教案-藥物血中濃度監測服務（Therapeutic drug monitoring service） 呂宛真 台灣大學臨床藥學研究所碩士 台北馬偕醫院 臨床藥學組組長 內科加護病房臨床藥師

教案-藥物血中濃度監測服務（Therapeutic drug monitoring service） 藥物血中濃度監測服務(不包含sample processing)屬於 “住院藥局-臨床藥事服務” 項目之一 針對 ”住院藥局藥師” 設計一教案，用以完成藥物血中濃度監測服務之訓練及執行本服務之成果評估 可將此教案進一步modify, 用以培訓中階TDM專責藥師或助理臨床藥師

教案設計 1. 介紹此教案之目的、目標、教學對象（學生 背景）、教學時間與教材等基本設計 2. TDM教案之特點與設計理念 3. 教學活動與教學方法 4. 作業設計 5. 藥師執行本服務之能力與成果評估 6. 經驗分享, 討論實際執行此教案可能遭遇的 問題

TDM教案 課程: 住院調劑組臨床藥事服務 主題: 藥物血中濃度監測作業 相關領域 1. 臨床藥學及治療學 2. 生物藥劑學 (藥品動態學) 相關領域 1. 臨床藥學及治療學 2. 生物藥劑學 (藥品動態學) 教學對象: 住院藥局藥師 - 已熟悉住院藥局基礎調劑作業 - 已完成基礎處方審核訓練, 並能進行用藥建議 - 熟悉SOAP之格式與撰寫

TDM教案-2 教學時數: 1週 教師之教材準備 1. TDM 與 PK 之相關參考書 2. 上課講義與投影片 3. 虛擬案例 4. 實際範例與實際案例

TDM教案 學生之課前準備 1. 自處方集了解本院可進行TDM之藥物 品項, 建議之抽血時間及治療濃度範圍 2. 工程用電子計算機

教學目標 了解TDM藥事服務之目的與特點 了解醫院TDM藥事服務之內容與流程 了解並能應用個別TDM藥物之PK參數與特性 學習判讀, 評估藥物血中濃度之數值 學習以實際抽血值去計算病患個別之PK參數 整合臨床反應(療效與副作用評估)以及其他臨床狀況(交互作用或服藥順從性問題)作出建議 以SOAP方式呈現建議內容並與其他醫護人員溝通討論 需能獨立完成線上即時之TDM藥事服務

教學之困難處 由於可監測血中濃度之藥物品項眾多, 每個藥物的PK特性, 計算公式, 臨床反應之signs/symptoms, 合併複雜之臨床狀況(藥物交互作用, 服藥順從性, 抽血時間之誤差, 肝腎功能異常, 特殊病人群等), 要使學生在短時間內熟悉所有藥物實屬不易

教學目的與設計理念 此教案之設計理念在於使學生了解, TDM藥事服務不只是計算公式與判讀數值的大小, 在判讀數值之前, 收集必要的資訊, 並結合臨床反應做出的評估與建議, 才是真正TDM藥事服務的價值(treat the patient, not the value) 不用死背公式, 但必須知道如何自參考書中找到正確的公式與藥動學參數, 並能加以應用

課程與活動設計 TDM作業綜論與簡介 - 90分鐘 不曾修過藥物動力學的藥師 - 需事先閱讀基礎藥物動力學 - 1天 - ”藥物動力學與藥效學之臨床應用” - 2小時 - 接受口頭與書面測驗

課程與活動設計 四大類常見TDM藥物: 30-60 分鐘課程 + 120 分鐘實際演練: 虛擬個案計算 (2-4人一組, 由種子老師帶領計算與討論) 1. aminoglycosides and vancomycin 2. digoxin 3. theophylline 4. anti-convulsants: phenytoin, valproic acid, phenobarbital, carbamazepine

實際病案演練 小組中每位藥師, 需選擇不同的單一藥物, 以曾發生過之實際病案進行演練, 並以10分鐘case report之方式, 向同組其他藥師及種子老師呈現評估與建議結果 獨立完成現行實際案例 (至少應包含aminoglycosides, vancomycin, digoxin, theophylline, phenytoin各一例), 進行建議並以SOAP格式書寫建議內容

