Masataka Katashima

Comparative pharmacokinetic/pharmacodynamic analysis of proton pump inhibitors omeprazole, lansoprazole and pantoprazole, in humans

SummaryThe relationship between plasma concentrations and inhibitory effects on gastric acid secretion by proton pump inhibitors (PPIs) omeprazole (OPZ), lansoprazole (LPZ) and pantoprazole (PPZ), was analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model in humans. The estimated values of apparent reaction rate constant of PPI and H+, K+-ATPase (K) were 1.34±0.17 (μM−1. h−1), 0.339±0.002 and 0.134±0.006 for OPZ, LPZ and PPZ, respectively. The estimated values of apparent turn-over rate constant of H+, K+-ATPase (k) were 0.0252±0.0019 (h−1), 0.0537±0.0006 and 0.0151±0.0002 for OPZ, LPZ and PPZ, respectively. The apparent dissociation constants of the H+, K+-ATPase-PPI complex (k/K.fp) corrected with plasma free fraction (fp) were about 1 nM for OPZ and LPZ and 2.3 nM for PPZ. Therefore, the potency of the inhibitory effect of PPZ on acid secretion may be slightly weaker than that of OPZ or LPZ. The apparent half lives (In2/k) of the inhibitory effect on acid secretion were 12.9 h for LPZ, <27.5 h for OPZ, and <45.9 h for PPZ, the recovery rate of the inhibitory effect of PPZ on acid secretion was slowest among these PPIs. In conclusion, the relationship between plasma concentrations and inhibitory effects of PPIs on gastric acid secretion could be analyzed by the PK/PD model.

Pharmacokinetics-pharmacodynamics of micafungin in Japanese patients with deep-seated mycosis

SummaryThe objective of this study was to describe the pharmacokinetic profile and investigate the effective concentration of micafungin in Japanese male patients with deep-seated mycosis. 66 patients were treated with i.v. micafungin 12.5–150 mg intravenously for up to 56 days. At this dose range, micafungin showed linear pharmacokinetics, and the mean values of Cmax and Cmin amounted to 3.16–12.9 μg/mL and 0.70–3.68 μg/mL, respectively. The mean value for the elimination half-life was 13.5 h (95 samples from 65 patients), and it remained almost constant over the dose range. In addition, the elimination half-life was not influenced by age, gender or weight, and was similar to that found in healthy subjects. The active metabolites Ml and M2 were detectable, but their exposure was lower than that of the unchanged drug. The pharmacokinetic-pharmacodynamics ob micafungin were then investigated. The overall clinical response rate against aspergillosis and candidiasis showed good results at a dose of 50 mg and over. The Cmax and Cmin at the latter dose amounted to 5.16 and 1.41 μg/mL, respectively.In conclusion, micafungin showed linear pharmacokinetics at doses ranging from 12.5 to 150 mg, and the effective concentration was considered to be over 5 μg/mL as maximum level in Japanese patients with deep-seated mycosis such as candidiasis and aspergillosis.

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.

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.

Smoking accelerates absorption of inhaled neutrophil elastase inhibitor FK706

We compared the pharmacokinetics of the inhaled novel neutrophil elastase inhibitor FK706 between healthy nonsmokers and smokers.

Evaluation of Food and Spherical Carbon Adsorbent Effects on the Pharmacokinetics of Roxadustat in Healthy Nonelderly Adult Male Japanese Subjects

Roxadustat is a hypoxia‐inducible factor prolyl hydroxylase inhibitor in late‐stage clinical development for the treatment of anemia in chronic kidney disease. Spherical carbon adsorbent (SCA) is used in patients with chronic kidney disease and has been shown to impact absorption of certain concomitant drugs. Two phase 1, open‐label, randomized, crossover studies were conducted in healthy adult Japanese males to investigate the effect of food and SCA on the pharmacokinetics of a single oral dose of roxadustat. Subjects in the food effect study received a single dose of 100‐mg roxadustat under fed and fasted conditions. Subjects in the SCA/roxadustat drug‐drug interaction study received a single dose of 100‐mg roxadustat alone, concomitantly with SCA, and 1 and 2 hours before and after SCA to consider the real‐world clinical situation and assess any potential impact of a lag time on the pharmacokinetics of roxadustat. Primary outcomes for both studies were area under the concentration‐time curve from the time of dosing extrapolated to infinity and maximum concentration of drug in blood plasma. In the food effect study (N = 16), the geometric mean ratio (fed/fasted) and 90% confidence interval for area under the concentration‐time curve from the time of dosing extrapolated to infinity and maximum concentration of roxadustat were 94.44 (89.93‐99.18) and 79.88 (72.09‐88.52), respectively. In the SCA/roxadustat drug‐drug interaction study, all geometric mean ratios and 90% confidence intervals (roxadustat + SCA/roxadustat) were within the no‐effect boundaries of 80% and 125%. Roxadustat was generally well tolerated. The effect of food on the pharmacokinetics of roxadustat and the drug‐drug interaction between roxadustat and SCA do not appear to be clinically relevant and support the safe use of roxadustat under these conditions.

