Therapeutic Drug (Concentration) Monitoring: Aminoglycosides

Aminoglycosides

Why?

Narrow Therapeutic index

Aminoglycosides are selected for very serious infections and if dosed correctly can produce bactericidal action.
Aminoglycosides are very toxic (accumulation in kidney, middle ear, etc.)

Weird relationship between efficacy and toxicity

High peak concentrations are necessary for optimal efficacy only rarely produce toxicity (and then unusual - e.g., musculoskeletal weakness).

It is important that the trough concentration (lowest concentration at the end of the dose interval) be allowed to fall in order to avoid accumulation.

So... Pulse dosing (large dose SID) reduces toxicity incidence without decreasing efficacy (probably) AND therapeutic monitoring can eliminate nephrotoxicity almost entirely.

Patient Variability

Considerable evidence for variability between normal individuals - disease and physiologic alterations make it even worse.

Dose regimen (normal)

Gentamicin - 2 - 3 mg/kg q 6 - 12 H
Amikacin - 7 - 10 mg/kg q 6 - 12 H
Neonates
 
Larger than normal Vz (larger ECF volume)
Normal = 0.15 Vz = 0.22 l/kg,
Foals = 0.25 - 0.4 l/kg
Clearance is "normal" (normal renal function and blood flow)
T1/2 lengthens proportional to increase in Vz		 Larger than "normal" doses of aminoglycosides at longer intervals
Geriatrics
 
Suspect reduced GFR, reduced fluid volumes
Longer than normal T1/2 (reduced lz)		 Longer dose intervals at (usually) normal doses
Renal Failure
 
Confirmed reduced GFR, variable fluid volumes		 Longer dose intervals (usually normal doses)

Target Concentrations

Gentamicin

Peak = 10 µg/ml
Trough = 1 µg/ml

Amikacin

Peak = 35 µg/ml
Trough = 4 µg/ml

When?

After the patient has "stabilized" - (fluid balance, etc.)

Therapeutic monitoring can accommodate first dose to any at steady state

Steady-State

Predictions will be more accurate
Dose regimen may be ineffective or toxic for some period of time

First-Dose

Dosing accuracy can be improved quicker
Mathematical projections are less accurate
Patients are less stable during first hours in hospital

What samples (sample times)?

Peak occurs 1/2 - 1 hour after (IM) dose

Trough occurs immediately before the next dose

Steady-State

Trough from one dose (interval), peak from the next

Dose 1 - 4 or 5

Peak and trough from same dose (interval)
Therapeutic monitoring of Gentamicin. Dose = 2.2 mg/kg, Interval = 12 hours. Sample 1 is taken 1 hour after the gentamicin dose and sample two is taken at the end of the dose interval.

How is adjustment made?1

Relationship between the dose given and the concentrations determined is controlled by the volume of distribution and clearance (which control elimination rate).

Calculations allow prediction of concentrations that will result when doses are changed

1 Sojka J.E. and Brown S.A. Pharmacokinetic Adjustment of Gentamicin Dosing in Horses with Sepsis. JAVMA, vol. 189 (7), 1986.

Glossary

lz = lambda z, elimination rate constant

T1/2 = half-life

C1 = Concentration at peak time (first sample)

T1= time for first sample

C2 = Concentration at trough time (second sample)

T2= time for second sample

D = dose

Vz = estimated volume of distribution

Cmax = desired maximum concentration

Tmax = optimum dose interval (based on Dm,max)

Cmin = desired minimum concentration

Dm, max = optimum maintenance dose

e = base of natural logs

Dm = recommended dose

T = (Tau) recommended dose interval

Step 1. Elimination rate and half-life


 lz = ln(C1/C2)
(t2 - t1)
T1/2 = 0.693
lz

Step 2. Estimate Vz and Co


 Vz = D
C2		 x 1-e-nlzT
1-e-lzT		 x e-lzT

Step 3. Estimate optimum interval


 Tmax = ln (Cmax/Cmin)
lz

Step 4. Estimate optimum dose


 Dm, max = Vz x (Cmax - Cmin)

Step 5. Adjust optimum dose and interval for practicality.


 Dm = Dm, max
Tmax		 x T