Cyclosporin pharmacokinetics in heart-lung transplant recipients with cystic fibrosis

Abstract

Cyclosporin (CsA) is currently the main immunosuppressive agent used in organ transplantation with considerable improvement in graft survival. Oral CsA solution is highly lipophilic, and its bioavailability may be reduced in cystic fibrosis (CF) heart-lung transplant recipients with pancreatic, gastrointestinal, and hepatic insufficiency. The bioavailability of oral CsA solution in 7 CF transplant recipients (5 male and 2 female with a mean age of 27 years and a mean weight of 49 kg) and 3 non-CF heart-lung recipients (1 male and 2 female with a mean age of 41 years and a mean weight of 60 kg) was studied. Following intravenous CsA administration, the kinetic curves were similar with no significant difference in the volume of distribution and clearance of CsA demonstrated between the CF and non-CF groups. The mean daily dose of oral CsA in 7 CF subjects (23.3 mg.kg-1) was significantly higher than the 3 non-CF heart-lung recipients (4.8 mg.kg-1). The mean maximum blood concentration of CsA for the oral dose was 776 ng.ml-1 for the 7 CF subjects, which was comparable with the mean peak values of 789 ng.ml-1 for the 3 non-CF control subjects. Poor enteral absorption of CsA probably accounts for the significantly lower mean bioavailability in the 7 CF subjects (14.9%) compared with the 3 non-CF control subjects (39.4%). The effects on the bioavailability of oral CsA solution by pancreatic enzymes (Creon) and histamine-2 antagonist (ranitidine) were also evaluated in the 7 CF subjects. No significant difference was demonstrated.

Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients

“…CF is well known to cause malabsorption and reduced bioavailability of several highly lipophilic compounds, such as vitamins A, D, E, and K (9), cyclosporine (30), and ibuprofen (12). Due to its high lipophilicity and low water solubility, absorption of voriconazole is associated with digestion of fat and the subsequent formation of micelles.…”

“…Due to its high lipophilicity and low water solubility, absorption of voriconazole is associated with digestion of fat and the subsequent formation of micelles. However, this process is severely impaired in CF patients for many reasons, including (i) pancreatic insufficiency, leading to decreased secretion of pancreatic enzymes (lipase), (ii) reduced activity of lipase due to low duodenal pH caused by decreased secretion of pancreatic bicarbonate (16) and gastric acid hypersecretion (6), (iii) precipitation of bile salts at low duodenal pH, leading to low duodenal bile salt concentration and a diminished bile salt pool (precipitated bile salts are not reabsorbed) (10), and (iv) intestinal mucosal dysfunction, alterations in the intestinal mucus layer, and accelerated intestinal transit time (8,30).…”

Absolute Bioavailability and Intracellular Pharmacokinetics of Azithromycin in Patients with Cystic Fibrosis

“…In particular, the bioavailability of lipid-soluble vitamins and oral cyclosporine (not microemulsion formulations) is reduced in patients with CF, which is attributed to reduced pancreatic lipase release (4,7,12,14,15,18,26). In addition, the volume of distribution of some drugs is altered when normalized for body weight due to the reduced adipose tissue in patients with CF.…”

Organ Transplantation for Cystic Fibrosis

“…Patients with pancreatic insufficiency should be vigilant in taking pancreatic enzyme supplements both pre-and posttransplant to maximize immunosuppressive medication absorption and avoid malnutrition. 80 Malnutrition has been viewed as a relative contraindication to transplantation and body mass index (BMI) is the most commonly used parameter to represent nutritional status in individuals with CF. 81 A BMI less than 18.5 has been associated with increased mortality both while awaiting lung transplantation and also post-lung transplant.…”