教學活動安排 Day 1: lecture: TDM總論 Day 2: lecture+ 虛擬案例計算

Day 1 目標: 1. 知道什麼是TDM藥事服務 2. 了解本院TDM藥事服務之內容與流程 教學活動: 2. 介紹處方集中 ”Guidelines to therapeutic drug monitoring” 之內容與用途 3. 示範本院TDM電腦系統之介面與作業方式 教具: 上課講義, 投影片, 處方集, 電腦 (院內醫療資訊 系統), 指定參考書

TDM作業綜論與簡介 – a brief review of pharmacokinetic parameters 台北馬偕紀念醫院 呂宛真

TDM作業之目的 運用PK之觀念與計算幫助臨床用藥決策 - decide an empirical dose - adjust dosage by serum level - deal with overdose - special population: obese, burned, pediatric, impaired renal / liver function - drug interactions

Interpretation drug concentration Data collection: S/S, lab data, drug Hx, dosing Hx Sampling time Steady-state - sample must be taken after S-S achieved? Compliance Sample Processing sampling error and Lab error Unreasonable value

Clinical Considerations: The necessity of dose adjustment - according to clinical results - lack of efficacy - r/o toxicity Treat the patient, not the value Concurrent disease state and medications

TDM 作業之執行 主動建議監測血中濃度 起始劑量估算與建議 檢測結果判讀與評估 -整合其他臨床狀況,檢驗數值,同時使 用之藥物,進行臨床決策與建議 以SOAP模式進行 醫師接受度與時效性

TDM 之計算 注意單位 工具書與公式的使用 Ref: 1. TDM therapeutic drug monitoring Schumacher GE 1995 2. Basic clinical pharmacokinetics 4th ed Winter ME

Day 2 / Day 3 目標: 1. 學習四大類藥物之TDM 2. 能運用正確的公式與PK參數來回答虛擬案例之問題 教學活動: 1. 課堂上課: 四大類藥物之TDM- 30-60分鐘 x 4 2. 120 分鐘實際演練 x 4: 虛擬案例計算 (2-4人一組, 每組一位種子藥師帶領討論與計算) 教具: 上課講義, 投影片, 處方集, 工程用電子計算機

Day 2 / Day 3 aminoglycosides and vancomycin digoxin theophylline anti-convulsants: phenytoin, valproic acid, phenobarbital, carbamazepine Day 2 早上: A 上課 + 虛擬案例計算 Day 2 下午: B 上課 + 虛擬案例計算 Day 3 早上: C 上課 + 虛擬案例計算 Day 3 下午: D 上課 + 虛擬案例計算

虛擬案例設計應含括 以文獻中PK parameters 來為病患決定最合適之初始劑量(如何計算 loading dose and maintenance dose), 並於何時建議抽血進行濃度監測 當得到藥物血中濃度值後, 能夠計算出病人實際的PK parameters, 並據此作劑量建議與調整 劑型轉換之案例 劑量過高或過低時之處理方式 藥品交互作用存在時或針對特殊病人群之計算

Day 4 目標: 1. 能夠蒐集必要之資訊, 完成一實際個案之TDM服務 2. 練習以SOAP方式呈現建議內容 教學活動: 1. 每位藥師分配不同之實際案例進行練習: 4 hrs 2. 用10分鐘向其他藥師報告你的SOAP與結論 3. 討論個案及實作練習中所遭遇之問題 教具: 實際案例, 處方集, 電腦, 指定參考書, 投影機/投影片/投影筆

Day 5 目標: 1. 需單獨完成2-3件當日實際個案, 用以評估個別藥師 執行TDM服務之能力與時效性 2. 能以SOAP方式完成建議並追蹤後續結果 教學活動: 1. 早上決定個案分配, 藥師必須進行資料收集, 必要時 可詢問護理人員或訪視病人 2. 下午檢驗值出來後, 須在30分至1小時內完成建議 3. 與種子藥師討論建議內容並加以修改 4. 與醫師討論評估結果, 並將建議內容以SOAP方式書 寫於病歷上 5. 追蹤醫師接受度與後續處置結果

Day 5 教具: 個案選定(病情複雜程度: 中~高等), 處方集, 電腦 (院內醫療資訊系統), 病房病歷, 指定參考書

執行能力與服務成果評估 能否運用公式並正確計算(虛擬案例練習): 15% 實際個案之演練與報告: 15% 完成現行之TDM個案: 70% 1. 以check list 逐項評估 2. 專業態度與溝通技巧 3. 相關知識與技能之評估: 包括對疾病治療之認 識, lab data及相關症狀之判讀 4. SOAP之撰寫

