Transcript Clinical Pharmacokinetics of VANCOMYCIN

Clinical Pharmacokinetics of
VANCOMYCIN
Mohd Bin Makmor Bakry, PhD, RPh
Senior Lecturer in Clinical Pharmacy
Faculty of Pharmacy
Universiti Kebangsaan Malaysia
Kuala Lumpur
INTRODUCTION
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Inhibits bacterial cell wall synthesis
Time-dependent effect
Gram positive bacteria
Indications :
• Documented infections:
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Methicillin/Cephalosporin-Resistant Staphycoccal infection.
Penicillin/Cephalosporin-Resistant Streptococcal infection.
Staphy./Strep. infection in patient allergic to penicillin.
Staphy. infection in patient with renal disease undergoing
hemodialysis.
• Penicillin-Resistant Diphtheroid infection.
• Severe antibiotic-associated enterocolitis.
• Indications (cont’) :
• Empiric Therapy:
• Suspected MRSA nosocomial infection.
• Meningitis in patient who had neurosurgery.
• Neutropenic febrile patient not responding or allergic to
penicillin.
• Suspected Staphy. infection in patient with renal disease
undergoing hemodialysis.
• Prophylaxis:
• Endocarditis in patient allergic to penicillin.
• Prosthetic valve placement in patient allergic to
penicillin.
ADVERSE DRUG REACTION
• Ototoxicity (tinnitus, fullness in the ear)
• Nephrotoxicity
• An increase in SrCr of 0.5mg/dL or greater, or as 50% increase
from baseline.
• Occurs at a rate of 5% with Vancomycin alone and increase to
22% with addition of Aminoglycosides.
• Red-Man Syndrome (hypotension, upper body
maculopapular rash)
• Cutaneous reaction (urticaria, angioedema, erythema)
• Neutropenia (within 15 – 30 days of drug initiation)
• Fever
PHARMACOKINETIC CHARACTERISTICS
• Two- or three-compartment model.
• Bioavailability
• Per oral < 5%
• Intravenous 100%
• Protein binding 30 – 55%
• Excretion
• Renal: >90% unchanged in urine
KEY PARAMETERS
• Ctarget
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F
Vd
CLVanco
t½
Ke
P = 40 – 50 mg/L
T = 10 – 15 mg/L
Continuous infusion Cavess = 12 – 18 mg/L
<0.05 PO
0.7 (0.5 – 1.0)
(L/kg)
0.65CLCr x 0.06
(L/H)
7
(H)
0.00083(CLCr) + 0.0044
(H-1)
Conventionally
*CLCr in ml/min
INITIATING VANCOMYCIN
• Cultures
• Appropriate C&S obtain within 48hrs before
starting therapy.
• Antibiotic therapy modified (if necessary) within
24hrs of the C&S results.
• Renal Function
• Estimated CLCr within 24hrs of initiating therapy.
• Monitoring CLCr every 3 – 5 days during therapy.
INITIATING VANCOMYCIN (CONT’)
• Dosage Regimen & Monitoring Needs
• Conventional dosing
• Peak & Trough concentration method
• Continuous infusion
• Trough concentration method
INITIATING VANCOMYCIN (CONT’)
• Conventional Dosage Regimen
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Initial per dose is between 10 – 15 mg/kg body wt
Dosage interval based on estimated CLCr.
Rate of infusion not more than 20 mg/min.
Adjustment based on measured levels.
• Serum Drug Concentration
• Levels taken at steady-state.
• If stable renal function, repeat trough levels once a
week.
• Trough levels obtained if with other nephrotoxic drugs.
• Trough and peak levels obtained if:
• Not responding to therapy.
• Altered physiologic parameters
INITIATING VANCOMYCIN (CONT’)
• Continuous Infusion Regimen
• Infusion rate is based on estimated CLCr and
targeted Cavess (15 mg/L).
