Taiji Sawamoto

Pharmacokinetics of an elevated dosage of micafungin in premature neonates.

Background: 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. Methods: A repeated dose, open-label pharmacokinetic, and safety trial of intravenous micafungin in 12 preterm neonates >48 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. Results: 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 &mgr;g′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. Conclusions: 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.

Tacrolimus, a Potential Neuroprotective Agent, Ameliorates Ischemic Brain Damage and Neurologic Deficits after Focal Cerebral Ischemia in Nonhuman Primates

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.

Assessment of Tacrolimus Absorption From the Human Intestinal Tract: Open-Label, Randomized, 4-Way Crossover Study

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 Cmax, Tmax after the capsule activation, AUC0-24, 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 AUC0-24 values revealed some site-specific absorption tendencies, the mean AUC0-24 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 AUC0-24, 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.

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects.

PURPOSE The objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a β3-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 Cmax and AUC0-∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax 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 Cmax 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.

Human mass balance, metabolite profile and identification of metabolic enzymes of [14C]ASP015K, a novel oral janus kinase inhibitor

Abstract 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 nicotinamide on M4 formation in the human liver was considered the reason for high CLint_in vitro of M4 formation, while each metabolic pathway made a near equal contribution to the in vivo elimination of ASP015K. ASP015K was cleared by multiple mechanisms.

Statistical analysis of Amenamevir (ASP2151) between pharmacokinetics and clinical efficacies with non-linear effect model for the treatment of genital herpes.

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.

Integrative pharmacokinetic–pharmacodynamic modeling and simulation of amenamevir (ASP2151) for treatment of recurrent genital herpes

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.

Pharmacokinetics, Pharmacodynamics, and Safety of ASP015K (Peficitinib), a New Janus Kinase Inhibitor, in Healthy Subjects

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 (AUCinf) by 27%. Mean peak JAK inhibition increased with dose, from 6% at 4 hours (median) following ASP015K 3 mg to 93% (range, 89%–98%) at 2 hours (median) after ASP015K 300 mg. In the multiple‐dose study, ASP015K plasma exposure reached steady state by day 3. On day 14, mean ASP015K peak concentration was 38%–65% higher than after the first dose; peak JAK inhibition following 100 or 200 mg twice daily was >85%. The most common adverse events (AEs) were neutropenia, headache, and abdominal pain; no serious AEs occurred. The safety findings at pharmacologically effective doses of ASP015K support further clinical development.

Lack of differences in the pharmacokinetics of sepantronium bromide (YM155) between US and Japanese patients with advanced solid tumors or non-Hodgkin lymphoma.

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.

THU0256 Pharmacodynamics of ASP015K, A Novel Janus Kinase Inhibitor, in Healthy Volunteers

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 tmax 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 Emax model with 50% of maximum effect (EC50) achieved at 48 ng/mL, estimated Emax 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