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Beraprost sodium (BPS), an orally administrable prostaglandin I2 derivative, is used for the treatment of chronic arterial occlusion and pulmonary arterial hypertension and has potential efficacy in nephropathy. Beraprost sustained release (beraprost SR) is an oral sustained-release formulation of BPS. To confirm the dose rationale reported in a multi-regional study of nephropathy patients in Asia, this open-label study evaluated ethnic differences in the pharmacokinetic profiles of BPS and its active diastereomer (BPS-314d) after beraprost SR administration among healthy Japanese, Chinese, and Korean adult males. Twelve healthy subjects in each ethnic group were enrolled. Subjects received a single oral dose of 120 μg beraprost SR under fasting conditions. The geometric mean ratio (90% confidence interval) of the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to time of the last quantifiable concentration (AUClast) of BPS was 1.12 (0.85–1.48) and 1.40 (1.05–1.86) in Chinese, and 1.18 (0.90–1.55) and 1.18 (0.89–1.58) in Korean compared to Japanese subjects. These differences were not clinically relevant. Similarly, differences in the Cmax and AUClast of BPS-314d were also small among the ethnic groups. Urinary excretion of BPS and BPS-314d was limited in all ethnic groups. Together, these findings indicate that the pharmacokinetics of beraprost SR are not affected by ethnic background. There were no clinically meaningful ethnic differences in the pharmacokinetics of BPS and BPS-314d following beraprost SR administration among Japanese, Chinese and Korean populations.

Background Methotrexate is frequently used to treat rheumatoid arthritis. Peficitinib (ASP015K; Smyraf®), an oral Janus kinase inhibitor indicated for the treatment of rheumatoid arthritis, may be coadministered with methotrexate. Objective The objective of this study was to investigate potential drug–drug interactions of peficitinib with methotrexate and the short-term safety of coadministration. Patients and Methods This phase I, open-label, single-sequence study included patients with rheumatoid arthritis taking a stable dose of methotrexate. Patients received their prescribed methotrexate dose (Day 1) and then peficitinib (100 mg) twice daily from Day 3 until the morning of Day 9; a second methotrexate dose was coadministered with peficitinib on Day 8. Serial blood samples were collected for methotrexate concentration after dosing on Days 1 (methotrexate alone) and 8 (methotrexate plus peficitinib) and for peficitinib concentration after dosing on Days 7 (peficitinib alone) and 8 (methotrexate plus peficitinib). Pre-dose concentrations of peficitinib were measured (Days 3–8). Results Peficitinib concentrations reached steady state on Day 5. Administration of peficitinib did not result in changes to methotrexate area under the concentration–time curve from time zero to infinity or maximum observed concentration following a methotrexate dose (15–25 mg), and there was no significant effect of methotrexate (15–25 mg) on peficitinib area under the concentration–time curve within a 12-hour dosing interval. There were no new tolerability or safety signals after coadministration of peficitinib and methotrexate. One patient experienced two serious adverse events and withdrew from the study without receiving peficitinib. Conclusions Pharmacokinetic results showed no significant interactions between peficitinib and methotrexate. ClinicalTrials.gov Identifier NCT01754805. Electronic supplementary material The online version of this article (10.1007/s40261-020-00937-z) contains supplementary material, which is available to authorized users.

ASP7991 is a calcimimetic that acts on the calcium-sensing receptor on parathyroid cell membranes and suppresses parathyroid hormone (PTH) secretion in the treatment of secondary hyperparathyroidism. The mass balance and metabolite profile of [14C]ASP7991 were investigated in six healthy male subjects after a single oral dose of [14C]ASP7991 [1 mg, 18.5 kBq (500 nCi)] in solution. [14C] radioactivity in plasma, urine and feces was analyzed using Accelerator mass spectrometry. ASP7991 was rapidly absorbed, metabolized and excreted. Mean recovery of [14C] radioactivity in urine and feces was 30.08% and 49.31%, respectively, and mean total recovery of [14C] radioactivity was 79.39%. The majority of [14C] radioactivity in urine and feces was excreted within the first 72 h following administration. Seven metabolites were detected in plasma, urine and feces samples, and their structures were determined by mass spectrometry. The main metabolic pathways of ASP7991 in humans were predicted to be N-dealkylation, followed by N-acetylation and taurine conjugation to a carboxylic acid moiety. Our findings show that a mass balance study using micro radioactivity doses is suitable for elucidating the pharmacokinetics of the absorption, metabolism and excretion of administered drugs.

Mirabegron, the first selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), inhibits cytochrome P450 isozyme CYP2D6. This study was performed in Japanese healthy postmenopausal female volunteers to assess any pharmacokinetic drug interaction between mirabegron and tolterodine, another OAB drug and a sensitive substrate of CYP2D6. Tolterodine 4 mg was orally administered from Days 1–7 and co-administered with mirabegron 50 mg from Days 8–14. Mirabegron 50 mg increased maximum concentration (Cmax) and area under the concentration-time curve from zero to 24 h after dosing (AUC24h) of tolterodine by 2.06-fold (90% confidence interval [CI] 1.81, 2.34) and 1.86-fold (90% CI 1.60, 2.16), respectively, and increased Cmax and AUC24h of the metabolite 5-hydroxymethyl tolterodine by 1.36-fold (90% CI 1.26, 1.47) and 1.25-fold (90% CI 1.15, 1.37), respectively. This suggested a weak pharmacokinetic drug interaction between mirabegron and tolterodine. Mean change from baseline of Fridericia's QT correction formula (ΔQTcF) was slightly higher on Day 14 than on Day 7. No subject had QTcF >480 msec or ΔQTcF >60 msec. All the treatment-emergent adverse events were mild. Mirabegron 50 mg was considered to be safe and well tolerated when coadministered with tolterodine 4 mg in healthy postmenopausal female volunteers.

