従来，臨床には， 「薬のさじ加減」 ということばが ある．これは医師が薬の用量−反応関係を経験的に 取得し，個々の患者に対し適切な薬物選択と用量設 定を行うことを意味する．しかし，この方法は普遍 性に乏しく，black box が大きいため，危険性も潜 んでいる．近年，薬の適正使用が唱えられ，各患者 に応じた個別化治療を行うことが，有効性のみなら ず安全性のうえで欠かせないとされる．その手段と して，各患者における生体内での薬物の動きと効果 を理解することは重要である． 薬物動態学とは 薬物の生体内での流れ・運命を薬物動態という． 生体内に薬を投与すると，吸収・分布・代謝・排泄 を経て除去される．この過程で薬の一部が作用部位 に到達し，薬物受容体と結合し，薬理効果が出現す る．体液中の薬物濃度の時間的推移を速度論的に解 析し，薬物の生体内動態を研究する領域を薬物動態 学 （pharmacokinetics） と呼ぶ．一方，薬物が受容体 と結合し，薬理効果が出現するまでの領域を薬力学 （pharmacodynamics） と呼び，薬物動態学と作用部 位における薬物濃度によって密接にかかわってい る．個々の薬物反応には年齢，性別，遺伝的差異， 環境因子，食事，生活習慣，基礎疾患，併用薬など 様々な因子が薬物動態および薬力学の双方を介し て影響する． 薬物血中濃度モニタリング 抗不整脈薬は強力な薬理作用を有している反面， 重篤な副作用も合わせもっており，単なるさじ加減 では管理が難しい面がある．このため抗不整脈薬の 分野では，ジゴキシン，キニジンに代表されるよ うに古くから薬物動態の検討が行われ，薬物血中 濃度モニタリング （Therapeutic Drug Monitoring : TDM） を治療に応用してきた 1） ． 尿中未変化体排泄率の高い （腎排泄型） 薬は，腎機 能の変化で容易に血中濃度が変わる．一方，肝代謝 型の薬は代謝酵素活性の個人差に左右される．チト クロム P450 （CYP） 2D6 で代謝されるアプリンジン やプロパフェノン，ベプリジルは代謝能の飽和現象 から，用量と血中濃度は非線形関係にある．また， 複雑な薬物動態を特徴とするアミオダロンやベプリジ ルは， 同じ用量であっても個人あるいは投与期間によ り血中濃度は異なるため，TDM が必要とされよう． べプリジルは日本でのみ抗不整脈薬として使用さ れており，日本人における血中濃度と抗不整脈効果 や安全性に関する報告が出されている 2）-6） ．これ らのデータを基に， ベプリジルの治療域濃度は 250-800 ng/ml とされた．また，そのクリアランスは低 体重や加齢とともに低下することが示されており， 高齢者での低用量化が求められる． 7）, 8） P-糖蛋白の問題 P-糖 蛋 白 は， ア デ ノ シ ン 三 リ ン 酸 （adenosine triphosphate : ATP） に依存して有害物質 （陽イオン 東京女子医科大学循環器内科 志賀 剛

SummaryDabigatran etexilate is an oral, reversible direct thrombin inhibitor that is approved in the EU and several other countries for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for other thromboembolic disorders. Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for routine coagulation monitoring. In certain clinical situations such as serious bleeding into critical organs (e.g. intracerebral bleeding), potential overdose and emergency surgery, clinicians will need to make an assessment of the anticoagulant status of a patient receiving dabigatran before deciding on future management strategies. If available, thrombin clotting time (TT), ecarin clotting time (ECT) and TT determined by Hemoclot ® thrombin inhibitor assay are sensitive tests to evaluate the anticoagulant effects of dabigatran. Prothrombin time (INR) is less sensitive than other assays and cannot be recommended. The activated partial thromboplastin time (aPTT) can provide a useful qualitative assessment of anticoagulant activity but is less sensitive at supratherapeutic dabigatran levels. There are limited data for activated clotting time (ACT). Overall, the aPTT and TT are the most accessible qualitative methods for determining the presence or absence of anticoagulant effect. Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. In case of potential overdose, the feasibility of early administration of activated charcoal and subsequent charcoal filtration are undergoing preclinical evaluation. Dabigatran can also be dialysed in patients with renal impairment. In instances of life-threatening bleeding, where conventional measures have failed or are unavailable, other non-specific prohaemostatic agents such as recombinant activated factor VII and prothrombin complex concentrates can be considered.

pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial.J Thromb Haemost 2011; 9: 2168-75.Summary. Background: Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity. Objectives: To characterize the pharmacokinetics of dabigatran in patients with non-valvular atrial fibrillation (AF) from the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters. Patients and methods: A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non-linear mixed-effects modeling. Results: The pharmacokinetics of dabigatran were best described by a twocompartment disposition model with first-order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup ÔSouth AsianÕ exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton-pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15-30 mL min )1 and patients with normal renal function receiving 150 mg twice daily. Conclusions: The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE-LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment.