Check list Subjective data / Objective data: - 病患基本資料, 肝腎功能, 現有疾病/診斷 - 使用此藥物之適應症, 用法, 用量及用藥史 - 病患進行血中濃度監測之原因 Assessment - 是否已達穩定狀態 - 抽血時間點是否正確 - 如何校正血中濃度 - 藥動學之計算結果 - 評估藥物之療效或副作用 - 是否有其他潛在問題會影響藥物血中濃度值 Plan - 劑量調整建議 - 如何監測, 評估此一新劑量是否合適 - 是否需要訪視病患並加以衛教

附件 上課講義 - TDM作業綜論與簡介 - 四大類藥物之TDM 虛擬案例設計 - 四大類藥物之虛擬案例 (每類3-5個案例)

討論 經驗分享 將本教案modify, 用以培訓中階TDM專責藥師或助理臨床藥師: 1. 實務經驗之累積(要求至少完成15-20例TDM) 2. 特殊案例之訓練與經驗分享 3. 特殊藥物訓練: MTX, cyclosporine 實際執行此教案可能遭遇的問題

討論 特殊案例訓練與經驗分享 - 處理overdose及藥物交互作用 - 何時需考慮lab error - 未達穩定狀態或抽血時間點有誤所得到 之血中濃度應如何應用與判讀 - 洗腎病患(HD/CVVH), 燒燙傷病人, 早產/新生兒等特殊病人群

Theophylline 之藥物血中濃度監測 補充資料 Theophylline 之藥物血中濃度監測 台北馬偕紀念醫院 呂宛真

Mechanism of theophylline Methylxanthine Adenosine antagonist Non-specific inhibition of phosphodiesterase PDE type III and IV: relaxes smooth muscles in pulmonary arteries and airways PDE type IV: antiinflammatory and immunomodulatory actions

Clinical use: a third-line agent in asthma Additive maintenance therapy for asthma is not adequately controlled with ICS Better adherence to oral regimen Cheap Additive acute therapy for inpatients fail to respond to vigorous inhaled ß2-agonists and systemic corticosteroids (iv aminophylline)

Clinical use: a third-line agent in asthma Not recommended for treat acute exacerbation of asthma Not recommended for treat mild asthma Add on LABA in hospitalized patients

Aminophylline The more soluble ethylenediamine salt of theophylline (1% soluble in water) Loading dose of aminophylline: - 5-6 mg / kg (300-500 mg)

Maintenance dose of aminophylline Non-smoking adults 0.5 mg/kg/hour Smoking adult 0.875 mg/kg/hour Liver dysfunction, cor pulmonale, sepsis with organ failure, shock, CHF 0.25 mg/kg/hour (max 500 mg/d) Elderly (> 60 y/o) 0.375 mg/kg/hour

Theophylline Maintenance dose： - non-sustained-release: 300-600 mg divided in 3-4 times per day - sustained-release 200-400 mg bid

Dosage for oral theophylline Patient population MD (mg/kg/d) Premature infant or newborn to 6 wk (for apnea / bradycardia) 4 6 wk to 6 mo 10 Infants 6 mo to 1y 12-18 Young children 1-9 y 20-24 Older children 9-12 y 16 Adolescents 12-16 y 13 Adult smokers > 16 y Adult nonsmokers > 16 y Adults with HF or liver d’z > 16 y 5

Theophylline in neonatal apnea: LD: 5-6mg/kg MD: 1mg/kg q8h or 2-3mg/kg q12h Age of neonate Dosage postnatal age up to 24 d 1 mg/kg q12h postnatal age beyond 24 d 1.5 mg/kg q12h

PK of theophylline Absorption: BA > 90% Distribution: 40% protein binding, distribution phase 60 mins, dose not distribute to adipose tissue Metabolism and Elimination: - 5-15% unchanged form excreted in urine - primary metabolize by liver (CYP1A2)

PK parameters F = 1 S = 0.8-0.84 for aminophylline Vd = 0.5 L/kg (0.3-0.7 L/kg) 0.7 in premature newborns (<1y/o) 0.6 in cystic fibrosis (Obese: use IBW to calculating Vd ?)