1. The human mass balance of 14C-labelled ASP015K ([14C]ASP015K), an orally bioavailable Janus kinase (JAK) inhibitor, was characterized in six healthy male subjects after a single oral dose of [14C]ASP015K (100 mg, 3.7 MBq) in solution. [14C]ASP015K was rapidly absorbed with tmax of 1.6 and 1.8 h for ASP015K and total radioactivity in plasma, respectively. Mean recovery in urine and feces amounted to 36.8% and 56.6% of the administered dose, respectively. The main components of radioactivity in plasma and urine were ASP015K and M2 (5′-O-sulfo ASP015K). In feces, ASP015K and M4 (7-N-methyl ASP015K) were the main components.2. In vitro study of ASP015K metabolism showed that the major isozyme contributing to the formation of M2 was human sulfotransferase (SULT) 2A1 and of M4 was nicotinamide N-methyltransferase (NNMT).3. The in vitro intrinsic clearance (CLint_in vitro) of M4 formation from ASP015K in human liver cytosol (HLC) was 11-fold higher than that of M2. The competitive inhibitory effect of...

Purpose The objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a β 3 -adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects. Methods In total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring. Findings After administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron C max and AUC 0–∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, C max was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single-dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for C max and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects. Implications Our studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western subjects. Furthermore, the effects of food on the pharmacokinetic profiles appeared to be similar among the 3 populations tested in our studies. The findings suggest that there are no significant pharmacokinetic differences among the Japanese, Taiwanese, and Chinese populations.

Japan Pharmacogenomics Data Science Consortium (JPDSC) has assembled a database for conducting pharmacogenomics (PGx) studies in Japanese subjects. The database contains the genotypes of 2.5 million single-nucleotide polymorphisms (SNPs) and 5 human leukocyte antigen loci from 2994 Japanese healthy volunteers, as well as 121 kinds of clinical information, including self-reports, physiological data, hematological data and biochemical data. In this article, the reliability of our data was evaluated by principal component analysis (PCA) and association analysis for hematological and biochemical traits by using genome-wide SNP data. PCA of the SNPs showed that all the samples were collected from the Japanese population and that the samples were separated into two major clusters by birthplace, Okinawa and other than Okinawa, as had been previously reported. Among 87 SNPs that have been reported to be associated with 18 hematological and biochemical traits in genome-wide association studies (GWAS), the associations of 56 SNPs were replicated using our data base. Statistical power simulations showed that the sample size of the JPDSC control database is large enough to detect genetic markers having a relatively strong association even when the case sample size is small. The JPDSC database will be useful as control data for conducting PGx studies to explore genetic markers to improve the safety and efficacy of drugs either during clinical development or in post-marketing.

ASP7991 is a calcimimetic that acts on the calcium-sensing receptor on parathyroid cell membranes and suppresses parathyroid hormone (PTH) secretion in the treatment of secondary hyperparathyroidism. The mass balance and metabolite profile of [

Amenamevir is the international non-proprietary name for ASP2151 synthesized by Astellas Pharma, Inc. It is a structurally novel class of helicase-primase inhibitor and demonstrated more potency in vitro anti-viral activity with low cytotoxicity against varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), and herpes simplex virus type 2 (HSV-2) than acyclovir (ACV). Phase II randomized trial assessed the safety and efficacy of ASP2151 for episodic therapy of recurrent genital herpes was conducted. Participants self-initiated with ASP2151 (100, 200, or 400 mg daily for 3 days), ASP2151 (1,200 mg as a single dose), placebo for 3 days, or Valacyclovir (500 mg twice daily for 3 days). We present a first population pharmacokinetic (PPK) modeling analysis of Amenamevir for genital herpes patients. The final model retained the effect of Weight and Albumin on CL. Statistical analysis between pharmacokinetics and clinical efficacies was done by using the time above 200 ng/mL (T200 ). T200 derived from the final PPK model to consider the correlation with Time to lesion healing and viral shedding. This finding suggested that it could be necessary to maintain the Amenamevir concentration above the threshold level to prevent the virus replication.

Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6. To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism. Two open-label, randomized, one-sequence crossover drug–drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype. Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C max) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123–172 %] and 181 % (90 % CI 163–201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50–86 %) and 56 % (90 % CI 49–65 %), respectively, without an effect on terminal elimination half-life (t ½). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30–47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C max was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated. Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.

