes in the murine model were measured with a single or multiple dose of ONO-7579 (0.06-0.60 mg/kg) administered once daily. The PK/PD/efficacy models were developed in a sequential manner. Changes in plasma concentrations of ONO-7579 were described with an oral one-compartment model. Tumor concentrations of ONO-7579 were higher than plasma concentrations, and changes in ONO-7579 tumor concentrations were described with an additional tumor compartment that had no influence on plasma concentrations. pTRKA in tumors was described with a direct Emax model, and the tumor ONO-7579 concentration causing 50% of the maximum effect was estimated to be 17.6 ng/g. In addition, a pTRKA-driven tumor growth inhibition model indicated that ONO-7579 started to sharply increase the antitumor effect at pTRKA inhibition rates >60% and required >91.5% to reduce tumors. In conclusion, the developed PK/PD/efficacy models revealed a "switch-like" relationship between pTRKA inhibition rate and antitumor effect in a murine KM12 xenograft model, demonstrating that pTRKA in tumors could serve as an effective biomarker for scheduling the dose regimen in early-stage clinical studies. SIGNIFICANCE STATEMENT: In recent years, clinical development of TRK inhibitors in patients with neurotrophic tyrosine receptor kinase fusion-positive solid tumors has been accelerated. This research found that phosphorylated TRKA was a useful biomarker for explaining the antitumor efficacy of TRK inhibitors using a pharmacokinetic/pharmacodynamic modeling approach in xenograft mice. This finding suggests a rational dosing regimen in early-stage clinical studies for ONO-7579 (N-{2-[4-(2-amino-5-chloropyridin-3-yl)phenoxy]pyrimidin-5-yl}-N'-[2-(methanesulfonyl)-5-(trifluoromethyl)phenyl]urea), a novel pan-TRK inhibitor.

Benefit-risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers.

Nivolumab 3 mg/kg every 2 weeks (Q2W) has been approved in Japan for various cancers; however, use of a flat dose is expected to simplify dosing and administration. A quantitative clinical pharmacology approach was used to assess the benefit-risk profile of nivolumab 240 mg Q2W relative to the approved dose of nivolumab 3 mg/kg Q2W in Japanese patients. Three exposure-response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune-mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types. Exposure-response analyses of efficacy were evaluated for overall survival and objective response rate. Exposures of nivolumab 240 mg Q2W were 37% higher than those of nivolumab 3 mg/kg Q2W in Japanese patients across the tumor types analyzed. Predicted safety profiles at the two doses differed by less than 2% across tumor types for adverse events leading to discontinuation/death, adverse events of grade 3 or higher, or immune-mediated adverse events of grade 2 or higher. In addition, the predicted 1-year and 2-year overall survival rates, the mean overall survival and the objective response rates were comparable between the doses regardless of the tumor type analyzed. Overall, these results demonstrated that the benefit-risk of nivolumab 240 mg Q2W was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types.

The Prevalence, Characteristics, and Patient Burden of Severe Asthma Determined by Using a Japan Health Care Claims Database.

BACKGROUND: Recently, several new biological drugs targeting severe asthma are on the market, and various studies on severe asthma have been reported worldwide. However, in Japan, the data are still limited regarding epidemiology and burden of disease on severe asthma. This study determined the prevalence, characteristics, and burden of disease of patients with severe asthma. METHODS: This retrospective study (HO-16-16484) used a nationwide health care claims database. Severity of asthma was defined according to the treatment during the baseline period (April 1, 2014-March 31, 2015). Eligible patients were >15-65 years of age with asthma during the 12-month baseline period and were followed up for 12 months. End points included the prevalence, characteristics, exacerbation frequency, and patient behavior in patients with severe, moderate, or mild asthma. Risk factors for exacerbations were explored in patients with all levels of asthma severity and in those with severe asthma. FINDINGS: Among the 16,107 patients with asthma, 2.4 (95% CI, 2.1-2.6) per 100 patients had severe asthma. During the baseline period, 130 (34.0%) of 382 patients with severe asthma had ≥1 asthma exacerbation. The exacerbation frequency was highest in patients with severe asthma, and most of the comorbidities increased in proportion to the asthma severity. During the follow-up period, exacerbation frequency increased with asthma severity. Approximately 70% of patients with severe asthma were treated at clinics, requiring outpatient visits ~10 times per year. Different exacerbation risk factors were identified between patients with all severity levels of asthma and those with severe asthma. With the severe asthma patients, experiencing exacerbations during the previous year was a risk factor for further exacerbations during the follow-up period. IMPLICATIONS: In Japan, 2.4% of patients with asthma have severe asthma, and there is a significant burden of disease in patients with severe asthma undergoing high-intensity treatment.

