Aminoglycoside Dosing: Pharmacokinetic Model

Rationale

Yazan Kherallah

Objectives• Understand the rationale supporting the

pharmacokinetic dosing model• Discuss and interpret pharmacokinetic

concepts that affect aminoglycoside dosing– Volume of distribution– Half-life / Elimination rate

• Utilize pharmacokinetics to properly dose aminoglycosides

Pharmacokinetics (PK) vs. Pharmacodynamics (PD)

• Definitions:– PK: The process by which a drug is absorbed,

distributed, metabolized, and eliminated by the body

– PD: The study of the action or effects of drugs on living organisms

• In other terms:– PK: what the body does to the drug– PD: how the drug acts on the body

• One must understand the PD of a drug before using PK to design a dosing regimen

Aminoglycoside PD

- Bactericidal- Bind to 50S subunit to

inhibit DNA synthesisConcentration dependent killing

Literature Support• Multiple studies have demonstrated the

relationship of PK/PD for aminoglycosides– Plasma levels and outcome

• Sepsis• Pneumonia

– Peak:MIC ratio– Altered Vd in the critically ill

• Goals– Provide efficacious dosing– Minimize drug toxicity

Association of Serum Levels and Outcome

• Initial doses of 2 mg/kg gentamicin or tobramycin (8 mg/kg amikacin) given to septic patients (n=89)– In combination with a β-lactam

• Therapeutic initial peaks– Gent/tobra: > 5 mcg/ml– Amikacin: > 20 mcg/ml

• Outcome = Mortality– Therapeutic: 2.4% (1/41)– Subtherapeutic: 20.9% (9/43)

J Infect Dis 1984;149(3):443-8

Association of Serum Levels and Outcome

• Initial doses of 2 mg/kg gentamicin or tobramycin (8 mg/kg amikacin) given to pneumonia patients (n=37)– In combination with a β-lactam

• Therapeutic initial peaks– Gent/tobra: > 7 mcg/ml– Amikacin: > 28 mcg/ml

• Outcome = “Successful Outcomes”– Therapeutic: 78% (14/18)– Subtherapeutic: 32% (6/19)

• Multivariate analysis– Most important predictor of positive outcome

Am J Med 1984;77:657-662

Importance of Peak:MIC Ratio• Initial doses of 2 mg/kg gentamicin or

tobramycin (8 mg/kg amikacin) given to sepsis patients (n=236)– In combination with a β-lactam

• 188/236 patients had favorable response to antibiotics

• Most important factors for favorable response (univariate analysis)– Favorable underlying prognosis (p=0.0001; R=0.36)– Maximal peak:MIC ratio > 10 (p=0.0005; R=0.21)

J Infect Dis 1987;155(1):93-9

Importance of Peak:MIC RatioTable of Peak:MIC ratios and relative odds of

favorable responseMax Peak:MIC

(mcg/ml)Relative Odds 95% Confidence

Interval

< 2 1.00

2-<4 1.63 0.84-3.16

4-<6 1.83 1.09-3.03

6-<8 4.35 2.53-7.46

8-<10 6.49 3.56-11.82

>10 8.41 4.62-15.33

J Infect Dis 1987;155(1):93-9

Achieving Acceptable Peak:MIC Ratios in the Critically Ill

• 53 SICU patients in septic shock given gent/tobra– Loading dose: 3 mg/kg of IBW or adjusted BW

• 50% of the difference between IBW and actual weight

• Mean initial peak = 8.1 + 0.3 mcg/ml– Only achieved in 50% of patients– Mean Vd = 0.29 L/kg (0.2-0.54 L/kg)– 34% had increased Vd

• 4mg/kg dose is back-calculated

Surgery 1998;124:73-78

Serum Level TargetsInfection Type

Goal Gent/Tobra Peak

Goal Gent/Tobra Trough

Goal Amikacin Peak

Goal Amikacin Trough

Pneumonia / Sepsis

8-10 mcg/ml < 2 mcg/ml 32-40 mcg/ml

< 8 mcg/ml

Aminoglycoside Elimination12

10

8

6

2

Beta Phase

Gamma Phase

AlphaPhase

Dosing ModalitiesTraditional Once-daily PK (SICU)

Dose 2mg/kg q8h 5-7mg/kg qday 4mg/kg once

Description Low peaks, high troughs

High peaks, low troughs

Therapeutic peaks / troughs

Use in … Floor patients (if at all)

Floor patients, stable Vd, CrCL

ICU patients

Advantages None? High Peak:MICPAELow toxicity

High Peak:MICPAELow toxicity

Sample Once-daily Nomogram

Nicolau DP et al. Antimicrob Agents Chemother 1995;39(3):650-55.

