Box 4-4: PK/PD Indices for Estimating Effective Dose

Patients differ with respect to the amount of drug present in the body for a given dose and in the susceptibility of the infecting agent. Consequently, finding the minimal dose likely to cure most patients is not straightforward. One strategy is to determine a pharmacodynamic (exposure) target (AUC24/MIC) for obtaining cure using a laboratory animal infection model. Then pharmacokinetic measurements (AuC24) are made with large numbers of persons using a given dose, and susceptibility measurements (MIC) are made with a large number of pathogen isolates. Then these two numbers are combined mathematically using a procedure called a Monte Carlo simulation. The output is an estimate of the fraction of patients expected to achieve the target PK/PD index (exposure) for the particular dose. (If the target represents favorable outcome, the Monte Carlo simulation indicates the percentage of treated patients likely to experience the favorable outcome.) That percentage of patients can be increased or decreased by changing the dose.88 The fraction of patients likely to reach the pharmacodynamic target, for example, likely to be successfully treated, can be balanced with toxic side effects associated with particular doses. Corrections may be needed for immune system differences between the experimental animal models and humans.

PK/PD analyses have led to antibiotics being grouped into two types, those for which higher concentrations kill more pathogen cells (cell death correlates with Cmax and AUC24) and those for which longer times above MIC give more killing. Members of the first antibiotic type are called “concentration-dependent killers.” They include such agents as fluoroquinolones and aminoglycosides. Members of the latter group are called “time-dependent killers.” They include p-lactams, such as penicillin.89

PK/PD indices are affected by a variety of complex factors, one of which is protein binding. When drugs are inside the human body, they bind to tissues and serum proteins. This binding may sequester the drug and reduce its effective concentration. Consequently, attempts are made to estimate “protein binding” so that a correction factor can be added to PK/PD indices for comparison of doses and compounds. With some compounds as much as 90% is considered to be protein bound, leaving only 10% of the total to control infection. Interpretation of the phenomenon is complex, because it may differ among locations in the body. Moreover, as drug concentration drops during the dosing interval, some bound drug may become unbound. In such cases, protein binding would have created a reservoir of drug. The importance of protein binding, which is controversial, can be estimated by measuring the efficacy of various antibiotics in animals and then determining whether those data fit better with in vitro data if corrected for protein binding.90

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