Aminoglycoside Pharmacokinetics Tom Johns, PharmD, BCPS Director, Pharmacy Services

Aminoglycoside
Pharmacokinetics
Tom Johns, PharmD, BCPS
Director, Pharmacy Services
UF Health Shands Hospital
Concentration-Dependent vs
Independent Bacterial Killing
Craig, et al Scand J Infect Dis, 1991;Suppl (74).
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Elimination
Eliminated primarily by glomerular
filtration in the kidney
 Half-life
 Adults: 2-4 hours
 Children: 0.5-2.5/Neonates: 2-9 hours
 Prolonged in renal insufficiency
 Removed by hemodialysis (~ 10% per
hour); removed less by peritoneal
dialysis

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Tri-phasic Elimination
Alpha – distribution of drug from blood to
tissues
Beta – elimination of drug through the
kidneys
Gamma – very slow release of drug from
tissue binding sites (kidneys, ears);
concentration not detectable by current
assays
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Adult Dosing Guidelines

Determine dose and interval necessary to achieve
desired concentrations
Site of Infection
Gent/tobra conc (mcg/mL)
CF, chronic bronchiectasis
Pneumonia, septic shock
Bacteremia, skin/soft
tissue, intra-abdominal,
pyelonephritis
UTI
Gram(+) synergy
Peaks 10-12; trough < 1.5
Peaks 8-10; trough < 1.5
Peaks 6-8; trough < 1.5

Peaks 4-6; trough < 1.5
Peaks 3-5; trough 0.5-1.5
Amikacin range (mcg/mL): peaks 20-35; trough < 8
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Aminoglycoside Blood Draws

Peak-30 minutes after end of infusion
(dose usually infused over 30 minutes)

Trough-immediately prior to dose (in
reality most schedule the trough 30
minutes prior to next dose)
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Stepwise Dose Individualization
1) Collect patient specific information
2) Determine dosing weight
3) Estimate volume of distribution (Vd)
4) Estimate creatinine clearance
5) Estimate elimination rate constant (ke)
6) Estimate serum half-life (t1/2)
7) Calculate dosing interval
8) Calculate dose
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Patient Case #1
A 35 year old WF is admitted to the
hospital with a diagnosis acute
pyelonephritis. The physician in charge
orders ampicillin 1g iv q4h and gentamicin
(to be dosed by pharmacy). Her TBW is
70 kg and height is 160 cm. Serum
creatinine is 0.7 mg/dl on the day of
admission.
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1-Patient Specific Information
Age, sex
 Height
 Total body weight (TBW)
 Renal function: serum creatinine
 Infectious disease being treated
 goal peak/trough concentrations

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2-Dosing Weight



Ideal body weight (IBW)
IBW (males) =
50 kg + 2.3 (ht-inches > 60 in)
50 kg + 0.9 (ht-cm >150 cm)
IBW (females) = 45.5 kg + 2.3 (ht-inches > 60 in)
45.5 kg + 0.9 (ht-cm >150 cm)
Adjusted body weight (ABW) - if TBW > 20% over
IBW
ABW= IBW + [(TBW-IBW) 0.4]
If TBW < IBW, use TBW for all calculations
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3-Volume of Distribution
Normal adult
s/p surgery, renal failure,
ascites
Cystic fibrosis, burns
Child
Neonate
Range
Average
(L/kg)
(L/kg)
0.22-0.33 0.25
0.27-0.32
0.3-0.35
0.3-0.45
0.4-0.7
0.30
0.32
0.37
0.55
Use dosing weight in step #2 for this calculation.
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4-Calculate Creatinine Clearance

Cockcroft-Gault Equation
CrCl (mL/min) =
(140-age) IBW
(x 0.85 for females)
72 (SCr)
SCr = serum creatinine in mg/dL
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5-Elimination Rate Constant (ke)




Estimate based on population equation
Dettli Equation:
ke (h-1) = 0.00293 (CrCl) + 0.014 (gent/tobra)
ke (h-1) = 0.0024 (CrCl) + 0.01 (amikacin)
6-Half-life (t1/2)
 t1/2 (hr)
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= 0.693/ke
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7-Calculate Dosing Interval (τ)
τ=
ln (Cpmax desired/Cpmindesired)
ke
+ ti
ti= infusion time (hours)
τ=dosing interval (hours)


Shortcut: Estimate dosing interval by multiplying t1/2
by 3
Round to nearest conventional interval:
8,12, 18, 24,36,48
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8-Calculate Dose
Dose = (Cpmaxdesired)(ke)(Vd)(ti)(1-e-keτ )
(1-e-keti)
 ti=infusion time (hrs), τ=dosing interval (hrs)
 Round doses to nearest 10 mg for adults for
adults