The prevalence and disease burden of severe eosinophilic asthma in Japan.

Background: There are limited data on the prevalence and burden of severe eosinophilic asthma (SEA) both in Japan and globally. This study aimed to assess the prevalence and burden of SEA in Japan. Methods: This study was a retrospective, observational cohort analysis using health records or health insurance claims from patients with severe asthma treated at Kyoto University Hospital. The primary outcome was the prevalence of SEA, defined as a baseline blood eosinophil count ≥300 cells/µL. Secondary outcomes included frequency and risk factors of asthma exacerbations, and asthma-related healthcare resource utilization and costs. Results: Overall, 217 patients with severe asthma were included; 160 (74%) had eosinophil assessments. Of these, 97cases (61%), 54cases (34%), and 33cases (21%) had a blood eosinophil count ≥150, ≥300, and ≥500 cells/µL, respectively. Proportion of SEA was 34%. Blood eosinophil count was not associated with a significantly increased frequency of exacerbations. In the eosinophilic group, lower % forced expiratory volume in 1 second and higher fractional exhaled nitric oxide were predictive risk factors, while the existence of exacerbation history was a predictive risk factor for asthma exacerbations in the non-eosinophilic group. Severe asthma management cost was estimated as ¥357,958/patient-year, and asthma exacerbations as ¥26,124/patient-year. Conclusions: Approximately, one-third of patients with severe asthma in Japan have SEA. While risk factors for exacerbations differed between SEA and severe non-eosinophilic asthma, both subgroups were associated with substantial disease and economic burden. From subgroup analysis, blood eosinophil counts could be an important consideration in severe asthma management.

Non-Fermi Liquids as Highly Active Oxygen Evolution Reaction Catalysts.

The oxygen evolution reaction (OER) plays a key role in emerging energy conversion technologies such as rechargeable metal-air batteries, and direct solar water splitting. Herein, a remarkably low overpotential of ≈150 mV at 10 mA cm-2disk in alkaline solutions using one of the non-Fermi liquids, Hg2Ru2O7, is reported. Hg2Ru2O7 displays a rapid increase in current density and excellent durability as an OER catalyst. This outstanding catalytic performance is realized through the coexistence of localized d-bands with the metallic state that is unique to non-Fermi liquids. The findings indicate that non-Fermi liquids could greatly improve the design of highly active OER catalysts.

Brain translocator protein occupancy by ONO-2952 in healthy adults: A Phase 1 PET study using [11 C]PBR28.

ONO-2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO-specific PET radioligand [11 C]PBR28 to confirm binding of ONO-2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO-2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO-2952 (n = 4 per dose). Two PET scans with [11 C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO-2952 administration. [11 C]PBR28 regional distribution volume (VT ) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (VND ) was obtained on an individual basis for each subject using linear regression as the x-intercept of the Lassen plot. The binding potential relative to VND (BPND ) was derived as the difference between VT in the ROI (VT ROI) and VND , normalized to VND ; BPND = (VT ROI - VND )/VND . TSPO occupancy was calculated as the change in BPND (ΔBPND ) from individual's baseline scan to the on-medication scan to the baseline BPND value. TSPO occupancy by ONO-2952 was dose dependent between 20-200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated Ki values ranged from 24.1 to 72.2 nM. This open-label, single-center, single-dose study demonstrated engagement of ONO-2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO-2952 could potentially modulate neurosteroid production by binding to brain TSPO.

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.

Strain engineering effects on electrical properties of lead-free piezoelectric thin films on Si wafers.

Using radio frequency - magnetron sputtering, calcium-doped barium zirconate titanate ((Ba(0.85)Ca(0.15))(Zr(0.1)Ti(0.9))O(3), BCZT) thin films were deposited on Si wafers with different bottom electrodes. The obtained BCZT thin film on a lanthanum nickel oxide (LNO) electrode had a highly c-axis preferred orientation, while the BCZT thin film on a Pt bottom electrode had (111) preferred orientation. Furthermore, the out-of-plane lattice constant of the BCZT on LNO/Si was 3.4% larger than that of the reported bulk material because of the compressive thermal stress from LNO with a large thermal expansion coefficient. This compressive thermal stress engenders an increase of the Curie temperature. The local piezoelectric response of the BCZT thin film on a LNO/Si structure was measured by piezoresponse force microscope.

