Section 2 - Vancomycin dosage calculation

Section 2 - Applied Pharmacokinetics

Vancomycin dosage calculation

Choosing a model

Vancomycin has a relatively long distribution phase and is best characterized with a 2-compartment model. However, after the 1 to 2 hour distribution phase, it collapses to a 1-compartment model. Therefore, if peak serum levels are drawn and targeted for at least one hour after the infusion, a 1-compartment model is sufficient.

The 2-compartment vancomycin model utilized by Kinetics is based on Lake and Peterson's data and is meant to approximate their published nomogram. L&P's method, which is the only published vancomycin dosing method to be independently verified, achieves target peaks of 20 to 30 mcg/ml and target troughs of 5 to 10 mcg/ml in 80% of patients.

Initial dosing

If a one-compartment model is utilized, the methodology is identical to that used for aminoglycoside dosing. But because we are attempting to fit a 2-compartment drug into a 1-compartment model, it is akin to forcing a square peg into a round hole. As a result, hybrids values are utilized for the pk parameters, hence they don't match up exactly with what you may read in the published literature.

Determine elimination rate (Kel)
Kel = 0.009 + (CL_cr x 0.0022)
where
Determine Volume of distribution (Vd)
Vd varies considerably between patients, the "normal" range is 0.4 to 0.9 L/kg. This disparity in reported Vd is the main reason why vancomycin serum concentrations and dosage requirements are so unpredictable.
Vd = DW x Vd_perkg
where
Determine ideal dosing interval (tau)

tau = t_inf + [ln(Cp_tmax / Cp_tmin) / Kel]
where
Determine ideal maintenance doses

MD = Kel x Vd x Cp_tmax x (1 - e^{-Kel x tau} / 1 - e^{-Kel x tinf})

where
Select a practical dosage and interval
- Choose practical, convenient doses and administration schedules.
- Odd doses and schedules may lead to errors in administration.
- A general rule of thumb is to round Vancomycin doses to the nearest 250mg.

only

small doses, more frequently

Determine clearance (CL)
Clearance is estimated from a Dettli plot of CL_cr vs Vanco CL. Because Clearance includes a volume term, it must be normalized to a population average weight.
CL = [0.17 + (CL_cr x 0.06)] x (DW / 70)
where

Determine dosing interval (tau)
The drawback to a 2-compartment model is that it does not provide a ready means of calculating a dosing interval. The equation below approximates the intervals recommended by Lake and Peterson's nomogram:

Creatinine Clearance Dosing interval
>90 6 hours
70-89 8 hours
46-69 12 hours
30-45 16 hours
15-29 24 hours

tau = 6 x (72 / [(10 * CL) + 1.9])

Determine ideal maintenance dose (k₀)
Note that in this 2-compartment equation, the target trough level drives the dose. This meshes perfectly with the concentration-independent killing property of vancomycin where our goal is to target a trough level which remains above the MIC.
k₀ = 1/{[(k₁₂-k_d) (1 - e^{k_d x tinf}) e^{k_d x t})] / [V_c x k_d (k_d-k_el) (1 - e^{k_d x tau})] +
[(k_el-k₂₁) (1 - e^{k_el x tinf}) e^{k_el x t})] / [V_c x k_el (k_d-k_el) (1 - e^{k_el x tau})]} / 1/CP_target
where
- k₀ = infusion rate (mg/hour)
- tau = dosing interval (hours)
- t_inf = infusion time (hours)
- t = time at which to predict serum concentration
- k₁₂ = rate constant for distribution from central to peripheral compartment (1.12 hr^-1)
- k₂₁ = rate constant for distribution from peripheral to central compartment (.42 hr^-1)
- V_c = Volume of central compartment (.205 L/kg)
- k_d (hybrid distribution rate constant) = (k₂₁ x k₁₀)/k_el
  where
- k_el (hybrid elimination rate constant) = CL/Vd
  where
- CP_target = Target trough level

1-compartment serum level analysis

For 1-compartment serum level analysis, Sawchuk and Zaske's method provides a simple way of calculating individualized pk parameters based on peak and trough levels. This is the same method utilized for aminoglycosides.

Important

elimination

Bayesian analysis

Bayesian analysis is always utilized to analyze serum levels when using the 2-compartment model, it is optional for the 1-compartment model.

The Bayesian method uses population-derived pharmacokinetic parameters, Vd and CL, as a starting point and then adjusts those parameters based on the serum level results taking into consideration the variability of the population-derived parameters and the variability of the drug assay procedure.

The appeal of this approach is that it mimics human thinking. That is, SDC's are interpreted in light of both our expectations from the population model and our knowledge of the variability of the test itself.

The main advantage of Bayesian analysis is that only one steady-state SDC, preferably a trough, is required to perform an accurate analysis.

Section 2 - Applied Pharmacokinetics

Creatinine Clearance	Dosing interval
>90	6 hours
70-89	8 hours
46-69	12 hours
30-45	16 hours
15-29	24 hours