ECFS 2020 - Optimizing pharmaceutical care in cystic fibrosis

46    www.ecfs.eu OPTIMIZING PHARMACEUTICAL CARE IN CYSTIC FIBROSIS PK AND PD TO GUIDE ANTIBACTERIAL THERAPY IN CF CHAPTER 3 response. This variability is due to the multiple CFTR mutations possible, the general clinical condition of the patient, the level of multiorgan impairment, and the patients’ life expectancy, which has decid- edly increased with the introduction of new therapeutic strategies. Full understanding PK in CF patients is further complicated by the extreme heterogeneity of PK data in the literature. Robust statistical interpretation is not always possible because the rele- vant studies were conducted in different historical periods, were often uncontrolled, with heterogeneous patient populations. Studies published before 1985 reported, for example, that beta-lactam clearance (CL) and volumes of distribution (Vd) at steady state were higher in CF patients than in healthy volunteers. More recent studies have shown a smaller difference between the two comparison groups. The pathophysiology of CF can affect the PK and PD of drugs in many different ways. In the following section, we describe these challenges to understanding PK and PD in the context of CF. 2.1. Gastrointestinal tract changes Defective CFTR protein causes decreased chloride secretion in the airways, associ- ated with an increase in sodium absorption mediated by the epithelial sodium channel (ENaC). The pathological triad of obstruc- tion, infection and inflammation, which is responsible for respiratory disease, also causes gastrointestinal tract malfunction. Absorption of orally administered drugs can be altered by gastrointestinal tract changes in CF, such as hypersecretion of gastric acid, malabsorption and lesions of the plasma concentrations of the antibiotic fall below the MIC [5-7]. Concentration-dependent antibiotics (such as aminoglycosides and quinolones) exert their activity in vivo on the basis of the Cmax reached and of a prolonged PAE. For these drugs, Cmax/MIC indicates efficacy and a single daily dose is appropriate. For both time-dependent and concentra- tion-dependent antibiotics, the AUC/MIC ratio can effectively express the extent of pharmacologically active exposure. Probably the most important risk factor for selecting antibiotic-resistant strains is repeated exposure of bacteria to subop- timal concentrations (often due to inappro- priate dose) [8]. In the presence of subop- timal antibiotic concentrations at the site of infection, the presence of a single bacterial mutation might confer a survival advantage. This could lead to selection of resistant pathogens, even with antibiotic concentra- tions above the MIC [8, 9]. Therefore, anti- biotic concentrations at the site of infection should be maintained high enough that a second mutation is needed to confer full antibiotic resistance. These higher concen- trations, called “mutant prevention concen- trations”, are therefore desirable, and can be achieved only with dosages greater than that required for clinical cure [10]. 2 Pathophysiological changes in CF: impact on PK/PD In CF, the PK of a medicine can vary signifi- cantly between patients, and even within the same patient, making it difficult to predict the PK trend of a drug and its PD