Modeling and simulation of bone mineral density response from a phase 2 study of ONO-5334, a new cathepsin K inhibitor, to support dose selection in osteoporosis.

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this modeling study were to (1) develop exposure-response (E-R) models to relate ONO-5334 exposure to bone mineral density (BMD), (2) predict BMD responses to various doses of ONO-5334 for both immediate release tablet (IRT) and sustained release tablet (SRT) formulations where only BMD response after administration of IRT had been studied to date, (3) inform selection of appropriate formulation/dose using simulation for future clinical trials. A population pharmacokinetic (PK) model was developed to simultaneously analyze data for both IRT and SRT. The exposure metrics at steady state were estimated by post hoc Bayesian prediction using the final population PK model. E-R models were developed using dose-ranging data with only IRT from postmenopausal females with osteoporosis. Based on the developed model, lumbar spine and total hip BMD after administration of ONO-5334 SRT as well as IRT were simulated. The simulation results showed that ONO-5334 SRT should provide comparable BMD responses at a lower dose relative to IRT (a finding consistent with the results from a previous population PK-PD modeling study with bone resorption markers).

Population pharmacokinetic and pharmacodynamic modeling of different formulations of ONO-5334, cathepsin K inhibitor, in Caucasian and Japanese postmenopausal females.

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50 ) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.

Population pharmacokinetics and exposure-response relationship of a muscarinic receptor antagonist, imidafenacin.

This study was designed to update the population pharmacokinetic model and investigate the exposure-response (efficacy and safety) and concentration-QT relationships for imidafenacin, a synthetic orally active muscarinic receptor antagonist. The population pharmacokinetic model was updated using data from 90 healthy subjects and 852 patients with an overactive bladder. Plasma concentration data from nine clinical studies were used, including new data from a long-term dose escalation study. The updated population pharmacokinetic model for imidafenacin adequately described the plasma concentration profile. The results were generally consistent with those obtained from the previous population pharmacokinetic analysis, indicating that no new covariates were found to influence the pharmacokinetics of imidafenacin. Exposure-response relationships in the long-term dose escalation study were investigated using a regression analysis with efficacy and safety endpoints as dependent variables. There was no clear relationship between exposure and any endpoint. The concentration-QT relationship was also evaluated to assess whether imidafenacin prolonged the concentration-dependent QT interval. There was no clear relationship between the plasma concentration of imidafenacin and QTc, indicating that concentration-dependent QTc interval prolongation was not observed.

Iron overload inhibits calcification and differentiation of ATDC5 cells.

There is a little information about the effects of iron overload on cartilage metabolism. In the present study, we examined the effects of excess iron on the differentiation and mineralization of cultured chondrocytes, ATDC5 cells. We used ferric ammonium citrate (FAC) as a ferric ion donor and desferrioxamine (DFO) as a ferric ion chelator. Neither chemical affected the production of proteoglycan, a marker of an early stage of ATDC5 differentiation. In contrast, FAC inhibited the deposition of calcium, a late-stage event in chondrocyte differentiation, by ATDC5 cells in a dose-dependent manner, and DFO accelerated it. Energy dispersive X-ray spectroscopy/scanning electron microscope analysis revealed that the levels of iron and calcium in cells treated with FAC were increased and decreased, respectively. Furthermore, FAC inhibited the expression of matrix metalloproteinase 13 mRNA, another marker of late-stage chondrocyte differentiation. In addition, we found that the heavy and light chains of ferritin were expressed specifically at a late stage of ATDC5 differentiation, and the levels of both proteins were enhanced by the addition of iron. These results suggest that iron overload might give rise to osteopenia and arthritis by inhibiting chondrocyte differentiation and mineralization.

The prediction of human response to ONO-4641, a sphingosine 1-phosphate receptor modulator, from preclinical data based on pharmacokinetic-pharmacodynamic modeling.