Background Mirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron is formulated as an extended-release tablet using oral controlled-absorption system (OCAS) technology. Objective This study was designed to assess the effects of food on the pharmacokinetic properties of mirabegron OCAS in accordance with regulatory requirements to support dosing recommendations. Methods In this single-dose, randomized, open-label, 3-period, parallel-dose-group, crossover study, mirabegron OCAS 50 or 100 mg was administered orally to healthy adult subjects in the fasted state or after a high- or low-fat breakfast. Dose administrations were separated by a washout period of at least 10 days. Blood samples were drawn up to 96 hours after dosing, and plasma concentrations of mirabegron were analyzed by LC/MS-MS. PK properties were determined using noncompartmental methods. Primary end points for the assessment of food effects were Cmax and AUC0–∞. For tolerability assessment, adverse events (AEs) were monitored using investigators' questionnaires and subjects' spontaneous reports, vital sign measurements, hematology, clinical chemistry, and ECG. Results Thirty-eight subjects (male, 50%; mean age, 32.1 years; mean weight, 77.3 kg; race, 76.3% white) were enrolled in the 50-mg dose group and 38 subjects (male, 52.6%; mean age, 30.9 years; mean weight, 74.5 kg; race, 63.2% white) in the 100-mg dose group. With either fed condition or dose, the 90% CIs for the fed/fasted ratios of both Cmax and AUC0–∞ of mirabegron fell below the predetermined range for bioequivalence (80.0%–125.0%), suggesting that food had no effect on exposure to mirabegron OCAS. With the 50-mg dose, mirabegron Cmax was reduced by 45% with a high-fat breakfast compared with fasted conditions (geometric mean ratio [GMR], 54.8% [90% CI, 43.7%–68.6%]) and AUC0–∞, by 17% (GMR, 83.2% [90% CI, 74.2%–93.4%]). With the 100-mg dose, mirabegron Cmax and AUC0–∞ were reduced by 39% (GMR, 61.3% [90% CI, 47.8%–78.7%]) and 18% (82.4% [72.6%–93.5%]), respectively, after a high-fat breakfast. With the 50-mg dose, mirabegron Cmax was decreased by 75% (GMR, 25.0% [90% CI, 19.9%–31.3%]) and AUC0–∞ by 51% (48.7% [43.3%–54.7%]) after a low-fat breakfast. Corresponding reductions with the 100-mg dose were 64% (GMR, 36.3% [90% CI, 28.2%–46.8%]) for Cmax and 47% (GMR, 53.2% [90% CI, 46.8%–60.5%]) for AUC0–∞. The fed/fasted ratios for mirabegron Cmax and AUC0–∞ were in general independent of dose or sex. Food delayed Tmax compared with the fasted state, with similar increases with the high- and low-fat meals (0.9 hours with 50 mg and 1.5–2.0 hours with 100 mg). Mirabegron was generally well tolerated, with no apparent difference in AE frequency between the fasted and fed states. Conclusions Mirabegron OCAS tablets exhibited a decrease in mirabegron plasma exposure with food that was independent of dose (50 or 100 mg) or gender but dependent on meal composition. A greater reduction in mirabegron exposure was observed after a low-fat breakfast compared with after a high-fat breakfast. Based on findings from previous studies, the effects of food observed in this study do not warrant dose adjustment in clinical practice. ClinicalTrials.gov identifier: NCT00939757 .

The analysis was designed to compare the pharmacokinetics (PK) of sepantronium between US and Japanese patient populations using data obtained from two phase 1 studies being conducted in a similar design, one conducted in the USA and the other in Japan. Patients with a confirmed advanced solid tumor or non-Hodgkin lymphoma (NHL) (US only) that were refractory to standard therapy or for which no standard therapy was available participated in these studies. Sepantronium bromide was administered as a continuous intravenous infusion for 168 h (7 days) every 21 days. During the first two treatment cycles, serial blood and urine samples were collected for up to 48 h after termination of sepantronium bromide infusion. Forty-one subjects in the US study (including five patients with NHL) and 33 patients in the Japanese study were enrolled in both studies and 35 in US and 32 in Japan had adequate samples for PK evaluation. The PK parameters were calculated by non-compartment analysis method and were compared in the US and Japanese populations. The geometric mean ratios (90% confidence intervals) of area under the concentration–time curve, steady state concentration and amount excreted into urine between Japanese and US populations were 1.068 (0.932–1.224), 1.141 (0.996–1.307) and 0.981 (0.855–1.125), respectively. There appear to be no PK differences between the US and Japanese patients with solid tumors or NHL. Copyright © 2012 John Wiley & Sons, Ltd.

Background and objectives Mirabegron is a potent and selective β3-adrenoceptor agonist in development for treatment of overactive bladder. Methods Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel-group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91). Results After oral dosing (25 - 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F. Conclusions Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.

Purpose The purpose of this analysis was to investigate the pharmacokinetics (PK) of sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of sepantronium. Methods Sepantronium was administered as a continuous intravenous infusion of 1.8–10.6 mg/m2/day for 168 h (7 days) to 33 patients. PK parameters were estimated via non-compartmental method. Renal function was categorized for the analysis based on the chronic kidney disease guidance using eGFR values at pre-dose. Results The PK of sepantronium was dose proportional in the dose range of 1.8–10.6 mg/m2/day. Age and sex did not significantly affect the PK of sepantronium. Results suggested that total clearance and renal clearance in patients with moderate renal impairment were 0.7-fold lower than those in patients with normal renal function, resulting in 1.3-fold higher steady-state concentration and area under the curve values. The PK parameters of sepantronium in patients with mild renal impairment were comparable to those in the patients with normal renal function. Conclusions While age and sex did not significantly affect the PK of sepantronium, moderate renal impairment increased exposure of sepantronium by about 30 %. The results suggest that no dose adjustment is required for patients with mild renal impairment.

We assessed the pharmacokinetics and interactions of steady-state micafungin (Mycamine) or placebo with steady-state voriconazole in 35 volunteers. The 90% confidence intervals around the least-squares mean ratios for micafungin pharmacokinetic parameters and placebo-corrected voriconazole pharmacokinetic parameters were within the 80%-to-125% limits, indicating an absence of drug interaction.

Amenamevir is a novel drug that targets the viral helicase-primase complex. While dose-dependent efficacy had been observed in non-clinical studies, no clear dose dependence has been observed in humans. We therefore developed a pharmacokinetic/pharmacodynamic (PK/PD) model to explain this inconsistency between species and to clarify the immune-related healing of amenamevir in humans. The model consisted of a non-linear kinetic model for a virtual number of virus plaques as a built-in biomarker. Lesion score was defined as an endpoint of antiviral efficacy, and logit model analysis was applied to the ordered-categorical lesion score. The modeling results suggested the time course profiles of lesion score could be explained with the efficacy terms in the logit model, using change in number of virus plaques as an indicator of the effects of amenamevir and time elapsed as an indicator of the healing of the immune response. In humans, the PD effect was almost dose-independent, and immune-related healing may have been the driving force behind the reduction in lesion scores. Drug efficacy is occasionally masked in diseases healed by the immune response, such as genital herpes. The PK/PD model proposed in the present study must be useful for explanation the PK/PD relationship of such drugs.