Clearance of theophylline: Disease states influences -- 0.04 L/kg/hr based on IBW Disease Factor Smoking history (last 3 mon to 1 yr) 1.6 CHF (depends on severity) 0.5 Cystic fibrosis 1.5 Acute pulmonary edema Acute viral illness Hepatic cirrhosis Severe obstructive pulmonary disease 0.8 Obesity IBW

Clearance of theophylline: Drug interaction -- 0.04L/kg/hr based on IBW Drug Factor Cimetidine 0.6 Ciprofloxacin 0.7 Erythromycin 0.75 Phenobarbital 1.3 Phenytoin 1.6 Propranolol Rifampin

Clearance of theophylline: A 85kg patient (IBW=60kg) with CHF, smokes 1ppd and takes phenytoin for convulsion d’z concurrently Cl of theophylline = (0.04 L/kg/hr)(60)(1.6)(0.5)(1.6) IBW smoking CHF phenytoin

Clearance of theophylline: The prediction is uncertain when multi-factor exists Dosage adjustment should be guide by steady-state serum level

LD and MD Vd decide LD Cl decide MD (S) (F) (Loading dose)=(Cp desired) (Vd) (S) (F) (maintenance dose)/ = (Cl) (Css)

Dosage Adjustment In Renal Failure: No - mainly metabolized in the liver - 10 % excret unchanged in the urine In Hepatic Insufficiency : Yes - clearance  > 50% During Dialysis: dialyzable - non SR form:  150% dose once prior to H/D - SR form (q12h):  125% dose once prior to H/D

Therapeutic range: 5-15 mg/L The bronchodilating effects are proportional to log concentration Historic therapeutic range: 10-20 mg/L 5mg/L: improve respiratory function COPD: 8-15 to minimize S/E Apnea of prematurity (AOP): 6-14 mg/L Many p’ts are well controlled in 5-10 mg/L

Therapeutic range: 5-15 mg/L Peak or Trough plasma level ? Peak: 10-15 mg/L with a product or dosing interval that will not result in large fluctuation

Keep in Mind !! Serum level 5-10 ug/ml some patients will not have an adequate therapeutic effect Serum level > 15 ug/ml some patients may not get additional benefit

Toxic plasma concentration N/V: 13-15 mg/L, usually >20 mg/L Premature atrial / ventricular contraction: >40 mg/L Insomnia, nervousness: over a wide range Seizure: > 50 mg/L

Sampling time Take sample any time if r/o toxicity After first dose to calculate Vd in special population Distribution follows a two-component model C max: 1-2 hr after dosing in non-sustained-release form

Sampling time IV - intermittent iv: 30’ after loading - iv infusion: any time after 12-24 hr of inf. Oral Peak - rapid release: after 2 hr - sustained-release: after 4 hr Trough - rapid release: before next dose - sustained-release: trough or midpoint

Sampling time Time to reach S-S: 3-5* T1/2 T1/2: 8 hr in adults Smokers or drug interaction: 3-4 hr Severe CHF or drug interaction: 18-24 hr Obesity: > 8hr Adult and children 1-2 days Newborn or infant 5 days Premature neonate 6 days

T1/2 in different age and disease Patients T1/2 (hr) Premature infants 20-30 Children (1-17 yr) 3-4 Adults 8-10 Acute pul edema 19 Liver cirrhosis 32 Cystic fibrosis 6

Dose adjustment Serum level (ug/ml) Dose adjustment, (recheck level in 3 d ) 5-7.5  25 % dose 7.5-10  25 % dose only in symptomatic p’ts 10-20 No change, consider  dose if > 15 20-25  10-25 % dose 25-30 Hold one dose,  25 % dose >30 Hold two doses, consider activated charcoal,  50 % dose

Dose adjustment Dose is proportional to concentration Consider decrease dose when toxicity occurred, even serum level within therapeutic range T1/2 and theophyllin level decide the time needed for holding theophylline Re-start a new MD after level < 15 Recheck serum level after 3-5* T1/2

Calculation- step by step Decide a loading dose of iv aminophyllin 1. age, IBW (BH/TBW), smoking Hx, disease states, drugs Hx 2. Calculate Vd 3. Cpss=10=(loading dose)(S)(F)/Vd - usually no more than 500mg - infuse > 30min to avoid toxicity - obese patients?

Calculation: Decide a maintenance dose 1. Calculate Cl (K, T1/2) 2. (MD)(S)(F) / = (Cpss)(Cl) 3. calculate the daily dose of iv aminophylline switch to other dosage form decide the dose and interval 4. calculated Cmax, Cmin

(S)(F)(dose) Vd (1-e -k) Cpss max = Cpss min = (Cpss max)(e -k) (S)(F)(dose/) Cl Cpss ave =

Thank you for your attention and awaking ! !