The pharmacokinetic (PK) and pharmacodynamic (PD) parameters of ONO-4641 in humans were estimated using preclinical data in order to provide essential information to better design future clinical studies. The characterization of PK/PD was measured in terms of decreased lymphocyte counts in blood after administration of ONO-4641, a sphingosine 1-phosphate receptor modulator. Using a two-compartment model, human PK parameters were estimated from preclinical PK data of cynomolgus monkey and in vitro human metabolism data. To estimate human PD parameters, the relationship between lymphocyte counts and plasma concentrations of ONO-4641 in cynomolgus monkeys was determined. The relationship between lymphocyte counts and plasma concentrations of ONO-4641 was described by an indirect-response model. The indirect-response model had an I(max) value of 0.828 and an IC(50) value of 1.29 ng/ml based on the cynomolgus monkey data. These parameters were used to represent human PD parameters for the simulation of lymphocyte counts. Other human PD parameters such as input and output rate constants for lymphocytes were obtained from the literature. Based on these estimated human PK and PD parameters, human lymphocyte counts after administration of ONO-4641 were simulated. In conclusion, the simulation of human lymphocyte counts based on preclinical data led to the acquisition of useful information for designing future clinical studies.

No effect of imidafenacin, a novel antimuscarinic drug, on digoxin pharmacokinetics in healthy subjects.

Plasma digoxin concentrations are increased by the coadministration of anticholinergic drugs, such as propantheline, which decrease gastrointestinal motility. The present study evaluated the effect of imidafenacin, a novel anticholinergic drug, on the pharmacokinetics of digoxin. The effect of imidafenacin on the pharmacokinetics of digoxin was examined in 14 healthy Japanese male subjects in a single-centre, open-label, randomized, two-way crossover study. Subjects received a daily oral dose of digoxin 0.25 mg on days 1 and 2 and digoxin 0.125 mg on days 3 to 8 (period 1). Following a 2-week washout period, digoxin was administered orally for 8 days in a similar manner (period 2). A twice daily dose of imidafenacin 0.1 mg was concomitantly administered with digoxin for 8 days either in period 1 or 2. The geometric mean ratios [GMR] (90% confidence intervals [CIs]) for digoxin C(max) and AUC(0-24) (with/without imidafenacin) at steady state were 0.88 (0.74, 1.04) and 1.00 (0.90, 1.10), respectively. The 90% CIs of GMR for digoxin trough concentration, urinary excretion amount and renal clearance at steady state fell within the range of 0.8 to 1.25. The steady-state pharmacokinetics of digoxin is not affected by concomitant administration of imidafenacin in healthy subjects.

Population pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapy-induced nausea and vomiting.

PURPOSE: To develop a population pharmacokinetic model of aprepitant and dexamethasone in Japanese patients with cancer, explore the factors that affect the pharmacokinetics of aprepitant, and evaluate the effect of aprepitant on the clearance of intravenous dexamethasone. METHODS: A total of 897 aprepitant concentration measurements were obtained from 290 cancer patients and 25 healthy volunteers. For dexamethasone, a total of 847 measurements were obtained from 440 patients who were co-administered aprepitant (40, 125 mg, or placebo). Plasma concentration of aprepitant and dexamethasone were determined by liquid chromatography connected with a tandem mass spectrometer and analyzed by a population approach using NONMEM software. RESULTS: The plasma concentration time course of aprepitant was described using a one-compartment model with first-order absorption and lag time. Oral clearance (CL/F) of aprepitant was changed by aprepitant dose at doses of 40 or 125 mg. Body weight was the most influential intrinsic factor to CL/F of aprepitant. Age, ALT, and BUN also had mild effects on the CL/F. Typical population estimates of CL/F, apparent distribution volume (V(d)/F), absorption constant (K(a)) and absorption lag time were 1.54 L/h, 72.1 L, 0.893/h and 0.295 h, respectively. Inter-individual variability in CL/F, V(d)/F and K(a) were 53.9, 21.0, and 141%, respectively; intra-individual variability was 27.7%. The plasma concentration time course of intravenous dexamethasone was also described using a one-compartment model. Clearance of dexamethasone was decreased 24.7 and 47.5% by co-administration of aprepitant 40 and 125 mg. All final model estimates of aprepitant and dexamethasone fell within 10% of the bootstrapped mean. CONCLUSIONS: A pharmacokinetic model for aprepitant has been developed that incorporates body weight, age, ALT, BUN and aprepitant dose to predict the CL/F. The results of population pharmacokinetic analysis of dexamethasone support dose adjustment of dexamethasone in the case of co-administration with aprepitant.