BASIC TDM
Aminoglycoside & Vancomycin
台大醫院藥劑部 吳建志藥師
2015/10/19
療劑監測 TDM
THERAPEUTIC DRUG MONITORING
Drug Concentration
Pharmacodynamics Clinical Pharmacology
Optimize Drug Therapy
Minimize possible toxicity
Increase therapeutic effect
Therapeutic Drug Monitoring
(TDM)
哪些藥品需要做TDM?
(1)藥物血中濃度與臨床療效具相關性
(2)藥物劑量與血中濃度相關性差,相同劑
量在不同個體的血中濃度差異很大
(3)治療範圍狹窄(narrow therapeutic
range drug: digoxin, theophylline,
phenytoin..)
Therapeutic Drug Monitoring
(TDM)
哪些藥品需要做TDM?
(4)藥物血中濃度與毒性相關
(5)療效(therapeutic effect)不易測量
(6)臨床上有經濟可靠且精確的測量方式
(HPLC, GC, 免疫螢光法)
Therapeutic Drug Monitoring
(TDM)
何種情況藥師應該建議醫師做TDM?
(1)懷疑病患遵醫囑性不佳
(2)藥物之臨床反應不理想時
(3)當病患出現該藥物之毒性症狀時
(4)藥物代謝個體差異性大,劑量決定不易時
(5)因疾病狀態改變(腎衰竭、肝衰竭等)導
致藥物代謝排除改變
Therapeutic Drug Monitoring
(TDM)
何種情況藥師應該建議醫師做TDM?
(6)不同劑型可能導致生體可用率(BA)不同
(例如：毛地黃更換廠牌時)
(7)懷疑發生藥品交互作用時
(8)改變服藥劑量、劑型或給藥途徑時
Therapeutic Range
~ Applied Pharmacokinetics＆Pharmacodynamics 2006
Drug Lists for TDM in NTUH
Aminoglycosides (gentamicin, amikacin)
Vancomycin
Antiepileptics (phenytoin, valproic acid,
phenobarbibal, carbamazepine)
Digoxin
Lithium
Immunosupressants (cyclosporin, tacrolimus,
sirolimus, everolimus)
Theophylline
Methotrexate
Aminoglycoside
Aminoglycoside Antibiotics
Gentamicin
Amikacin
Streptomycin（TB）
TDM not available in NTUH
Neomycin（topical use only --- pre-surgical gut
sterilization, treatment of hepatic encephalopathy,
ophthalmic infections, bladder irrigation.）
Target Peak/Trough
Gentamicin Amikacin
Peaks (mg/L) for efficacy, 30 mins after
infusion. 2hr for ESRD and ODD
Viridans streptococcal or enterococcal 3-4
endocarditis
Serious infections 6-8 20-25
Life-threatening 8-10 25-30
Troughs (mg/L) for toxicity, before next
dose
Viridans streptococcal or enterococcal ~0
endocarditis
Serious infections 0.5-1 1-4
Life-threatening 1-2 4-8
Sampling Time
Steady State (treatment with a constant
dose over at least 4 half-life) 一般而言，維
持劑量給 4-5 doses 後可達穩定狀態
Peak : 30mins after the infusion
completion (infusion time usually 30mins)
For ESRD and ODD patients: 2hrs after end of
infusion
Trough: Just before next dose
Record Exact Time！！
Steady state (1)
Rate of drug going in = rate of drug going
out
Cmax2 = Cmax1 + Cmax1*e-kτ
Cmaxn = Cmax1 [1+e-kτ +e-2kτ +….e-(n-1)kτ]
Cmaxn = Cmax1*(1-e-nkτ)/ (1-e-kτ )
How many time needed to reach 95% Css?
0.95Cmax1/ (1-e-kτ ) = Cmax1*(1-e-nkτ)/ (1-e-kτ )
e-nkτ = 0.05
nτ = 4.32 t1/2
Steady state (2)
Half life Steady state concentration reached (%)
1 50
2 75
3 87.5
4 93.75
5 96.875
6 98.4735
7 99.25
For practical purposes, steady state will be reached after 4-5 dose
(if dosing interval ~ half life).