Two randomized, double-blind, placebo-controlled studies are reported that had the objective to evaluate the pharmacokinetics, pharmacodynamics, and safety of ASP015K (peficitinib), a Janus kinase (JAK) inhibitor, in healthy subjects. The single-dose study included 7 male groups (3-300 mg) and 2 female groups (30 or 200 mg), n = 8/group (6 on ASP015K and 2 on placebo in each group). The multiple-dose study included 1 female and 3 male groups, n = 12/group (9 on ASP015K and 3 on placebo in each group), who received ASP015K (30 mg) or placebo every 12 hours (twice a day) for 14 days. In the single-dose study, plasma ASP015K concentration increased dose-proportionally. Food increased ASP015K exposure (AUC

Purpose. The objective of this investigation is to develop a rational design of Osteotropic Drug Delivery System (ODDS), which we have proposed as a novel method for drug delivery to the skeleton via bisphosphonic prodrug, based on the relationship between physicochemical and pharmacokinetic properties of bisphosphonates.

Background Tacrolimus is an established immunosuppressant used for the prevention and treatment of allograft rejection in solid organ transplantation. An immediate-release oral formulation of tacrolimus has been commercially available since 1994 that is administered orally BID. To improve the compliance and quality of life of transplant patients, a once-daily modified release (MR) formulation is an attractive option. However, to be successful, the drug of interest must be sufficiently well absorbed from the distal region of the gastrointestinal tract. Objective To facilitate the development of an MR formulation, we investigated the absorption of tacrolimus from different regions of the human gastrointestinal tract, proximal and distal small bowels, and ascending colon. Methods The study was performed as an open-label, randomized, 4-way crossover design in 6 healthy white male subjects. For each subject, 1 mg (2 mg/mL) of tacrolimus solution in polyethylene glycol 400 was administered to each location in the gastrointestinal tract via a site-specific radiolabeled delivery capsule, which can release tacrolimus solution at specific sites of the gastrointestinal tract. Real-time visualization of capsule location and tacrolimus release at each target site was performed by using γ-scintigraphy. Blood samples were collected to determine tacrolimus levels in the blood. The pharmacokinetic parameters C max , T max after the capsule activation, AUC 0–24 , and mean residence time were determined from the concentration–time profiles. Results Ten healthy male subjects underwent dosing. Six subjects completed all 4 treatments. Three adverse events (mild headache [n = 1], small amount of blood in stool [n = 1], and mild syncopal episode [n = 1]) that were possibly study drug related were reported in 3 different subjects. Tacrolimus was absorbed from not only the small intestine but also from the colonic region of the gastrointestinal tract. Although AUC 0–24 values revealed some site-specific absorption tendencies, the mean AUC 0–24 values obtained were similar regardless of the location of tacrolimus release from the capsule. Conclusions Tacrolimus was absorbed from the duodenum to the colon in these male subjects, although differences were observed in the value of AUC 0–24 , possibly due to variation in cytochrome P450 3A4 activity in the intestine. Although this study was conducted in small group of healthy fasting men, the present results indicate that tacrolimus is suitable for MR formulation development due to a wide absorption window throughout the intestine in humans.

A new method based on gastrointestinal transit kinetics has been developed for estimation of the absorption profiles of drugs administered orally as aqueous solutions. The utility of the method was evaluated in rats. The gastrointestinal transit profile for each segment was estimated by in-vivo studies using phenol red, an unabsorbable marker. The gastrointestinal transit profile of phenol red was well explained by a linear gastrointestinal transit kinetic model with eight segments. We also introduced the absorption process into the gastrointestinal transit kinetic model and the plasma profile was predicted by the convolution method. The absorbability of drugs in each segment was assessed by an in-situ absorption study. The validity of the model was evaluated for model drugs with different absorption characteristics. The plasma profiles predicted for ampicillin, theophylline and cephalexin were in good agreement with those observed. The overestimated plasma profile of propranolol suggests that the low bioavailability of propranolol is a result of first-pass metabolism by the intestine wall and the liver, because the calculated absolute absorption is almost perfect. This proposed model is also suitable for estimation of segmental absorption, which is useful for the development of drug delivery systems. We have demonstrated that the plasma profile of orally administered drugs can be predicted by use of gastrointestinal transit and segmental absorbability information and that this method is especially useful for estimating separately the effect of absolute absorption and first-pass metabolism on the bioavailability of drugs.

The effect of conjugated-metabolite, acetaminophen sulfate (APAPS), on the pharmacokinetics of its parent drug, acetaimnophen (APAP), was examined in rats. Following the i.v. bolus administration of APAP with APAPS, the plasma elimination of APAP was delayed and the distribution volume of APAP was increased at the APAPS coadministration with 60 mg APAP equivalent per kg (eq/kg). The percentages of dose excreted in the urine and bile in 4 h as APAP and its conjugated metabolites, APAPS and acetaminophen glucuronide, were significantly decreased. On the other hand, following the i.v. bolus administration of APAP under the steady-state concentration of APAPS, the distribution volume and total body clearance of APAP were significantly increased. Competitive displacement in serum protein binding of APAP by APAPS was ascertained in vitro and in vivo. A part of the conflict between the bolus and infusion experiment may be explained by the changes in the distribution volume of APAP contributed to the APAPS concentration-dependent serum protein binding of APAP. It was speculated that the pharmacokinetics of APAP was partly interacted with APAPS by the displacement of serum protein binding.