Background-Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran etexilate and influence the safety and efficacy of dabigatran. Methods and Results-We successfully conducted a genome-wide association study in 2944 Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) participants. The CES1 single-nucleotide polymorphism rs2244613 was associated with trough concentrations, and the ABCB1 single-nucleotide polymorphism rs4148738 and the CES1 singlenucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (P<9×10 ) in dabigatran-treated participants, with a consistent but nonsignificant lower risk of major bleeding (odds ratio, 0.66; 95% confidence interval, 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002), with carriers having less bleeding with dabigatran than warfarin (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P=5.2×10 − 5) in contrast to no difference in noncarriers (hazard ratio, 0.96; 95% confidence interval, 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events. Conclusions-Genome-wide association analysis identified that carriage of the CES1 rs2244613 minor allele occurred in 32.8% of patients in RE-LY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600. (Circulation.

Background-Norepinephrine transporter (NET) inhibition increases the responsiveness to vasoactive medications and attenuates the response to sympathetic stimuli. The phenomenon may be a result of impaired regulation of sympathetic vasomotor tone. Methods and Results-We studied the effects of the selective NET blocker reboxetine and placebo on baroreflex control of heart rate (HR) and sympathetic traffic in a randomized, double-blind, crossover manner in healthy subjects. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. ECGs were measured for HR, brachial and finger blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Sympathetic and parasympathetic baroreflex slopes were determined by use of incremental phenylephrine and nitroprusside infusions. The dose to reach BP changes of 12.5 mm Hg was significantly lower during NET inhibition (0.25 versus 0.64 g · kg Ϫ1 · min

Dabigatran, administered orally as the prodrug dabigatran etexilate (DE), is a direct thrombin inhibitor shown to be effective in the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The aim of this analysis was to derive a modeling and simulation-based dose and dosing regimen for AF patients with severe renal failure who could potentially benefit from the use of DE. The exposure was simulated for AF patients with severe renal impairment for several combinations of doses (75, 110, 150 mg) and posologies (BID, QD, Q2D). Simulations were based on a population pharmacokinetic model derived from data from 9522 patients from the pivotal phase III study (RE-LY). Atrial fibrillation patients with a creatinine clearance (CRCL) of <30 to ≥15 mL/min treated with a dose of 75 mg DE BID have target plasma level and exposure data largely within the concentration range proven to be safe and effective in AF patients with CRCL >30 mL/min receiving 150 mg BID. This dosing algorithm was also confirmed and supported by the United States Food and Drug Administration Clinical Pharmacology Division using their model based on the data from the dedicated renal impairment study and taking into account the safety and efficacy information from RE-LY.

No abstract

Changes that accompany older age can alter the pharmacokinetics (PK), pharmacodynamics (PD), and likelihood of adverse effects (AEs) of a drug. However, older adults, especially the oldest or those with multiple chronic health conditions, polypharmacy, or frailty, are often under‐represented in clinical trials of new drugs. Deficits in the current conduct of clinical evaluation of drugs for older adults and potential steps to fill those knowledge gaps are presented in this communication. The most important step is to increase clinical trial enrollment of older adults who are representative of the target treatment population. Unnecessary eligibility criteria should be eliminated. Physical and financial barriers to participation should be removed. Incentives could be created for inclusion of older adults. Enrollment goals should be established based on intended treatment indications, prevalence of the condition, and feasibility. Relevant clinical pharmacology data need to be obtained early enough to guide dosing and reduce risk for participation of older adults. Relevant PK and PD data as well as patient‐centered outcomes should be measured during trials. Trial data should be analyzed for differences in PK, PD, effectiveness, and safety arising from differences in age or from the presence of conditions common in older adults. Postmarket evaluations with real‐world evidence and drug labeling updates throughout the product lifecycle reflecting new knowledge are also needed. A comprehensive plan is needed to ensure adequate evaluation of the safety and effectiveness of drugs in older adults.