Metabolites and Drug response - Clinical practice
14 important questions on Metabolites and Drug response - Clinical practice
What is empirical dosing?
What is pharmacodynamic dosing?
What is pharmacokinetic dose adaptation?
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What do you do when you need to give an advice about the risk of possible toxicities?
- You ask the dose
- You look up the Vd
- You ask for the persons' body weight
- You calculate the cmax by using the formula cmax = dose / vd. (for the vd in this case you have to multiply it by the persons'body weight.
- You think about what the risks are of the drug.
What do you do when a male patient (70 kg, 54 years ans serum creat 80 micromol/L) must be treated with tobramycin? The physician starts with 300 mg once daily at 12:00. He measured the plasma concentrations at 13:00 and 21:00.
- Assume that the concentration at 13:00 is the C(0). Then you can calculate the Vd.
- From the 2 data points you can get the t1/2.
Whether you should continue with a next dose of 300 mg or not is dependent of th PD and the therapeutic targets. For Tobramycine for example the cmax/ MIC is 8-10.
What is the MIC of tobramycin?
For a recovery of tobramycin toxicity the Cmin must be lower than 0,5 mg/L. To reach this at least 5 hours are needed
What are the required data for the "a priory" dose?
- Target value for relevant PK/PD determinant: Peak/through (aminoglycosides), AUC (vancomycin, fluorchinolones), T above MIC (beta-lactam antibiotics)
What is the TDM scheme based on Bayes principles?
So, what is the practical protocol for tobramycin TDM?
- Draw peak serum level 0,5 hrs after first dose
- Draw second level 1.44 x average t1/2 (6-12 hours) after first dose.
- Analyse the samples, calculate individual PK parameters
- Calculate next dose and dosing interval
- Repeat sampling.
What is different about ICU patients?
How is the distribution in ICU patients changed?
- decreased albumin concentration
- increased alpha-1-acid glycoprotein
- alterations of blood pH
- septic shock
Cmax is reduced in those patients, CL is unchanged and T1/2 is increased. Also the time to steady-state is increased. This means that there is a decreased efficacy of concentration dependent drugs (aminoglycosides)
What if a decreased albumin level occurs?
What happens if AAG (alpha-1- acid glycoprotein increase?
How is the drug excretion in ICU patients?
- ICU patients often have a renal disfunction.
- If a ICU patient has a good renal function an augmented clearance can occur due to release of inflammatory cytokines or use of e.g. norepinephrine (vasopressive drug).
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