Aminoglycoside Dosing Regimen• Usually based on actual body weight (ABW)• Administer:

– Gent/Tobra 4 mg/kg IV x 1– Amikacin 16 mg/kg IV x 1

• Draw 1 hour post-infusion peak and 8-12 hour random level

• Goal peaks– Gent/Tobra = 8-10 mcg/ml– Amikacin = 32-40 mcg/ml

Pharmacokinetic Equations• Calculate Vd

– Needed for dose adjustment– Vd = Dose given (mg) / peak (mg/L)

• Calculate ke and t1/2

– Determine frequency of drug administration– ke = ln (peak/random) / Δt– t1/2 = 0.693 / ke

• In how many half lives should you re-dose?• Predict when appropriate to re-dose

– Ct = Co e (-ke x t)

Case: Volume of Distribution• JK is a 75 yo male is POD 2 ex lap for SBO

and is now septic and hypotensive• Discussion on rounds leads to the initiation of

antibiotics– Pip/Tazo 3.375 g IV q6h– Vancomycin 1 g IV q12h– Gentamicin….

Case: Volume of Distribution• Patients weight:

– Actual = 85 kg– IBW = 76 kg

• What dose do you want to give of gentamicin?

• When do you draw levels to calculate regimen?

Gentamicin 340 mg IV x 1 over 30 minutes

Draw levels 1 hour and 8 hours post infusion

Case: Volume of Distribution• Gentamicin is ordered and given at 0900

(after speedy pharmacy processing!)• Levels to follow

– 1030: 11.2 mcg/mL– 1800: 6.7 mcg/mL

• Calculate Vd

• Normal Vd is:

Vd = 340 mg / 11.2 mg/L = 30.3 L = 0.36 L/kg

0.25-0.3 L/kg

Case: Elimination and Half-life• JK’s levels

– 1030: 11.2 mcg/mL– 1800: 6.7 mcg/mL

• Calculate ke

• Calculate T1/2

ke = ln (1 hr level/8 hr level) / change in time ln (11.2 / 6.7 ) / 7.5 0.0685 hrs-1

t1/2 = 0.693 / ke

≈ 10 hrs

Case: When to re-dose?• If clearance remains stable, it can be

assumed that the next dose could be given in 4 half lives

• Ct = Co e (-ke x t) can be used to predict when a level will be < 2 mcg/ml– Re-arrange equation to

– This will give you how many hours until serum concentration is < 2 mcg/ml

– JK:

t = [ln Co – 0.693] / ke

≈ 18 hours must elapse until level is < 2 mcg/ml

Case: The Next Dose• Utilizing the patient-specific Vd for JK, what is the

next dose of gentamicin?

• Things to consider…– Changing Vd

• Active diuresis?• Third spacing?

– Changing ke• CVVHD

– Clotting? Increasing flow rates?• Declining/improving renal function?

Dose = Vd x desired increase in serum level = 30.3 L x 8 mg/L (why 8 mg/L?) = 240 mg

Take Home Points• Aminoglycosides should be administered with

the goal of achieving therapeutic peaks early• Dose is related to Vd

– As volume increases, so does the dose (and the reverse is true)

– Dose is independent of elimination• Frequency of dose is related to half-life and

elimination

Equations to Know• Dose is 4 mg/kg of actual or adjusted weight• Volume of distribution:

– Vd = Dose given (mg) / peak (mg/L)• Elimination constant (ke)

– ke = ln (peak/random) / Δt• Half-life

– t1/2 = 0.693 / ke

• Time until level is safe for redosing:– t = [ln Co – 0.693] / ke (for gent/tobra)– t = [ln Co – 2.01] / ke (for amikacin)