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.

高チロシン血症I型治療薬ニチシノン（オーファディン®カプセル）の薬理学的特徴および臨床試験成績

要約:ニチシノン(オーファディンカプセル)は,4ヒドロキシフェニルピルビン酸ジオキシゲナーゼ (HPPD)阻害薬であり,高チロシン血症I型(hereditary tyrosinemia type 1:HT-1)患者の治療を適応として, これまでに世界 37 ヵ国にて承認されている.本邦に おいては,2010 年 2 月の「第 1回医療上の必要性の高 い未承認薬・適応外薬検討会議」で検討され,開発企 業の募集または開発要請を行った医薬品のリストに掲 載されたことを受けて,アステラス製薬株式会社は本 邦での承認取得申請に取り組み,2014 年 12 月に 「オーファディンカプセル」として承認された.HT-1 の原因は,チロシン分解経路の最終段階にあるフマリ ルアセト酢酸ヒドロラーゼ(FAH)の欠損であり,肝 臓および腎臓において,FAHより上流の中間代謝物で あるフマリルアセト酢酸(FAA)およびマレイルアセ ト酢酸(MAA)が組織中に蓄積され,これら臓器に障 害をもたらすと考えられている.ニチシノンは,ラッ ト肝臓のサイトゾル画分を用いた in vitro試験におい て,チロシン分解経路における FAAやMAA産生の上 流に位置する HPPDに対して阻害作用を示した.ま た,マウスおよびラットにおいてニチシノンの単回 投与によって肝臓中HPPD活性が阻害されることが確 認された.さらに,HT-1 のモデル動物と考えられる FAH欠損マウスにおいて,FAHホモ欠損マウスの 新生児期での肝機能障害による致死性がニチシノンの 投与により回避された.以上の結果より,ニチシノン はチロシン分解経路において FAHより上流の酵素 である HPPDを阻害し,反応性の高いチロシンの中間 代謝物の産生・蓄積を抑制することによって,HT-1 患者の病態を改善すると考えられる.ニチシノンの HT-1 患者に対する有効性および安全性を検討した試 験である NTBC(2-[2-nitro-4-(trifluoromethyl)benzoyl] cyclohexane-1,3-dione)試験において,ニチシノンは HT-1 に特徴的な生化学的パラメータに加え,死亡,肝 移植,肝細胞がん,および急性ポルフィリン症等の HT-1 の臨床的転帰を改善した.NTBC試験で最もよ く報告された有害事象は眼障害であり,ニチシノンの 薬理作用によって生じる血漿中チロシン濃度の上昇に よるものである可能性が考えられた.眼症状の発現確 率とチロシン最高血漿中濃度との間に有意な相関が認 められたことから,チロシンおよびフェニルアラニン を制限した食事療法との併用により血漿中チロシン濃 度を低く保つ必要がある.また,NTBC試験および欧 米での市販後成績から,ニチシノン投与に関連すると 考えられる重篤な有害事象はほとんど報告されていな く,忍容性は良好であると考えられた.

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.

Evaluation of the effect of lanthanum carbonate hydrate on the pharmacokinetics of roxadustat in non-elderly healthy adult male subjects

Roxadustat is a hypoxia‐inducible factor prolyl hydroxylase inhibitor currently being investigated for the treatment of anemia in chronic kidney disease. Lanthanum carbonate is a phosphate binder that is commonly used to treat hyperphosphatemia in patients with chronic kidney disease. This study investigated the effect of lanthanum carbonate on the pharmacokinetics, safety and tolerability of a single oral dose of roxadustat in healthy non‐elderly adult male subjects.