The effect of three positional isomers, o-, m- and p-acetylaminophenyl sulfate (AOAPS, AMAPS and APAPS (acetaminophen sulfate), respectively), on the pharmacokinetics of acetaminophen (APAP) was investigated in rats. All of the intravenously administered positional isomers were rapidly eliminated from plasma, and approximately 80% of the dose was excreted in an unchanged form in the urine within 4 h, while biliary excretions represented a small percent of the doses. Following the intravenous bolus injection of APAP, plasma elimination of APAP was accelerated and the distribution volume of APAP was increased under a steady state concentration (about 10 microg APAP eq/ml) of AOAPS or APAPS, but not AMAPS, as compared with saline infusion. Total body clearances of APAP were increased from 18.3 ml/min/kg for the control to 23.9 and 26.9 ml/min/kg for AOAPS and APAPS coadministration, respectively. AOAPS and APAPS competitively displaced the serum protein binding of APAP, while AMAPS had little effect. The distribution volume of unbound APAP was anomalously increased by APAPS, while it was not affected by AOAPS or AMAPS. Tissue-to-plasma concentration ratios of APAP were significantly increased by APAPS in the liver, kidney and brain, while they were only slightly increased by AOAPS. It was suggested that APAPS has not only the displacing activity of serum protein binding but also other specific effectiveness on the distribution of APAP.

Amenamevir is the international non-proprietary name for ASP2151 synthesized by Astellas Pharma, Inc. It is a structurally novel class of helicase-primase inhibitor and demonstrated more potency in vitro anti-viral activity with low cytotoxicity against varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), and herpes simplex virus type 2 (HSV-2) than acyclovir (ACV). Phase II randomized trial assessed the safety and efficacy of ASP2151 for episodic therapy of recurrent genital herpes was conducted. Participants self-initiated with ASP2151 (100, 200, or 400 mg daily for 3 days), ASP2151 (1,200 mg as a single dose), placebo for 3 days, or Valacyclovir (500 mg twice daily for 3 days). We present a first population pharmacokinetic (PPK) modeling analysis of Amenamevir for genital herpes patients. The final model retained the effect of Weight and Albumin on CL. Statistical analysis between pharmacokinetics and clinical efficacies was done by using the time above 200 ng/mL (T200 ). T200 derived from the final PPK model to consider the correlation with Time to lesion healing and viral shedding. This finding suggested that it could be necessary to maintain the Amenamevir concentration above the threshold level to prevent the virus replication.

The polymorphisms in the human leukocyte antigen (HLA) region are powerful tool for studying human evolutionary processes. We investigated genetic structure of Japanese by using five-locus HLA genotypes (HLA-A, -B, -C, -DRB1, and -DPB1) of 2,005 individuals from 10 regions of Japan. We found a significant level of population substructure in Japanese; particularly the differentiation between Okinawa Island and mainland Japanese. By using a plot of the principal component scores, we identified ancestry informative alleles associated with the underlying population substructure. We examined extent of linkage disequilibrium (LD) between pairs of HLA alleles on the haplotypes that were differentiated among regions. The LDs were strong and weak for pairs of HLA alleles characterized by low and high frequencies in Okinawa Island, respectively. The five-locus haplotypes whose alleles exhibit strong LD were unique to Japanese and South Korean, suggesting that these haplotypes had been recently derived from the Korean Peninsula. The alleles characterized by high frequency in Japanese compared to South Korean formed segmented three-locus haplotype that was commonly found in Aleuts, Eskimos, and North- and Meso-Americans but not observed in Korean and Chinese. The serologically equivalent haplotype was found in Orchid Island in Taiwan, Mongol, Siberia, and Arctic regions. It suggests that early Japanese who existed prior to the migration wave from the Korean Peninsula shared ancestry with northern Asian who moved to the New World via the Bering Strait land bridge. These results may support the admixture model for peopling of Japanese Archipelago.

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. The pharmacokinetics and the targeting efficiency of a bisphosphonic prodrug of carboxyfluorescein (CF), disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP), was investigated in rats. After intravenous injection, CF-BP was rapidly taken up into the skeleton, and subsequently cleared from the bone by hydrolysis of its ester linkage at a half-life of 3.2 days. On the other hand, the bone concentration of regenerated CF gradually increased to reach the maximum at 14 days and slowly decreased up to 56 days. Kinetical analysis revealed that bone tissue acts as a reservoir of regenerated CF to supply the parent compound into the systemic circulation. In contrast with CF-BP, CF injected intravenously showed rapid clearance from the plasma and extremely low bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for CF in the bone and plasma after injection of CF-BP and CF, were 1551 and 6689, respectively. These results suggest that ODDS has a potential to improve not only apparent potency but also therapeutic index of the drugs which exhibit their pharmacological effects in the bone.

This first-in-human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003-10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration-time curves ranging from 0.7 to 251.6 μg/mL and 6.5 to 55409.6 h·μg/mL following doses 0.1 mg/kg-10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose-dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested.

Mirabegron is a potent and selective β3-adrenoceptor agonist in development for treatment of overactive bladder.Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel-group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91).After oral dosing (25 - 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F.Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.

The analysis was designed to compare the pharmacokinetics (PK) of sepantronium between US and Japanese patient populations using data obtained from two phase 1 studies being conducted in a similar design, one conducted in the USA and the other in Japan. Patients with a confirmed advanced solid tumor or non-Hodgkin lymphoma (NHL) (US only) that were refractory to standard therapy or for which no standard therapy was available participated in these studies. Sepantronium bromide was administered as a continuous intravenous infusion for 168 h (7 days) every 21 days. During the first two treatment cycles, serial blood and urine samples were collected for up to 48 h after termination of sepantronium bromide infusion. Forty-one subjects in the US study (including five patients with NHL) and 33 patients in the Japanese study were enrolled in both studies and 35 in US and 32 in Japan had adequate samples for PK evaluation. The PK parameters were calculated by non-compartment analysis method and were compared in the US and Japanese populations. The geometric mean ratios (90% confidence intervals) of area under the concentration-time curve, steady state concentration and amount excreted into urine between Japanese and US populations were 1.068 (0.932-1.224), 1.141 (0.996-1.307) and 0.981 (0.855-1.125), respectively. There appear to be no PK differences between the US and Japanese patients with solid tumors or NHL.

