PK

• Therapeutic Drug Monitoring involves either PK monitoring or PD monitoring.
• Examples of PD monitoring include: blood glucose for antidiabetic drugs, blood lipids for hypolipidemic drugs, and blood pressure for antihypertensive drugs.
• PK monitoring applies to narrow TI drugs as it is easier to over or underdose pts, so we will not be using empirical dosing, we will be individualizing the dose to the patient.
• Individualizing will result in improved outcomes.
• The process of Therapeutic Drug Monitoring involves:

  • a diagnosis is made
  • drug is selected and a therapeutic objective is defined
  • dosing regimen is chosen to reach the target Css and appropriate response
  • the drug is administered + the patient is assessed
  • Css is measured
  • the PK model and clinical judgment are applied
  • adjustments to the dosage are made if necessary using pt PK and then manipulating controllable variables (dose and tau).
• Therapeutic Drug Monitoring is used to individualize patients dosage regimen, screen for potential toxic compounds causing medical emergency, and sometimes to individualize a dosage regimen.
• We cannot use Cp for non-linear drugs because it causes unpredictable changes and with narrow TI drugs, a small change in dose can lead to a wide Cp change
• TR is only an initial guideline – you will use clinical response and Cp to individualize and optimize pt therapy
• Only recourse is to use Cp to know if the DR is appropriate for the therapeutic outcome.
• This is what allows us to predict a DR based on the Cp alone.
• Clinical Pharmacokinetics: application of PK principles to the design of individualized dosage regimens that optimize therapeutic response and minimize chances of an adverse reaction
• TDM Goals:
• Remember however that there is pharmacodynamic variability and not everyone will respond to a drug in the same way
• Have a predictable Css vs response relationship
• Most drugs exhibit linear PK which is important because: It allows use of drug Cp,ss to assess responsiveness and compute an individualized DR because PK parameters are constants: Cls, Vd, t1/2, and F
• Therapeutic Range is a population parameter: TDM promotes optimum drug therapy by maintaining Css,ave in a TR
• TR establishes the probability of success in a typical population
• TDM is based on the assumption that Css,ave is proportional to response
• We assume that there is a relationship between the Cp and the receptor site [ ]
• There is a relationship between [ ] at the receptor site and clinical response
• Exhibit an appropriate clinical response
• Initially we use the population mean PK parameters then adjust based on the patients drug concentrations
• Initiating therapy – we have empirical dose and individualized dose
• In Linear PK if we double the dose, we double the [ ]
• Steady state is the intermediate endpoint, there is no quantifiable therapeutic endpoint or pharmacological effect
• The goal of DRs is to attain therapeutic concentrations and maintain them
• The dose can then be modified to attain therapeutic Css,ave
• If you dose someone into the TR but they are showing obvious signs of toxicity, then it is likely that their TW is smaller than the populations
• To get steady state [ ] (Css) in the therapeutic range.
• The contribution of PK (ADME) variability to the dose requirements can be identified by measuring Css,ave
• We want to know the levels of unbound drug at the receptor site
• For a drug to be therapeutically monitored it must meet the following criteria:
• Cp that does not correlate with clinical response tells us nothing about it therefor we cannot use Cp alone to determine efficacy
• If a person normally has a 20 mL/min Cl and then gets hepatic disease which lowers Cls to 10 mL/min, providing that new level is constant and the disease is constant then this will just be a new constant – but it is still a constant
• The basic premise of PK and using PK information:
• Wide interpatient variation in PK parameters because a patients PK characteristics determine Cp following dose, so if lots of variability then there will be lots of variability in Cp’s!
• The symptoms of toxicity are the same as the symptoms of the disease state.
• Previous Cps of this drug in this pt
• Psychotherapeutics: lithium, TCAs (amitriptyline, imipramine)
• Have a narrow range of safe and effective Css (narrow TI) because it is dangerous and potentially deadly to use the empirical regimen.