Theophylline Q&A Q1. A 50 y/o male patient, 160cm/80kg, has severe COPD, CHF, smokes 1ppd, who presents at ER due to asthma attacking. We want to start iv aminophylline treatment Please calculate the loading dose of iv aminophylline Calculate MD of continuous infusion aminophylline When can we check serum level

a. IBW=(160-80)*0.7=56 80/56=143%, obese p’t LD: use TBW or IBW皆可, 以IBW較保守, 適合老年人 但也有研究指出以IBW會underestimated, 可2種方式都算 以TBW: 算法1: 5-6mg/kg=5*80=400mg 算法2: Vd=0.5*TBW=0.5*80=40L (Loading dose)=(Cp desired) (Vd)/ (S) (F) =10*40/1/0.8=500 以IBW算則為350mg 因病患有CHF, 一般LD不會超過500mg, infusion > 30min

b. Cl=0.04*IBW*CHF factor*smoking factor =0.04*56*1.6*0.5=1.792L/hr=43L/day (maintenance dose)/ = (Cl) (Css)/ (S) (F) MD/day=43*10/1/0.8=537.5mg/day, infusion 500mg over 24hr c. k=Cl/Vd=1.792/0.5*56=0.064/hr T1/2=0.693/0.064=10.8hr 約1.5-2 days達S-S

Q2. A 40 kg, 80y/o female patient received iv aminophylline 25mg/hr for 5 days. N/V, tachycardia attacked, theophylline serum level = 40mg/L now. How to deal with this p’t? Time needed of holding aminophylline Calculate a new MD of iv aminophylline Calculate a new MD using oral theophylline Predicted peak and trough level of above oral regimen When to recheck serum level

a. (S) (F) (maintenance dose)/ = (Cl) (Css) 0.8*1*25mg/hr=Cl*40mg/L Cl=0.5L/hr, Vd=0.5*40=20L k=0.5/20=0.025/hr, T1/2=0.693/0.025=27.7hr hold 2 days b. 25mg/hr level=40, if level=10, dose=25/4=6.25mg/hr c. 6.25*24=150mg/day aminophylline=120mg theophylline MD= SR theophylline(125mg) 1# QD

d. Cpss max =(S)(F)(dose)/(Vd )(1-e -k) Cpss min = (Cpss max)(e -k) Cpss max=1*1*125/20/(1-e-0.025*24)=13.88 Cpss min=13.88*e-0.025*24=7.62 (這是指non-sustained form, SR form的fructuation會更小) e. 3*27.7hr=3.5days

Q3. Dr. Lee prescribes a SR theophylline 300mg q12h for a 31y/o female p’t with asthma, her BW=60kg. A trough level 2 weeks after OPD is 10.9ug/ml, and she is asymptomatic. She was diagnosed as having TB and started INH 300mg/d and RIF 600mg/d. After 2 wks of TB therapy, this patient had an acute asthma attack and went to ER. Her serum theophylline level 6 hrs after her last dose is 2.4ug/ml. How to deal with this patient?

RIF使Clearance增加所造成的結果 可考慮re-load = (10-2. 4). Vd/S. F=7. 6(0. 5. 60)/1 RIF使Clearance增加所造成的結果 可考慮re-load = (10-2.4)*Vd/S*F=7.6(0.5*60)/1*1=228mg  give 250mg iv drip MD(Goal 5~10ug/ml): 600mg/2.4*(5~10)=1250-2500mg/day 漸進式增加劑量並監測血中濃度 600mg q12h600mg q8h 當TB用藥劑量改變或停藥時必須重新調整劑量

Q4. A 7 day-old premature neonate, BW=1402g, diagnosis: AOP Loading iv 7mg aminophylline, then 3mg q12h After 4 days, a blood sample of theophylline was taken at 10am to decide an optimal dose (administrated aminophylline at 9am to 9:30). The obtained serum level is 12.78 ug/dl. Do you think the LD and MD were suitable for this patient? How do we adjust the dose of aminophylline?

LD=5mg/kg=5*1.402=7mg MD=2-3mg/kg q12h=3-4mg q12h Vd=0.7L/kg in premature neonate=0.98L Peak = trough + (dose)(S)(F)/Vd 12.78 = trough + (3*0.8*1/0.98),  trough=10.33   Cpss max =(S)(F)(dose)/(Vd )(1-e -k) 12.78=[0.8*1*3/0.98(1-e –k*12)] * e –k*1