Determining the safety and pharmacokinetics of antifungal agents in neonates is important. A previous single-dose pharmacokinetic study of micafungin in neonates demonstrated that doses of 0.75 to 3 mg/kg produced lower plasma micafungin concentrations than in older patients because of increased apparent plasma clearance of micafungin in neonates. The primary objective of this study was to assess the safety and pharmacokinetics of an increased (15 mg/kg/d) dose of micafungin.A repeated dose, open-label pharmacokinetic, and safety trial of intravenous micafungin in 12 preterm neonates48 hours of life with suspected systemic infections. Neonates received 15 mg/kg/d of micafungin for 5 days. Blood samples were drawn relative to either the fourth or fifth dose. Systemic exposure was assessed by examination of the plasma area under the curve.The median birth weight and gestational age of the neonates were 775 g and 27 weeks, respectively. No adverse events related to micafungin were detected. The mean area under the curve and clearance for the cohort was 437.5 microg'h/mL and 0.575 mL/min/kg, respectively. The calculated clearance and volume of distribution for neonates was greater than that observed in older children and adults.These data suggest that 15 mg/kg dosing in premature neonates corresponds to an exposure of approximately 5 mg/kg in adults. No adverse events related to micafungin were observed.

To characterize the pharmacokinetics of tacrolimus after topical application in adult and pediatric patients with moderate to severe atopic dermatitis from all clinical trials in which tacrolimus blood levels were obtained.Tacrolimus ointment 0.03% or 0.1% was applied twice daily. In the adult and pediatric pharmacokinetic studies, serial blood samples were obtained after single and repeated topical application. During the 12 clinical efficacy trials of tacrolimus ointment, single blood samples were obtained at various times relative to tacrolimus ointment application.In the pharmacokinetic studies, 89% to 95% of tacrolimus whole blood concentration samples were less than 1 ng/mL; mean maximum concentrations ranged from 0.2 to 1.6 ng/mL and mean area under the blood concentration-time curves (0-12 hours) ranged from 1.4 to 13.1 ng x hr/mL. Likewise, in the clinical efficacy trials, the majority (85%-99%) of tacrolimus concentration samples were less than 1 ng/mL.Tacrolimus ointment is associated with minimal systemic absorption and no evidence of systemic accumulation in patients with moderate to severe atopic dermatitis and extensive disease.

The immunosuppressive agent FK506 (tacrolimus) has neuroprotective properties not only in rodents but also in nonhuman primates. To improve the accuracy of clinical studies of acute stroke, clinical dose setting based on brain concentrations of agents in humans is very helpful. We have already established a rapid-synthesis method for (11)C-labeled FK506; therefore, in the present study, we aimed to establish a method to measure brain concentrations of FK506 using (11)C-FK506 PET in monkeys.Studies were performed on 3 male cynomolgus monkeys (Macaca fascicularis). FK506 (0.1 mg/kg) containing (11)C-FK506 was intravenously injected into the monkeys, and dynamic PET images were acquired for 30 min afterward. Arterial blood samples were collected 5 and 15 min after injection, and their radioactivities were measured by a gamma-counter. FK506 concentrations in brain and blood were calculated in units of moles per liter using the specific activity of the injected FK506. The PET study data were validated using an enzyme-linked immunosorbent assay.Seven minutes after administration, the radioactivity in the brain became constant and was maintained up to 30 min. We succeeded in measuring the FK506 concentration in the brain using (11)C-FK506 PET. Fifteen minutes after FK506 (0.1 mg/kg) administration, the concentrations in the cortex and striatum were 20.0 +/- 1.7 ng/g and 14.1 +/- 1.7 ng/g, respectively. FK506 concentrations in the blood correlated significantly with those measured by enzyme-linked immunosorbent assay.We successfully measured FK506 concentrations in anesthetized monkey brain and blood using (11)C-FK506 PET. These results indicate a potential method to measure FK506 concentrations in human brain. Additionally, a potential use for the PET technique in drug development has been demonstrated.

Tacrolimus (FK506), an immunosuppressive drug, is known to have potent neuroprotective activity and attenuate cerebral infarction in experimental models of stroke. Here we assess the neuroprotective efficacy of tacrolimus in a nonhuman primate model of stroke, photochemically induced thrombotic occlusion of the middle cerebral artery (MCA) in cynomolgus monkeys. In the first experiment, tacrolimus (0.01, 0.032, or 0.1 mg/kg) was intravenously administered immediately after MCA occlusion, and neurologic deficits and cerebral infarction volumes were assessed 24 hours after the ischemic insult. Tacrolimus dose-dependently reduced neurologic deficits and infarction volume in the cerebral cortex, with statistically significant amelioration of neurologic deficits at 0.032 and 0.1 mg/kg and significant reduction of infarction at 0.1 mg/kg. In the second experiment, the long-term efficacy of tacrolimus on neurologic deficits and cerebral infarction was assessed. Vehicle-treated monkeys exhibited persistent and severe deficits in motor and sensory function for up to 28 days. A single intravenous bolus injection of tacrolimus (0.1 or 0.2 mg/kg) produced long-lasting amelioration of neurologic deficits and significant reduction of infarction volume. In conclusion, we have provided compelling evidence that a single dose of tacrolimus not only reduces brain infarction but also ameliorates long-term neurologic deficits in a nonhuman primate model of stroke, strengthening the view that tacrolimus might be beneficial in treating stroke patients.

