| Section 2 - Applied Pharmacokinetics |
Initial dosing
Kel = 0.01 + (CL_{cr} x 0.0024)
where
Vd = DW x Vd_{perkg}
where
Serum level analysis
Kel = (ln Cpmax/Cpmin') / t"
where
VD = [(Dose/t_{inf}) / Kel] x (1- e^{-Kel x tinf}) / Cpmax - (Cpmin x e^{-Kel x t'} )
where
Bayesian analysis
The Bayesian method uses the population-derived pharmacokinetic parameters, Vd and Kel, 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.
Determine ideal dose
tau = t_{inf} + [ln(Cp_{tmax} / Cp_{tmin}) / Kel]
where
MD = Kel x Vd x Cp_{tmax} x (1 - e^{-Kel x tau} / 1 - e^{-Kel x tinf})
where
Cpss_{max} = (MD / t_{inf }x Vd x Kel ) x (1 - e^{-Kel x tinf} /1 - e^{-Kel x tau} )
Cpss_{min} = Cpss_{max} * e^{-Kel x (tau - tinf)}
where
Extended interval method
Extended-interval (aka "once-daily" or "pulse") aminoglycoside dosing has gained popularity
in recent years. This simplified dosing method is appropriate in young, otherwise
healthy patients with sepsis. Keep in mind however, there are many patient groups
who are not candidates for EI dosing. For detailed information please read the
following 1997 consensus statement:
Initial dose
MD = DW x QD-dose
where QD-dose is:
CL_{cr} | Interval |
---|---|
Over 60 | 24 hours |
40-59 | 36 hours |
30-39 | 48 hours |
Less than 30 | Use traditional dosing method |
If the 6 to 16 hour level is undetectable and the infection is not responding, consider changing to a traditional dosing method.
The three interval break points on the Hartford interval adjustment nomogram are the approximate decay curves from a 7mg/kg gentamicin dose. These decay curves were calculated using a one compartment model with a volume of distribution of 0.25 L/kg and an elimination rate calculated from creatinine clearances of 25, 40, and 60 ml/min for 48, 36, and 24 hour intervals respectively. The authors of the Hartford nomogram then flattened these decay curves to simplify the nomogram.^{5}
It is important to note that the Hartford interval adjustment nomogram is only valid for a 7mg/kg dose. A nomogram for the less aggressive dose of 5mg/kg/day was developed by a consensus panel.^{23} For 15mg/kg doses of amikacin multiply the drug-level scale by a factor of three. This same consensus panel argues that the 48 hour interval should be abandoned, that patients with a CrCl < 40ml/min should be dosed by traditional pharmacokinetic methods.
The consensus panel also suggests that younger patients with excellent renal function may require Q 12 hour dosing. A dosing algorithm for this subpopulation has been proposed by Urban and Craig.^{24}
Some have questioned the validity of all ODA nomograms because they are based on one-compartment parameters derived from traditional dosing methods. Some pk studies have shown that the pharmacokinetics of aminoglycosides at high doses differ significantly from those at traditional doses. Therefore, it is argued that nomograms based on an assumption of similar kinetics are invalid. ^{25}
| Section 2 - Applied Pharmacokinetics |