Date of Award

2004

Degree Type

Thesis

Degree Name

Master of Science in Applied Pharmaceutical Sciences

Specialization

Pharmacokinetics

Department

Applied Pharmaceutical Sciences

First Advisor

Sara Rosenbaum

Abstract

Pharmacokinetics involves the analysis of plasma concentration and time data to obtain models that summarize the absorption, distribution and elimination parameters of a drug. The population approach to pharmacokinetics involves the estimation of mean pharmacokinetic parameters and their variability within the population.

Cyclosporine is a widely used immunosuppressive agent, and its pharmacokinetic parameters are characterized by a large variation in blood concentrations after oral or intravenous administration. Cyclosporine being a narrow therapeutic index drug is associated with significant consequences if the drug is present in 'sub-therapeutic' or 'supra-therapeutic' concentration. Optimization of therapy is challenging owing to variable pharmacokinetic parameters and narrow therapeutic index.

Population pharmacokinetic approach is used in this study to identify and characterize demographic and pharmacological variables that influence the pharmacokinetics of cyclosporine in lung transplant recipients.

Cyclosporine concentration-time data obtained through a randomized, prospective clinical trial was re-analyzed. A total of 1004 abbreviated cyclosporine profiles were available from 48 patients at 1, 2, 3, 4, 12, 24, 36 and 52 post operative weeks. Population modeling was performed using NONMEM (Version V). A one compartment model with first-order absorption and elimination was used to model the data. Exponential models were used for inter-individual variation on oral clearance (CL/F) and volume of distribution (V/F). A proportional model was used for residual error.

Estimates of CL/F and V/F (±S.E) were 26.4 (3 .7) Uh and 183 (37) L/h, respectively. Concomitant itraconazole and diagnosis of cystic fibrosis were identified as significant covariates for CL/F. Time post transplant and different formulations were significant when modeled on bioavailability. With this model the estimated coefficients of variation were 18.5% and 49.6% for interpatient variability in CL/F and residual variability, respectively. Patients taking itraconazole were found to have a CL/F of 11.6 (4.3) L/h, 43.9% that of the other patients. Patients with cystic fibrosis had CL/F of 52.3 (6.9) L/h, 50% higher than patients without cystic fibrosis. Relative bioavailability of cyclosporine from Sandimmune® was 87% that of Neoral®.

In conclusion, the covariates which influenced the pharmacokinetics of study population were concomitant itraconazole, diagnosis of cystic fibrosis, time post transplant and different formulation.

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