Background ASP015K is an oral Janus kinase (JAK) inhibitor with moderate selectivity for JAK3, a key enzyme for interleukin-2 (IL-2) signaling. With IL-2 stimulation, JAK1/3 augments STAT5 phosphorylation (STAT5-P), which is an integral step in the T cell activation pathway. Objectives In two phase1 dose-escalation trials, we evaluated the pharmacodynamics (PD) of ASP015K after single and multiple doses in healthy subjects measuring STAT5-P as a biomarker of JAK1/3 activity. Methods Study A: single doses of ASP015K (3, 10, 30, 60, 120, 200, 300 mg) or placebo (PBO) were given in 9 sequential groups (n=6 active and 2 PBO per group). Study B: 3 groups of men received ASP015K (30, 100, 200 mg twice daily [BID]) or PBO, and 1 group of women received ASP015K (100 mg BID) or PBO (n=9 active and 3 PBO per group) for 13.5 days. PD variables included serial measures of percentage reduction of IL-2–stimulated STAT5-P in T cells; total lymphocyte count and peripheral lymphocyte subtypes pre- and postdose. Results The median peak STAT5-P inhibition occurred at 1–2 hours after a single dose, consistent with the median t max in plasma ASP015K concentrations. ASP015K inhibited STAT5-P in a dose dependent manner, with mean peak percentage inhibitions of 84%, 85%, 92%, and 93% after 60, 120, 200, and 300 mg doses, respectively. The relationship between plasma ASP015K concentration and percentage STAT5-P inhibition was described by an E max model with 50% of maximum effect (EC 50 ) achieved at 48 ng/mL, estimated E max close to 100%, and a shape factor (γ) of ~1.2. With multiple doses on days 1, 7, and 14, median percentage of STAT5-P inhibition peaked at ~2 hours postdose, median peak inhibition ranged from 89%–98% with ASP015K at 100 and 200 mg on all days. The percentage STAT5-P inhibition was similar in men and women after single-dose 30 mg as well as with multiple doses (100 mg BID). After multiple doses, a small decrease in lymphocyte count from baseline was seen with 100 and 200 mg BID doses in men on day 17, with no dose dependency. Dose-dependent decreases in NK cells, a lymphocyte subset, were seen with ASP015K on day 17. Conclusions ASP015K showed dose- and concentration-dependent inhibition of STAT5-P. Total lymphocyte count showed no dose-dependent changes. A dose-dependent reduction in NK cells was seen with multiple doses. These results are consistent with the pharmacologic effect of JAK1/3 inhibition by ASP015K. In a phase 2a study, ASP015K decreased disease severity in psoriasis patients; studies to test safety and efficacy of ASP015K in rheumatoid arthritis patients are underway. Disclosure of Interest T. Zhu Employee of: Astellas Pharma Global Development, U. Valluri Employee of: Astellas Pharma Global Development, M. Lewand Employee of: Astellas Pharma Global Development, Y. Cao Employee of: Astellas Pharma Global Development, K. Cho Employee of: Astellas Pharma Global Development, J. Holman Employee of: Astellas Pharma Global Development, T. Sawamoto Employee of: Astellas Pharma, Inc., J. Keirns Employee of: Astellas Pharma Global Development

Background ASP015K is an oral Janus kinase (JAK) inhibitor of JAK1/3 in development for treatment of autoimmune diseases (eg, psoriasis, rheumatoid arthritis). Objectives Pharmacokinetics (PK), safety, and tolerability of ASP015K were assessed in 2 double-blind, placebo-controlled, dose-escalation trials in healthy subjects. Methods Study A: single doses of ASP015K 3–300 mg or placebo (PBO) were given in 9 sequential groups (n=6 active: 2 PBO/group). Study B: 3 groups of men received ASP015K 30, 100, or 200 mg twice daily (BID) or PBO, and 1 group of women received 100 mg BID or PBO (n=9 active:3 PBO/group) for 13.5 days. Plasma PK parameters were calculated with noncompartmental methods. Adverse events (AEs), clinical labs, vital signs, and electrocardiograms (ECGs) were evaluated. Results After single doses under fasted conditions, ASP015K was rapidly absorbed with median time to maximum observed concentration (tmax) ≤1.75 hours. Mean maximum observed concentration (Cmax) and area under the curve from time 0 extrapolated to infinity (AUCinf) increased dose proportionally. Elimination was multiphasic with terminal mean half-life (t1/2) of 7.0–13 hours at clinically relevant doses (≥60 mg). Food increased Cmax by 5% and AUCinf by 27% and delayed tmax by ∼2.5 hours. After BID dosing in a fed state, exposure reached steady state on day 3, with Cmax and AUC12h increasing relatively dose proportionally. Mean accumulation factor (day 14 vs day 1) was 1.12–1.65 for Cmax, 1.38–1.65 for AUC12h, and 2.02–2.71 for Ctrough. There was no statistically significant sex difference in PK with single or multiple doses. There was no evidence of dose-limiting toxicities or significant safety findings with single doses. With multiple doses, 75% (27/36) of ASP015K subjects and 42% (5/12) of PBO subjects had AEs, mostly mild or moderate; no serious AEs occurred. The most common AEs were neutropenia, headache, and abdominal pain, with apparent dose dependency. Three subjects discontinued due to AEs (1 man with moderate vomiting [100 mg]; 1 man with mild-to-moderate neutropenia [200 mg BID]; 1 woman with severe neutropenia [100 mg BID]). There were no clinically significant changes in labs, vital signs, or ECG (no positive correlation between ASP015K concentration and QTcF). Conclusions ASP015K was generally well tolerated and showed rapid absorption with small food effect, elimination t1/2 >7 hours at clinically relevant doses, and modest accumulation after BID dosing. Plasma exposure was relatively dose proportional, with no significant sex differences in PK. Disclosure of Interest T. Zhu Employee of: Astellas Pharma Global Development, T. Sawamoto Employee of: Astellas Pharma, Inc., U. Valluri Employee of: Astellas Pharma Global Development, M. Lewand Employee of: Astellas Pharma Global Development, Y. Cao Employee of: Astellas Pharma Global Development, S. Swan: None Declared, K. Lasseter: None Declared, M. Matson: None Declared, J. Holman Employee of: Astellas Pharma Global Development, J. Keirns Employee of: Astellas Pharma Global Development

