Ana MartÃn Suárez (1,4), John C Lukas (1), Rosario Calvo (2), M Paz Valverde (3), M Victoria Calvo (3), José M Lanao (4) and Alfonso DomÃnguez-Gil Hurlé (3,4)
1 Resource Facility for Population Kinetics, Department of Bioengineering, University of Washington, Seattle, WA 98195; 2 Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA 98195; 3 Service of Pharmacy, University Hospital, University of Salamanca, Spain.; 4 Department of Pharmacy and Pharmaceutical Technology, University of Salamanca, Spain
Immunosuppression with cyclosporine A has proven successful in preventing allograft rejection. However during the first months, twice daily cyclosporine oral dosification is complicated because of apparently non-steady state pharmacokinetics and requires frequent dose adjustment based on blood concentration (Cb) monitoring usually of Cb at the predose trough and optimally of Cb at 2 h post dose. A large temporal scale trend (compared to cyclosporine kinetics) is observed in a hyperbolic, rather than linear, oral dose versus Cb relationship in transplanted patients. This is associated with large inter and intra individual variability and is possibly due to a changing bioavailability which stabilizes after 50 to 80 days. We analyzed 318 Cb observations of Sandimun Neoral Cyclosporine (Novartis Pharma AG) at 2 h, 3 h and trough points in 11 renal transplant patients with a first-order absorption monocompartmental model coupled to an empirical function describing the temporal (days post transplantation, DPT) dependence of an apparent bioavailability, F. Model fits were performed with the NONMEM package (FOCE method). The population parameters (for unknown true bioavailability, f) were, [mean (inter individual CV%)] systemic clearance CL/f = 16.5 L/h (10%), central compartment volume of distribution V/f = 132 L (6.5%), Ka = 4 L/h (fixed) and F = 1-0.62 x EXP(-Lamda x DPT), with Lamda = 0.032 1/day (26%). The average F was 0.64 and reached 99% of its maximum value after 80 DPT. The model and population fit parameters were validated by retrospective simulation of the dosage regimen in 10 renal transplant patients with 683 trough observations and was within 10% of the objective function for the same model fit in the 10 patient validation group (2LLD% = 221/2349). The monocompartmental plus empirical bioavailability model can be used for dosage titration in renal transplant patients.
Reference: PAGE 10 (2001) Abstr 246 [www.page-meeting.org/?abstract=246]
Poster: poster