Empirical Dosing Method
Adults
NTUH Formulary 2013 p.442-444
Loading dose: use IBW, if obese patient use
Adjusted BW= (IBW+0.4(TBW-IBW))
Note: Modified Cockcroft and Gault
equation
40< CLCr < 80, dose with q12h frequency
CLCr < 40, dose with q24h frequency
Supplemental dose for patient under
dialysis
Body Weight used for LD and Vd
TBW< IBW ，use TBW
TBW> 130% IBW (obesity)，use adjusted BW
IBW<TBW<130% IBW，use IBW
Ideal body weight (IBW) For Orientals (東方人)
Male IBW (in kg) = (Ht (cm) - 80)x 0.7
Female IBW (in kg) = (Ht (cm) -70) x 0.6
Obesity: TBW>130% IBW or BMI>30
BMI= weight (kg)/( Height(m))2
Adjusted BW= IBW + 0.4(TBW-IBW)
(used for LD and Vd)
Empirical Dosing Method
Not use for pediatrics,
patients under HD, PD
Sarubbi FA et al. Ann Intern Med 1978; 89: 612-618
Empirical Dosing Method
Pediatric dosage
Gentamicin, Tobramycin
Loading dose: Neonates, Infants 3-5 mg/kg
Maintenance dose:
Neonates:
Premature neonate (<38 weeks), <1000g: 3.5 mg/kg/dose q24h
Postnatal age 0-4 weeks, <1200g: 2.5 mg/kg/dose q18-24h
Postnatal age < = 7 days: 2.5 mg/kg/dose q12h
Postnatal age > 7 days: 1200-2000g: 2.5 mg/kg/dose q8-12h
> 2000g: 2.5 mg/kg/dose q8h
Infants and children: 2.5 mg/kg/dose q8h
~ Pediatric dosage handbook 15th
PK parameter dosing method
Volume of distribution
Vd=0.26L/kg x LBW
For obese patients
Vd=0.26L/kg x [LBW + 0.4 (TBW-LBW)]
For third spacing
Vd=0.26L/kg x dry weight + xs. Fluid in Kg
Elimination rate constant
K(hr-1)=0.00293xCLCr(ml/min)+0.014
CL = K*Vd
First Order Kinetic –Bolus Model
Prediction of Cpeak and Ctrough
After LD
Cp0= D /Vd
Cpt= Cp0 x e-kt = D x e-kt /Vd
Steady State
Cp0 =D/[Vd(1-e-kt)]
Cpt = Cp0 x e-kt = D x e-kt /[Vd(1-e-kt)]
Css peak= Cp0 x e-kt ( t=1)
Css trough=Cp0 x e-kt
ln C
t=0 t=peak t=trough
First Order Kinetic –Infusion Model
Prediction of Cpeak and Ctrough
After LD
Cp0= R(1-e-ktin) /Cl = D(1-e-ktin) /(tin x Cl)
Cpt =Cp0 x e-kt = D(1-e-ktin) e-kt/(tin x Cl)
Steady State
Cp0= D (1-e-ktin )/[tin x Cl(1-e-kt)]
Cpt=Cp0 x e-kt=D(1-e-ktin)x e-kt /[tin x Cl(1-e-kt)]
Css peak= Cp0 x e-k(1-tin)
Css trough=Cp0 x e-k(t-tin)
Cp0
ln C
tinf t0 tpeak ttrough
Estimate of AUC
t’: infusion time
Ct: trough level
Ke: elimination rate constant
Ceoi’ = End of infusion level= Ct/e-k*(τ-t’)
Τ = dosing interval
Advanced Drug Delivery Reviews 2014;77:50–57
Pharmacokinetic method
First order kinetic, one compartment model
If infusion time < 1/6 x t1/2
bolus model
If infusion time > 1/2 x t1/2
infusion model
If 1/6 x t1/2 < infusion time < 1/2 x t1/2
bolus model or infusion model
Practical points
隨時follow病人的感染情況及腎臟功能 (BUN/Scr,
U/O etc.).
預期使用超過五天以上,或臨床上有腎衰竭可能(休
克)，務必請醫師抽血檢查.
注意peak level 是否足夠
不要因為trough 太低而提高劑量或縮短frequency
不要隨便請醫師重抽血
注意臨床情況勝過你的計算
報告請填寫完整
TDM計算原則
Empirical 估計濃度
CLCr
Vd
K
有實際抽血濃度 (C1, C2)
K
Vd (bolus model)
K x Vd = Cl
Once Daily Aminoglycoside Dosing
(ODD)
Rationale
Concentration-dependent bactericidal
activity
Post-antibiotic effect (PAE)
Prevent adaptive resistance
Reduce nephrotoxcity and ototoxicity
Once Daily Aminoglycoside Dosing
(ODD)
Rationale
Concentration-dependent bactericidal
activity
Administration of large doses would produce
higher peak drug concentration needed to
maximize the rate of bactericidal activity
( Cmax /MIC ratio of at least 8:1 to 10:1) and
more rapid killing action.
Once Daily Aminoglycoside Dosing
(ODD) - PAE
Maintain efficacy as concentrations fall
below the MIC.