Survivin is a member of IAPs. YM155 is a compound that suppresses survivin, and has been shown to exhibit anti-tumor activity in preclinical and clinical studies. The current analysis is designed to compare the pharmacokinetics (PK) of YM155 between US and Japanese patient populations using data obtained from two phase 1 trials, one done in Japan and the other in the US. Patients with a confirmed solid tumor or NHL (US only) that were refractory to standard therapy or for which no standard therapy was available participated in these trials. YM155 was administered as a continuous IV infusion for 168 hours, every 21 days. During the first two treatment cycles, serial blood and urine samples were collected for up to 48 hours after the discontinuation of YM155 infusion on Day 7. Forty-one subjects in the US trial (including 5 subjects with NHL) and 33 subjects in the Japanese trial had adequate samples for PK evaluation. The maximum tolerated dose (MTD) was 4.8 mg/m2/day and 8.0 mg/m2/day in the US and Japanese populations, respectively. In both populations, median YM155 concentration appeared to reach steady-state 12–24 hours after the start of the YM155 infusion. After discontinuation of the YM155 infusion, plasma YM155 concentration declined rapidly in a biphasic pattern with mean terminal half-life between 6 and 29 hours. The geometric mean ratio [90 % confidence interval(CI)] of steady-state YM155 concentration (Css) and area under observed YM155 concentration-time curve extrapolated to infinity (AUCinf) between cycle 2 and cycle 1 was 1.09 (0.99 –1.29) and 1.02 (0.90–1.16) in the US, and 0.98 (0.80 – 1.21) and 1.00 (0.97–1.03) in the Japanese populations, respectively, suggesting that there was no time-dependence in YM155 exposure. The slope of regression of natural logarithm transformed Css and AUCinf on natural logarithm transformed dose (mean and 95% CI) was 0.66 (0.31–1.00) and 0.65 (0.29–1.00) in the US and 1.00 (0.86–1.14) and 0.99 (0.85–1.12) in the Japanese populations, respectively. At the US MTD dose of 4.8 mg/m2/day, Css (mean ± SD) during cycle 1 was 7.6 ± 2.6 ng/mL (n=24) in the US and 8.7 ± 1.4 ng/mL (n=6) in the Japanese populations. The geometric mean ratios (90 % CI) of AUCinf, Css, and clearance between Japanese and US populations were 1.06 (0.93 – 1.22), 1.14 (1.00 – 1.31) and 0.80 (0.70 – 0.92), respectively. In conclusion, data currently available suggests that PK of YM155 is time-independent in both the US and Japanese patient populations; there appear to be no differences between U.S. and Japanese patients in terms of blood plasma YM155 concentration and its time course, although high variability was observed. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C134.

Background Mirabegron is a human β3-adrenoceptor agonist for the treatment of overactive bladder. The pharmacokinetic profile of mirabegron has been extensively characterized in healthy Caucasian subjects. Objective The objective of this study was to evaluate the pharmacokinetics, dose-proportionality, and tolerability of mirabegron following single and multiple oral doses in healthy Japanese male subjects. The results were compared with those reported in non-Japanese (primarily Caucasian) subjects. Methods Two studies were conducted. In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study (Study 1), mirabegron oral controlled absorption system (OCAS) tablets were administered at single doses of 50, 100, 200, 300, and 400 mg, with eight subjects (six active, two placebo) per dose group (Part I), and once daily for 7 days at 100 and 200 mg with 12 subjects (eight active, four placebo) per group (Part II). In an open-label, three-period, single-ascending dose study (Study 2), mirabegron OCAS was administered to 12 subjects at 25, 50, and 100 mg in an intra-subject dose-escalation design. Plasma and/or urine samples were collected up to 72 h after the first and last dose and analyzed for mirabegron. Pharmacokinetic parameters were determined using non-compartmental methods. Tolerability assessments included physical examinations, vital signs, 12-lead electrocardiogram, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event (AE) monitoring. Results Forty and 24 young male subjects completed Part I and II, respectively, of Study 1. Twelve young males completed Study 2. After single oral doses (25–400 mg), maximum plasma concentrations (Cmax) were reached at approximately 2.8–4.0 h postdose. Plasma exposure (Cmax and area under the plasma concentration–time curve) of mirabegron increased more than dose proportionally at single doses of 25–100 mg and approximately dose proportionally at high doses of 300 and 400 mg. A more than dose proportional increase in plasma exposure was noted in the body of the same individual. Mirabegron accumulated twofold upon once-daily dosing relative to single-dose data. Steady state was reached within 7 days. Mirabegron was generally well-tolerated at single doses up to 400 mg and multiple doses up to 200 mg. The AE with the highest incidence was increased pulse rate at 400 mg in Study 1. Conclusions Mirabegron OCAS exhibits similar single- and multiple-dose pharmacokinetic characteristics and deviations from dose proportionality in healthy Japanese male subjects compared with those observed in non-Japanese (primarily Caucasian) subjects in previous studies.