Shortcut:
1mg/kg for low peak range, 2 mg/kg for mid-peak
range, 2.5-3 mg/kg for high peak range
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Serum Drug Concentration Evaluation
1) Plot measured concentrations on graph
2) Determine patient’s true PK parameters: ke, t1/2, Cpmax,
Cpmin, Vd
3) Adjust dose and/or interval to achieve desired serum
drug concentrations
Cpmax = extrapolated peak
Cpmin = extrapolated trough, true trough
Used to
calculate Vd
Clinical peak=1/2 hour after end of infusion (this is our
targeted peak for efficacy determination)
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Plot Serum Concentrations
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Calculate PK Parameters





ke = ln (C2/C3)
∆t
t1/2 = 0.693/ke
Cpmax =
C2
∆ t = τ – infusion time – time from
measured trough to true trough – time
from measured peak to true peak
Extrapolated peak occurs at end of
infusion, t = difference between ext.
peak (Cmax*) and measured peak (C2)
e-(ke)(t)
Clinical peak = Cpmaxe –ke(0.5)
Clinical peak occurs ½ hour after end of
infusion
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Calculate PK Parameters


Cpmin = (C3)e-(ke)(t)
Vd=
True trough occurs
immediately prior to dose.
t = difference between true
trough (Cmin*) and measured
trough C1/C3
( D/ti) [1-e-(ke)(ti)]
ke [Cpmax- (Cpmine-(ke)(ti))]
Use extrapolated peak and true trough for
this calculation.
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Calculate New Dose and/or
Interval




Calculate using patient’s true PK parameters
Subtherapeutic peak
 Increase dose
Supratherapeutic trough
 Lengthen dosing interval
Supratherapeutic peak with non-toxic trough
 Lower dose
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Monitoring for Toxicity



Renal/ototoxicity associated with sustained
trough > 2 mcg/mL
Repeat trough level every 5-7 days
depending on:
 changes in patient’s renal function
 changes in SCr
 changes in urinary output
Monitor for ototoxicity:
 hearing loss, tinnitus, vertigo
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Patient Case #2
DP is a 58 year old male admitted with prostate cancer. Admitting
labs were: SCr: 1.2 mg/dl
TBW=90 kg Height=176 cm
Initial blood culture was negative; urine culture grew >100,000 gram
negative rods (identification and sensitivities were pending).
The physician asked you for a recommendation for tobramycin
dosing.
1.
What is the goal peak and trough?
2.
Calculate estimated ke, half-life, volume of distribution and an
initial regimen for this patient.
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Patient Case #2
DP is started on tobramycin (120 mg IV q12h) based upon your
recommendation. Peak and trough to be drawn around third
dose. The 3rd dose is infused from 1800-1830.
Laboratory values are reported as :
Trough
2 mcg/ml
drawn at 1730
Peak
8 mcg/ml
drawn at 1900
1.
2.
3.
4.
Calculate the ke and t1/2.
Calculate the Cpmax, Cpmin, and Vd.
Calculate the clinical peak.
What is your recommendation for further therapy
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Once Daily Dosing of
Aminoglycosides
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Aminoglycoside Pulse Dosing

Rationale:
 Concentration-dependent killing
 Post-antibiotic effect
 Period of continued bacterial growth
suppression despite serum levels less
than MIC of organism
 Tissue penetration
 Toxicity related to sustained elevated
troughs
 Renal accumulation is saturable
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Aminoglycoside Pulse Dosing




Gentamicin and tobramycin
 7 mg/kg based on dosing weight
Amikacin
 15-20 mg/kg based on dosing weight
Obtain random level and apply to nomogram
Repeat random level every 5-7 days (based on
clinical judgment)
 More frequent if Scr rises ≥ 0. 5 mg/dL above
baseline
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Once-a-day Aminoglycosides
These values are double for amikacin.
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Aminoglycoside Pulse Dosing

Avoid in:
 CrCl < 40 mL/min (Age > 65)
 Pregnancy
 Endocarditis
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Case #1
JW is a 41y/o WM diagnosed with a ruptured appendix
with abscess. Antimicrobial therapy (along with
surgery) was initiated with piperacillin 5gm iv q8h,
metronidazole 500mg iv q12h, and gentamicin per
protocol.
Ht 165cm, Wt 100kg, Scr 1.5 mg/dL



Is this patient a candidate for pulse dosing?
Calculate appropriate initial dose and interval.
Describe appropriate monitoring parameters.
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Case #2
YR is a 24y/o BF s/p vaginal delivery 2 days ago. She
has been spiking a fever during this time; postpartum endometritis is suspected. Antimicrobial
therapy with ampicillin 1gm iv q6h, clindamycin
600mg iv q8h, and tobramycin per protocol. Cultures
are pending.
Ht 157cm, TBW 60kg, SCr 0.5 mg/dL
 Is this patient a candidate for pulse dosing
aminoglycoside?
 If so, what dose is appropriate?
 First dose is administered at 1200.
 Random tobramycin level was drawn at 2200 and
reported as 4.2 mcg/ml.
 What is your recommended dosing interval?
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Clinical Pearls





Carefully assess sampling and dose administration times for
accuracy
Don’t allow sample to sit for extended periods of time at room
temperature
Review nursing notes to identify:
 problems with administration (IV access, patient off the floor)
 changes in urine output
Visit the patient to assess:
 accuracy of physical description (height, weight, age)
 disease resolution (WBC count, fever)
Monitor culture and sensitivity results to determine
appropriateness of aminoglycoside
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