In vivo, PAEs of 2 to 7 hours have been
observed in neutropenic and 9 to 13
hours in normal individual.
The higher concentration, the longer of
PAE
PAE was not seen for S. pneumonia
ODD – clinical use suggestion
Freeman C.D. et al. Journal of Antimicrobial Chemotherapy (1997) 39, 677–686
ODD dosing method
Method 1
Sum of divided dose
Gentamicin 1.7mg/kg q8h = 5 mg/kg q24h
Amikacin 7.5mg/kg q12h = 15 mg/kg q24h
Higher dose (25mg/kg) needed for severe sepsis and
septic shock patients Critical Care 2010;14:R53
Pros and cons
Pros: Low trough (< 1 mg/L) is expected
Cons: peak may not achieve target goal (gentamicin:
16-24mg/L) in patients with increased Vd (critically ill
patient)
Method 1
Dosing by actual body weight, if TBW > 135% IBW, use adjusted BW = (IBW+0.4*(TBW-IBW))
Method 1
Question
Gentamicin/Amikacin MIC breakpoint：4/16
Cpeak need at least 32/128 mg/L, almost 100%
nephrotoxicity occurred.
MIC: 0.5 mg/L V.S 1mg/L
Clinical Infectious Diseases 2007; 45:753–60
Method 2 - Nicolau’s nomogram
Gentamicin 7 mg/kg
Dosing by actual body weight, if TBW > 120% IBW, use adjusted BW
= (IBW+0.4*(TBW-IBW))
Nicolau DP et al. Nomogram for gentamicin
Nomogram for Amikacin from Washington
University
ODD Monitoring
Obtain 6-14 hour post dose level (1st dose) to
decide adequate dosing interval
• Then f/u trough concentration at steady state,
often undetectable (<1 mg/L)
If Vd↑or pathogen has higher MIC (gentamicin
≧2mg/L, Amikacin≧8mg/L), f/u peak level is
necessary (2hrs post-infusion)
Vancomycin
PK parameters
Poor absorption
Vd:0.7 L/kg
↑in critically ill, renal failure
Protein binding ~ 50%
T1/2: 5-11hrs, prolong when renal failure
ESRD: 200-250 hrs
~80-90% excrete by kidney
PK/PD
AUC/MIC > 400
AUC = D/{[(CLCr*0.79)+15.4]*0.06}
Only for stable renal function (SCr increase < 0.2 mg/dL)
Clin Pharmacokinet 2004;43:925-42.
Moise-Broder PA, Clin Pharmacokinet 2004; 43 (13): 925-942
Empirical dosing method (1)
LD: 15~25 mg/kg, based on TBW
25 mg/kg should be used for severe sepsis
MD: 30-60 mg/kg/day in q8-12h interval
Adjusted dose according to renal function
If U/O increase, may need higher dose
Ex. Mannitol use simultaneously
PK parameter dosing method
(Bauer’s method)
• Volume of distribution
Vd(L)= 0.7*TBW
If obese, Vd(L)= 0.7*IBW*30/25
• Clearance
CL(L/hr)= [(0.695*CLCr (mL/min/kg) ) +0.05]*BW*60/1000
• K = CL/Vd
Trough goal: 10-20 mg/L
Vancomycin Nomograms
Source Dose Interval
Package insert 500 mg Q 6 hrs
1 gram Q 12 hrs
Nielson LD = 25 mg/kg Not specified
MD = [(15 x CrCl) + 150]
mg/day
Rotschafer 6.5-8 mg/kg Q 6-12 hrs
Moellering See nomogram See nomogram
Matzke LD = 25 mg/kg, MD = 19 mg/kg See nomogram
Lake & 8 mg/kg CrCl Interval
Peterson 90 and above 6 hrs
70 to 89 8 hrs
46 to 69 12 hrs
30 to 45 16 hrs
15 to 29 24 hrs
Empirical dosing method in NTUH
Rodvold et al.
Dose (mg/kg/24hr)* = 0.227*CLCr + 5.67 (CLCr: mL/min/70kg)
CLCr-males (mL/min/70 kg) = (140- age)/Scr
CLCr-females (mL/min/70 kg) =0.85×CLCr-males
Dosing interval
CLCr (mL/min/70kg) τ(h)
>65 8
40-65 12
20-39 24
10-19 48
* 將算出的每日劑量隔日給予
Target Ctrough = 5-10 mg/L
Rodvold et al. Antimicrob Agents Chemother 1988;32(6):848-52.
Question：how is the accuracy?
