Challenges of conventional PK/PD indices Sample Clauses

Challenges of conventional PK/PD indices. Although PK/PD indices based on MIC are widely used for target exposures, there are some inherent drawbacks of these indices. Firstly, the PK/PD indices are mostly based on animal studies, but the species differences in pharmacokinetics are not taken into account. Secondly, the in vitro MIC is a static threshold value often established with poor precision, that is obtained in experiments with static antifungal concentrations, while it is not known how fungal susceptibility towards the antifungals is impacted by the dynamics in the exposure in vivo, nor how this impacts the development of resistance. By not considering the concentration-time course in a dosing interval, these indices are basically assumed to be independent of the drug pharmacokinetics. Finally, the indices do not take the hosts’ immune response to the fungal infection into account, which may decrease the required in vivo drug exposure needed to obtain the same antifungal effect as in an in vitro setting. Figure 3 illustrates how the currently applied PK/PD indices for antifungals relate to the pharmacological and physiological processes that occur in vivo. Upon antifungal administration a dynamic concentration-effect profile is obtained. Subsequently, it is the combination of the antifungal effect of the dynamic drug exposure as well as the immune system of the host that will determine the fungal burden. The fungal burden then drives the responses that are observed in preclinical or clinical studies. The PK/PD indices ignore most of this mechanistic information by summarizing the dynamic exposure into a single value and empirically establishing which of the available exposure metrics best correlates with the observed responses, using the MIC value obtained in in vitro experiments with static exposure and in the absence of host immune response. In the field of antibacterial drugs, more mechanism- based PK/PD models that do take this mechanistic information into account have been established to overcome the weaknesses associated with the use of the PK/ PD indices [101-104]. Unfortunately, this approach has not yet been applied in the antifungal field. This should yield better target exposure values as well as improved between-species scaling of findings.
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