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Population Pharmacokinetic Model to Predict Steady-State Exposure to Once-Daily Cyclosporin Microemulsion in Renal Transplant Recipients

Clinical Pharmacokinetics volume 41, pages 59–69 (2002)Cite this article

Abstract

Background

The microemulsion formulation of cyclosporin (CsA-ME) has a less variable absorption profile than the standard formulation (CsA-S), but only limited information is available about once-daily administration of CsA-ME.

Objective

To develop a population pharmacokinetic model for once-daily CsA-ME that enables the prediction of individual steady-state area under the concentration-time curve (AUC) on the basis of blood concentration measurements and patient covariates.

Patients and method

The steady-state pharmacokinetics of once-daily cyclosporin were studied in 60 stable renal transplant recipients before and after conversion from CsA-S to CsA-ME. For each formulation, 7 blood samples were collected from 50 patients (group A) at sparse timepoints over 2 weeks, and 10 blood samples were collected from 10 patients (group B) at fixed timepoints over 24 hours. A 2-compartment population model assuming time-lagged first-order oral absorption was fitted to the data from group A, using nonlinear mixed effects modelling (NONMEM). The data from group B were used to evaluate the predictive performance of the model.

Results

Mean [± SD; coefficient of variation (%CV)] CsA-S doses of 245mg (±92) resulted in cyclosporin blood concentrations of 214 µg/L (± 70) after 12 hours and 108 µg/L (± 23) after 24 hours; the mean estimated AUC to 24 hours was 7658 µg · h/L (30%). With mean CsA-ME doses of 206mg (± 59), cyclosporin blood concentrations were 212 µg/L (± 33) and 132 µg/L (25%) after 12 and 24 hours, respectively, and the mean estimated AUC24 was 9357 µg · h/L (23%). A strong correlation between 12-hour concentrations and AUC24 was observed for CsA-ME (r = 0.95, p < 0.001), but not for CsA-S (r = 0.59, nonsignificant); the correlation between 24-hour trough concentrations and AUC24 was weaker for both formulations (r = 0.64, p < 0.05 and r = 0.37, nonsignificant, respectively). On the basis of the population model derived from group A, the single best timepoint to predict AUC24 from blood cyclosporin concentration was at 8 hours [AUC24 µg · h/L) = 19.6 · cyclosporin concentration at 8 hours µg/L) + 3035], resulting in a prediction error of 8.3 + 6.6% when applied to the measured AUC24 of group B. Adverse events were observed after conversion in 18 patients; these events generally resolved spontaneously or after dosage reduction, but twice-daily administration was required in some patients.

Conclusions

Switching from once-daily CsA-S to CsA-ME results in more consistent and predictable cyclosporin pharmacokinetics. Adjustment of dosage or regimen may be required in some patients.

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Notes

  1. Use of tradenames is for product identification only and does not imply endorsement.

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Acknowledgements

This work was supported by grant no. 32-49585.96 from the Swiss National Science foundation and by a grant from Novartis (formerly Sandoz).

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  1. Division of Nephrology and Hypertension, University of Berne, Freiburgstrasse, 3010, Berne, Switzerland

    Franziska Schädeli, Hans-Peter Marti, Felix J. Frey &  Dominik E. Uehlinger

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  1. Franziska Schädeli
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  2. Hans-Peter Marti
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Schädeli, F., Marti, HP., Frey, F.J. et al. Population Pharmacokinetic Model to Predict Steady-State Exposure to Once-Daily Cyclosporin Microemulsion in Renal Transplant Recipients. Clin Pharmacokinet 41, 59–69 (2002). https://doi.org/10.2165/00003088-200241010-00005

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Keywords

  • Cyclosporin
  • Renal Transplant Recipient
  • Trough Concentration
  • Population Pharmacokinetic Model
  • Microemulsion Formulation