ECFS 2020 - Optimizing pharmaceutical care in cystic fibrosis

European Cystic Fibrosis Society   47  OPTIMIZING PHARMACEUTICAL CARE IN CYSTIC FIBROSIS PK AND PD TO GUIDE ANTIBACTERIAL THERAPY IN CF CHAPTER 3 normalized to height or body surface area (BSA) rather than body weight [12]. For example, tobramycin Vd was similar in CF patients compared to healthy people, when normalized to BSA; but Vd was significantly higher in people with CF, when normal- ized to body weight. In patients with CF, the lean body mass (LBM) represents the largest percentage of total body weight. Therefore drugs with wide distribution in lean tissue will have high Vd (e.g. ceftazi- dime) whilst drugs with high distribution in adipose tissue will have high CL. Indeed, if we adjust the values for LBM, Vd in CF patients in good health does not differ from Vd in healthy people [13]. 2.3. Hepatic clearance The hepatic clearance of drugs largely depends on hepatic blood flow or on intrinsic clearance for molecules with high and low extraction ratios, respectively. Depending on the molecule, altered hepatic blood flow or impaired liver enzyme activity will impact hepatic drug clearance. About 30‑40% of CF patients have some degree of hepatobiliary dysfunction including eleva- tion of the liver enzymes γ -glutamyl trans- peptidase, aspartate amino transferase and alanine amino transferase. Nonetheless, many drugs appear to have greater hepatic clearance in people with CF. Some studies do not exclude increased hepatic blood flow [14], but at the moment it is consid- ered unlikely that the CFTR gene defect is directly involved [15]. It is difficult to predict to what extent drug metabolism, depen- dent on phase 1 and/or phase 2 hepatic biotransformation, may significantly differ in CF compared to healthy subjects. The the proximal mucosa of the small intestine. Some studies have not shown significant changes in bioavailability, while others seem to suggest an increase in the oral bioavailability of some drugs. Although the extent of absorption is highly variable, the absorption rate is generally slower. Once absorbed, most drugs circulate in the blood bound to plasma proteins such as albumin, α 1-acid glycoprotein, and α -globulins. The degree of plasma protein binding differs from drug to drug and may affect activity, tissue distribution, and hepatobiliary and urinary excretion. 2.2. Serum protein The success of antibiotic treatment in CF can be significantly affected by changes in body mass, imbalances in plasma protein concentration, and endothelial dysfunction [11]. People with CF have low levels of many serum proteins (such as albumin, glob- ulin, prothrombin and coagulation factors), mainly because of reduced synthesis. This can also result from hypervolemic conditions up to 1.4-fold higher than in healthy people due to reduced arterial oxygen saturation associated with pulmo- nary dysfunction. Reduced serum protein levels in CF could result in increased free drug concentrations, especially for drugs that bind tightly to serum protein. Patients with hypervolemia and/or hypoalbumin- emia can therefore have increased Vd and CL, complicating the maintenance of adequate plasma drug concentrations. Of note, Vd and CL differences in CF patients compared to healthy people seem less pronounced when these parameters are