Dose adjustment strategy for oral microemulsion formulation of cyclosporine: Population pharmacokinetics-based analysis in kidney transplant patients

Kenji Tokui, Tsukasa Kimata, Kazuharu Uchida, Hiroaki Yuasa, Yayoi Hayashi, Takeharu Itatsu, Toshitaka Nabeshima

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The present study aims to determine the population pharmacokinetic parameters of cyclosporine (CsA) after multiple oral administration of the microemulsion formulation, Neoral®, in kidney transplant patients and to propose a limited sampling strategy to predict AUC0-4h using them and the Bayesian method. The AUC0-4h is a parameter that has recently been recommended as an index for the dose adjustment in therapeutic drug monitoring of CsA. Blood samples were obtained at the trough level and at hourly intervals up to 5 hours from 125 patients (78 male and 47 female) who were receiving Neoral® twice daily, and whole-blood concentrations of CsA were measured. The population pharmacokinetic parameters were estimated using the NONMEM computer program and a linear two-compartment model with first-order absorption. The observed AUC0-4h and concentrations at different sampling times were compared with those computer-predicted by the Bayesian method, using the population pharmacokinetic parameters and 2 or 3 concentrations from those at 0 h (C0), 1 h (C1), and 2 h (C2) after administration. Typical values for the absorption rate constant (ka), elimination rate constant (kel), apparent volume of distribution for the central compartment (Vd/F), and oral clearance (CL/F) calculated by population pharmacokinetic analysis were 2.16 hours-1, 0.547 hours-1, 43.3 L, and 23.7 L/h, respectively. The CsA concentrations predicted using either the 2-point or 3-point sampling strategy exhibited an excellent correlation with the observed values (R2 > 0.81), and accordingly, the predicted AUC 0-4h values were in excellent agreement with those observed. The best predictability of AUC0-4h was found for the 3-point sampling strategy using C0-4h, C1, and C2, closely followed by a 2-point sampling strategy using C1 and C2. The present findings suggest that a simplified strategy based on population pharmacokinetics can accurately predict AUC0-4h from concentrations at 2 or 3 sampling time points, providing an excellent method for the daily dose adjustment of Neoral® in routine clinical use for kidney transplant patients.

Original languageEnglish
Pages (from-to)287-294
Number of pages8
JournalTherapeutic Drug Monitoring
Volume26
Issue number3
DOIs
Publication statusPublished - 01-06-2004
Externally publishedYes

Fingerprint

Cyclosporine
Pharmacokinetics
Transplants
Kidney
Bayes Theorem
Population
Drug Monitoring
Area Under Curve
Oral Administration
Software

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Tokui, Kenji ; Kimata, Tsukasa ; Uchida, Kazuharu ; Yuasa, Hiroaki ; Hayashi, Yayoi ; Itatsu, Takeharu ; Nabeshima, Toshitaka. / Dose adjustment strategy for oral microemulsion formulation of cyclosporine : Population pharmacokinetics-based analysis in kidney transplant patients. In: Therapeutic Drug Monitoring. 2004 ; Vol. 26, No. 3. pp. 287-294.
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Dose adjustment strategy for oral microemulsion formulation of cyclosporine : Population pharmacokinetics-based analysis in kidney transplant patients. / Tokui, Kenji; Kimata, Tsukasa; Uchida, Kazuharu; Yuasa, Hiroaki; Hayashi, Yayoi; Itatsu, Takeharu; Nabeshima, Toshitaka.

In: Therapeutic Drug Monitoring, Vol. 26, No. 3, 01.06.2004, p. 287-294.

Research output: Contribution to journalArticle

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AU - Tokui, Kenji

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AU - Nabeshima, Toshitaka

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