Early non-steady-state population pharmacokinetics of oral cyclosporine in renal transplant recipients

Abstract

This study aimed to evaluate the change in the pharmacokinetics (PK) of cyclosporine in the non-steady-state period in the first week after renal transplantation; the factors influencing this change, including genetic variability; and the time point concentration that correlated best with drug exposure. Data were obtained from 69 patients, and PK studies were conducted on postoperative days (PODs) 2, 3, and 7. Samples were taken pre-dose and at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration. MDR1, CYP3A4, and CYP3A5 were genotyped. A population PK analysis and correlational analysis between the concentration at each time point and the area under the time-concentration curve were performed. A two-compartment model with first-order absorption was chosen. The rate and extent of drug absorption showed a significant increase on POD3, followed by a slight decrease on POD7. Until POD3, 8 hours post-dose was the single time point concentration that correlated best with drug exposure and 3 hours was the best time point on POD7. In both analyses, the MDR1 genotype showed potential as a factor influencing PK change. We conclude that oral administration of cyclosporine and dose adjustment based on a single concentration measurement might result in unexpected drug exposure during this early posttransplantation period.

Keywords: cytochrome P450; multidrug resistance 1 (MDR1) gene; renal transplantation.

Figure 1

Goodness-of-fit plot for final pharmacokinetic model (A–F). Notes: (A and B) Solid line: line of identity. (D–F) Straight line indicates CWRES =0. (A–F) Broken lines indicate locally weighted scatterplot smoothing. Abbreviations: CWRES, conditonal weighted residuals; |IWRES|, absolute value of individual weighted residuals; POD, postoperative day.

Figure 2

Relationships between parameters and covariates (A–C). Notes: Broken lines indicate locally weighted scatterplot smoothing. Abbreviations: D7F1, relative bioavailability on POD7 compared with POD3; POD, postoperative day; k_a, absorption rate constant; V2, volume of the central compartment.

Figure 3

Visually predicted checks using observed and simulated CsA concentration for each study day (A–C). Notes: For easier visual comparison, the observed concentration data are given as open circles in all panels. Lines: median (solid) and 90% prediction interval (broken). Abbreviations: CsA, cyclosporine; POD, postoperative day.