Variability of the serum protein binding of theophylline in patients with asthma and cystic fibrosis.

Abstract

1. The serum protein binding of theophylline was studied in 28 asthmatics and 11 patients with cystic fibrosis (CF) who were receiving the drug regularly. Peak theophylline samples were collected at 2 week intervals on four occasions in each asthmatic and on three occasions in each CF patient. The binding was measured using ultrafiltration at 37 degrees C and pH 7.4. The total and free (unbound) theophylline concentrations were measured using high‐performance liquid chromatography. 2. The mean free‐fractions (+/‐ s.d.) in asthmatics (0.50 +/‐ 0.03) and in CF patients (0.51 +/‐ 0.04) were not significantly different. The intra‐ and inter‐subject variability in the free‐fraction (fu) was relatively small in both patient groups. The binding was found to be concentration‐independent at serum theophylline concentrations up to 30.9 micrograms ml‐1. The effects of age, gender, serum albumin and total serum protein on the free fraction were evaluated. 3. The results indicate that the binding of theophylline is similar in the two disease states. The low degree of variability in serum theophylline binding indicates that measurements of total serum theophylline concentrations will reflect unbound serum concentrations with acceptable accuracy in both patient groups studied.

Investigating the Role of Altered Systemic Albumin Concentration on the Disposition of Theophylline in Adult and Pediatric Patients with Asthma by Using the Physiologically Based Pharmacokinetic Approach

“…It is already known that exposure of drugs with low hepatic clearance is susceptible to changes in plasma protein binding (Zhivkova, 2017). Since theophylline is a low hepatic clearance drug that is bound to albumin, any change in serum albumin concentration can potentially affect its ADME and systemic concentrations (Fleetham et al, 1981;Blanchard et al, 1992). Moreover, it is reported that asthma is associated with pathophysiological reduction in serum albumin concentration and that these reductions in HSA levels may affect serum concentration of theophylline in patients with asthma (Blanchard et al, 1992).…”

“…It has been reported that human serum albumin (HSA) concentrations are altered in patients with asthma (Blanchard et al, 1992;Shima and Adachi, 1996;Picado et al, 1999;Vural and Uzun, 2000;Misso et al, 2005;Ejaz et al, 2017). The serum albumin concentration is reduced to 41 g/l in patients with asthma (Blanchard et al, 1992).…”

“…It has been reported that human serum albumin (HSA) concentrations are altered in patients with asthma (Blanchard et al, 1992;Shima and Adachi, 1996;Picado et al, 1999;Vural and Uzun, 2000;Misso et al, 2005;Ejaz et al, 2017). The serum albumin concentration is reduced to 41 g/l in patients with asthma (Blanchard et al, 1992). To predict systemic drug concentrations in patients with asthma, the model input value of serum albumin concentration was reduced from 50.34 g/l in male patients and 49.38 g/l in female patients to 41 g/l (similar in both male and female patients) within the Simcyp population library.…”

“…The changes in serum albumin concentration occurring in asthma can potentially affect the unbound drug concentrations, particularly for the drugs with low hepatic clearance. Therefore, the changes in serum albumin levels should be considered while describing the pharmacokinetics (PK) of drugs being administered in asthma (Blanchard et al, 1992;Shima and Adachi, 1996;Picado et al, 1999;Vural and Uzun, 2000;Misso et al, 2005;Ejaz et al, 2017).…”

Individualization of theophylline infusion rate on the basis of a nonlinear compartmental pharmacokinetic model

“…The drug binds to plasma proteins and approximately 37.5% of its total plasma concentration is bound, mainly to albumin (23); the interindividual variability in the fraction of the drug bound is very small (23,24).…”