Rodvold method
Target trough (10 – 15 mg/L)
< 30% can achieve this goal
Unstable renal function – 22.2%
CLCr ~ 10-30 mL/min – 12.5%
CLCr > 30 mL/min – 28.2%
Bauer’s method
Target trough (10 – 20 mg/L)
Match of prediction and true trough level ~ 50%
• When SCr < 0.5, only ~ 25%
Closely monitor vancomycin level is mandated.
It is not possible to use one equation to apply to all patient population
陳淑君等臺大醫院住院病人使用萬古黴素 (vancomycin) 起始給藥方法之評估及藥物動力學參數之分析
Empirical dosing in renal failure
HD : 20 mg/kg LD, then 7-8 mg/kg TIW after each
dialysis
CVVH：LD, then 10-15mg/kg q24-48h
NTUH experience:7.5mg/kg q12h
Depends on ultra-filtration rate, AK material, residual
renal function
PD：LD, then 500-1000 mg q48-72 hr
CAPD-related peritonitis: 15-30mg/kg q5-7D IP
Stamatakis MK. et al. Am J Health-Syst Pharm. 2003; 60:1564-8
Pai AB. et al. Am J Health-Syst Pharm. 2004; 61:1812-6
Ariano RE. et al. Am J Kidney Dis. 2005;46:681-687.
Vandecasteele SJ. et al. Clinical Infectious Diseases 2011;53(2):124–129
Piraino B. et al. Perit Dial Int. 2005 Mar-Apr;25(2):107-31
Vancomycin empirical dosing
Pediatric dosage
Maintenance dose:
Neonates:
Postnatal age < = 7 days:
<1200g: 15 mg/kg/dose q24h
1200-2000g: 10-15 mg/kg/dose q12-18h
>2000g: 10-15 mg/kg/dose q 8-12h
Postnatal age > 7 days:
<1200g: 15 mg/kg/dose q24h
1200-2000g: 10-15 mg/kg/dose q8-12h
>2000g: 15-20 mg/kg/dose q8h
Infants and children: 40 mg/kg/day in divided doses
every 6-8 hours (Staphylococcal CNS infection: 60mg/kg/day)
~ Pediatric dosage handbook 15th
Target levels
Steady state
> 5 half life, usually after 4th dose
Peak: 18-26 mg/L (2 hour after end of infusion)
Not related to efficacy and toxicity
Routinely following peak level was not recommended
now except individual PK parameter are needed. (burn,
acute renal failure, obese etc.)
Trough: 10-20 mg/L (just before next dose)
According to MRSA MIC and infection site
15-20 mg/L for MRSA MIC >= 1mg/L, osteomyolitis,
endocarditis, pneumonia, meningitis etc.
IF MRSA MIC>= 1.5 mg/L, shift to other antibiotics
ESRD
Check pre-dialysis level before 3rd hemo-dialysis
Am J Health Syst Pharm 2009;66:82-98.
Distribution phase
Overestimated elimination rate
Trough concentration vs. outcome
Clinical Infectious Diseases 2011;52(8):975–981
Role of vancomycin TDM
Monitoring of serum levels in following situations
Patients at higher risk of nephrotoxicity
Patients receive vancomycin/ aminoglycoside combo
Anephric patients undergoing hemodialysis receive
infrequent doses of vancomycin
Rapid changing of renal function
Deteriorated
Improved
When patients receive aggressive dosing
higher-than-usual doses of vancomycin
Prolonged courses of therapy
Rybak M, et al. Am J Health-Syst Pharm 2009;66:82-98. Levine DP. CID 2006;42:S5-12.
Rybak MJ. CID 2006;42:S35-9. Cantu TG, et al. CID 1994;18:533-43. Moellering RC, CID
1994;18: 544-6.
Monitoring Frequency
Treatment course 5 days:
At least 1 steady state trough concentration
Repeated as clinically appropriate
Target trough concentrations 15~20 mg/L
Limited data supporting the safety of sustained
trough concentrations of 15–20 mg/L
Hemodynamically stable patients: qweek
Hemodynamically unstable: more frequent or daily
trough
Rybak M, et al. Am J Health-Syst Pharm 2009;66:82-98.
Reference Books
臺大處方集-2013年版（附錄704~719）
Bauer LA. Applied Clinical Pharmacokinetics. 2008
Schumacher GE. Therapeutic Drug Monitoring. 1995
Winter ME. Basic Clinical Pharmacokinetics. 5th ed. 2010
Evans WE. Applied Pharmacokinetics &
Pharmacodynamics: Principal of Therapeutic Drug
Monitoring 4th ed. 2006
Dipiro JT. Concepts in Clinical Pharmacokinetics 5th ed.
2010.
Thank you for your attention