• Rate of infusion, Ro (mg/H)
Ro = CLvancoCavess
= VdKeCavess
• Adjustment based on measured Cavess
• Lake’s Method
INITIATING VANCOMYCIN (CONT’)
• Target serum levels:
T = 5 – 10 mg/L (30 min before the next infusion)
P = 20 – 30 mg/L (15 min after the end of infusion)
• Maintenance dose (per dose) = 8 mg/kg (LBW)
• To be give at Q H interval:
CLCr (ml/min)
 (H)
>90
6
70 – 89
8
46 – 69
12
30 – 45
18
15 – 29
24
INITIATING VANCOMYCIN (CONT’)
• Rodvold’s Method
• Target serum levels:
T = 5 – 10 mg/L (30 min before the next infusion)
P = 30 – 40 mg/L (15 min after the end of infusion)
• Daily maintenance dose
Dose (mg/kg TBW per 24H) = (0.227(CLCr) + 5.67
• Interval:
CLCr (ml/min)
>65
46 – 65
20 – 39
10 – 19
 (H)
8
12
24
48
ADJUSTING THE DOSAGE REGIMEN
ln Cp
Cmax
Cpostdos
Ct,max
e
C*predose
ti
C*

Cmin
t
ADJUSTING THE DOSAGE REGIMEN (CONT’)
• Sawchuck-Zaske Method
(Conventional/Multiple short infusion)
• Determine the t½
Ke = ln (Cpeak/Ctrough) / (ttrough – tpeak)
t½ = 0.693 / Ke
• Determine the Vd
Vd = Ro x
1 – e-Keti
.
Ke (Cmax – (Cmine-Keti)
*Ro = mg/H infusion
• Determine the new
new = ln (Cmax desired / Cmin desired) + ti
Ke
ADJUSTING THE DOSAGE REGIMEN (CONT’)
• Sawchuck-Zaske Method (cont’)
• Determine the Ronew ()
Ronew = Ke Vd Cmax desired x 1 – e-Ke
1 – e-Keti
• Predict Ct,max at t after the end of infusion and Cmin
Ct,max = Ro x
1 – e-Keti
x e-Ket
Ke (Cmax – (Cmine-Ke)
Cmin = Ct,maxe-Ke( - (ti – t)
ADJUSTING THE DOSAGE REGIMEN (CONT’)
• Continuous Infusion Method
• Determine the CLvanco
CLvanco* = Ro / achieved Cavess
• Determine the new Ro (mg/H)
Ro = CLvanco* x targeted Cavess
EXAMPLE OF CASES
CASE 1
• Mr. AD, 62 years old patient was diagnosed to
have MRSA and allergic to penicillin, Body
weight is 98 kg and height is 165 cm.
Lab results: SrCr 95 mol/L, Urea 8.5
Suggest the best Vancomycin dosage regimen to achieve
Cpeak = 40.0 mg/L and Ctrough = 10.0 mg/L.
Estimate the dose to be given through continuous
infusion, Cp = 15 mg/L
CASE 2
• Mrs. PS, 55 years old patient was diagnosed to
have MRSA sepsis. Body weight is 85 kg and
height is 170 cm.
Given Short Inf. for 0.5H Vancomycin 500 mg Q8H
Lab results: C&S S. aureus., SrCr 150 mol/L, Urea
9.2, Cpeak = 40 mg/L, Ctrough = 24.0 mg/L
Adjust the Vancomycin dose regimen to achieve
Cpeak = 40.0 mg/L and Ctrough = 10.0 mg/L.
CASE 3
• Mrs. SP, 40 years old patient was diagnosed to
have endocarditis and allergic to penicillin.
Body weight is 45 kg and height 165 cm.
Given Short Inf. for 1H Vancomycin 750 mg Q12H
Lab results: C&S S. aureus., SrCr 120 mol/L, Urea
9.0, Cpeak = 30 mg/L, Ctrough = 22.0 mg/L
The doctor would like to change the method of
administration to continuous infusion for 24 hours
and targeted Cp = 15mg/L.
Suggest new dosage regimen to reach this later target
and when to start this new regimen?
CASE 4
• Mr. IZ, 50 years old patient was diagnosed
with CoNS and allergic to penicillin. Body
weight is 60 kg and height 150 cm.
Given continuous infusion of Vancomycin 80 mg/H
Lab results at day 3: SrCr 200 mol/L (120 mol/L
at D1), Cave = 26.0 mg/L
The doctor would like to change the method of
administration to conventional method and targeted
Ctrough = 10 mg/L.
Suggest new dosage regimen to reach this later target
and when to start this new regimen?
THANK YOU