A. Rousseau, F. Saint-Marcoux, J. Debord, P. Marquet.
Department of Pharmacology and Toxicology, University Hospital, Limoges, France.
Background: Cyclosporine (CsA) pharmacokinetics exhibits flat and delayed absorption profiles. Previously a model where the absorption time profile of CsA was described by a Gamma distribution, which convoluted with a two-compartment open model, was implemented in an in-house pharmacokinetic software.
Objectives: development of a population pharmacokinetic (PK) model in lung transplant patients, in order to study the influence of cystic fibrosis on interpatient variability in systemic exposure.
Patients and methods: a PK population model was developed using concentration-time data from 65 patients receiving oral cyclosporine either twice or three times daily, using NONMEM 5 under Visual-NM. Twenty seven patients had cystic fibrosis (CF) and 38 had not. Post-transplantation delay was 2 weeks to 5 years (15 patients were grafted for less than 3 months). 539 blood concentrations were available (5 to 12 for each patient). The absorption phase was modelled using a subset of gamma distribution simulated using n sequential compartments. This multistage modelling process is characterized by two parameters: the number of compartments (n) and the transfer rate constant. The classical first-order absorption model is a special case of this model since it is obtained when n=1. CsA was assayed by EMIT assay.
The influence of the following individual covariates was studied: age, weight, height, BSA, serum creatinine, and cystic-fibrosis (CF=1 if patient had cystic-fibrosis, otherwise CF=0). In a second approach, the medical status (CF/non-CF) was replaced by different bioavailability factors in the two groups of patients : after attributing a mean arbitrary bioavailability factor F equal to 1 to the non-CF patient group, F’ the bioavailability in CF patients and the variability of F and F’ were estimated.
Results: A pharmacokinetic model which combined an absorption phase simulated by 6 sequential compartments and a two-compartment open model better described the data than those using classical zero or first order absorption, even with one lag compartment. Interindividual variability was described by an exponential error model. For all the CsA profiles studied, the mean absorption time (MAT), apparent clearance (Cl/F) and apparent volume of the central compartment (Vc) were 0.71 h, 32.7 L/h and 85.4L respectively (inter-individual variability CV » 25.7; 27.7; 57.4 %). A good estimation of all the population PK parameters was obtained (standard error of estimates/mean 1.7, 4.5 and 8.6% for MAT, CL/F and Vc respectively). The mean Bayesian apparent clearance was significantly higher in patients with CF (p<0.01; 36.0 ± 8.2 versus 30.1 ± 7.7 L/h). This result is consistent with the well-known reduced bioavailabity in cystic fibrosis patients. Of the individual covariates tested, only CF led to a significant decrease of the Objective Function ( i.e. 40 points). Both CL/F and Vc/F were significantly (p<0.001) dependent on cystic fibrosis. Introduction of CF as a covariate on CL/F and Vc/F simultaneously was not redundant. However, the inter-individual variability obtained with the final model was not significantly reduced with respect to the model without covariates (CL/F 28 vs 25% and Vc/F 57 vs 52%). Residual variability consisted of a combined additional (10.2 µg/L) and proportional error (13.6%).
When taking into account the drug bioavailability instead of the medical status, it was found that F’/F = 0.73, meaning that CsA bioavailability in CF patients was on average 73% that of non-CF patients. Moreover, F and F’ showed a variability of 24% and decreased the Objective Function by 50 points.
Conclusion: A population PK model was successfully applied in patients with and without cystic fibrosis that could be useful to improve CsA dose adjustment in this context. No of the following covariates: weight, height, BSA, serum creatinine exhibited any clinically influence on the pharmacokinetics parameters of CsA.
Reference: PAGE 12 () Abstr 364 [www.page-meeting.org/?abstract=364]
Poster: poster