Keep it simple stupid.

PK modeling of vancomycin

Vancomycin pharmacokinetics vary widely between patients.

"Compared with aminoglycosides, the variability in the distribution volume of vancomycin is extreme. Published inter-patient variability has been reported as 0.26 to 1.30 L/kg, 0.21 to 1.51 L/kg, 0.2 to 1.3 L/kg, and 0.37 to 1.40 L/kg in a series of studies.

The average Vd also varies widely in the literature, with early reports suggesting a value of 0.9 L/kg and more recent studies indicating a smaller Vd of 0.5 L/kg.

There does not appear to be any readily identifiable clinical characteristic to explain this variability. Unlike the aminoglycosides where one can often predict a larger or smaller than average Vd based on fluid status, variability in vancomycin Vd appears to be completely unpredictable."22

This is illustrated by comparing distribution curves for Vd. For vancomycin we see a fat tailed bell curve indicating there are more complex interdependent factors affecting the volume of distribution:

Figure 1. Comparative Vd Distribution of Aminoglycosides and Vancomycin
bell curve

 

Comparing Vancomycin Pharmacokinetic Models

The following table summarizes several vancomycin one-compartment models, collected from the published literature and from colleagues.

Table 1. Vancomycin One-compartment Model Parameters
Source Elimination rate/Clearance Volume of distribution
Ambrose
(2001)
CL ml/min = CrCl (0.17 [age in years]) + (0.22 [ABW in kg]) + 15
Bauer
(1982)
CL ml/min/kg = 0.05 + (CrClml/min/kg x 0.695) 0.47 L/kg
Birt
(1990)
Kel = 0.0726 + (CrCl x 0.000545) 0.54 L/kg
Burton
(1989)
CL ml/min = 0.04 + (CrCl x 0.0075) 0.47 L/kg
Burton revised
(1991)
CL L/hr = CrCl x 0.048 0.706 L/kg
Matzke
(1985)
CL ml/min = 3.66 + (CrCl x 0.689) 0.72 L/kg if CrCl is >60 mL/min
0.89 L/kg if CrCl is 10 to 60 mL/min
0.90 L/kg if CrCl is <10 mL/min.
Matzke variation
(1991)
Kel = 0.009 + (CrCl x 0.0022) 0.90 L/kg
Moellering
(1981)
Kel = 0.074 + [CrClml/min/kg x 0.08] 0.90 L/kg
Rodvold
(1988)
CL ml/min = 15.7 + (CrCl x 0.79) 0.50 L/kg if CrCl is >70 mL/min/70 kg
0.59 L/kg if CrCl is 4070 mL/min/70 kg
0.64 L/kg if CrCl is 1039 mL/min/70 kg
Abbott
(1992)
CL L/hr = 0.05 + (CrCl x 0.75) 0.65 L/kg
Creighton
(1992)
Kel = 0.0044 + (CrCl x 0.00083) 0.70 L/kg
VA
(1992)
CL ml/min = CrCl x 0.9 0.70 L/kg
Winter
(1994)
CL L/hr = CrCl x 0.065 0.7 L/kg

The following table summarizes several vancomycin two-compartment models, collected from the published literature.

Table 2. Vancomycin Two-compartment Model Parameters
Source CL Vp Vc k21 hr-1 k12 hr-1 Q (L/hr)
Uaamnuichai
(1987)
(CrCl x 0.0075) + 0.04
Rodvelt
(1989)
(CrCl x 0.75) + 0.05 0.65 L/kg 0.21 L/kg 0.48 1.12
Burton
(1991)
CrCl x 0.048 0.77 L/kg
Ito
(1993)
[(CrCl x 0.72) + 3.5] x 0.06 0.74 L/kg TBW 0.12 L/kg TBW 0.41 1.12
Fernandez
(1996)
(CrCl x 0.75) + 0.05 0.82 L/kg 0.21 L/kg 0.48 1.12
Teramachi.
(2002)
60.7 L 0.213 0.525
Llopis-Salvia
(2006)
(CrCl x 0.034) + 0.015 1.32 L/kg 0.41 L/kg 7.48
Thomson
(2009)
2.0 x [1 + 0.015 x (CrCl - 66)] 0.68 L/kg 0.732 L/kg 2.28
Yamamoto
(2009)
(CrCl x 0.032) + 0.32 0.48 L/kg 8.81 L 60.6
Sanchez
(2010)
(CrCl x 0.563) + 0.157 0.283 L/kg 32.2 x (Age/53.5) 0.111
Purwonugroho
(2012)
CrCl x 0.44 0.542 x Age 44.2 L 6.95
Medellin-Garibay
(2016)
CrCl x 0.49 0.74 L/kg 5.86 L/kg 0.81


Vancomycin Dosing Nomograms

Below is a summary of older vancomycin dosing nomograms which were designed to achieve target troughs of 10 mcg/ml.

Table 3. Vancomycin Dosing Nomograms
Source Dose Interval
Package insert 500mg Q 6 hrs
1g Q 12 hrs
Lake & Peterson
(1985)
8 mg/kg
CrCl Interval
90 and above 6 hrs
70 to 89 8 hrs
46 to 69 12 hrs
30 to 45 16 hrs
15 to 29 24 hrs
Matzke
(1985)
LD = 25 mg/kg
MD = 19 mg/kg
Figure 2. Matzke Vancomycin Dosing
Matzke
Moellering
(1981)
Figure 3. Moellering Vancomycin Dosing
Moellering
Nielsen
(1975)
LD = 25 mg/kg
MD = [(15 x CrCl) + 150] mg/day
Not specified
Rotschafer
(1982)
6.5-8 mg/kg Q 6-12 hrs


In 2016 Elyasi and Khalili compared fourteen published nomograms which target higher trough levels (15-20 mcg/ml).35 Some of the more interesting nomograms from this review are:

Figure 4. Kullar nomogram (2011)
Kullar


Figure 5. Lima nomogram (2014)
Lima


Figure 6. Golenia nomogram (2013)
Golenia


Figure 7. Saugel continuous infusion nomogram (2013)
Saugel


Conclusion

In 2006 Murphy, et al published an evaluation of the accuracy of seven popular vancomycin dosing methods. The methods were ranked by least bias or greatest precision. The Burton method using an adjusted body weight was ranked number one. Matzke's method using actual (total) body weight was ranked second.

Murphy and colleagues concluded "The seven methods studied for estimating vancomycin pharmacokinetic parameters varied widely in predicting vancomycin trough concentrations compared with measured serum concentrations and were not sufficiently reliable to replace therapeutic monitoring of vancomycin serum concentrations."21

In their review of newer dosing nomograms, Elyasi and Khalili concluded that "the percentage of target level achievement has been between 40 and 70% in most of cases, which is not ideal, and thus it seems necessary to continue development of more accurate nomograms for vancomycin dosing."35

One take-away from this conflicting data is, use the model that's best for your patient population. Don't rely on someone else's model to dose your patients. If you treat a diverse patient population, you may need multiple vancomycin models. This is where the population analysis utility included with Kinetics© and APK© will help you to create models fitted to your patient population.

Population models of vancomycin can not be relied upon to accurately predict individual patient pk parameters. Vancomycin has both a highly variable Vd and an unpredictable Nonrenal clearance component. Therefore, initial pharmacokinetic predictions should be viewed as rough estimates of dosage requirements. Experienced clinicians suggest a weight-based nomogram for estimating initial dosage needs, with subsequent pharmacokinetic analysis of serum level data, as the best common sense strategy for dosing vancomycin.

Click here to read an interesting vancomycin case.


References

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