Document Detail

Time-dependent pharmacokinetics of cyclosporine (Neoral) in de novo renal transplant patients.
MedLine Citation:
PMID:  16336287     Owner:  NLM     Status:  MEDLINE    
PURPOSE: A model for the large scale temporal trend in the oral bioavailability of microemulsion cyclosporine (Neoral) (CsA) is established, with dependence on post-(renal) transplantation day (PTD). METHODS: Twenty de novo adult renal transplant recipients were monitored for CsA administered orally q12 h. A model development group (11 patients, 315 blood concentration samples) was screened at 2 h (C(2); n = 92), 3 h (C(3); n = 56) and at predose troughs (C(min); n = 167) over periods of up to 75 days. The final model was tested in nine patients with C(min) (n = 580) monitored across 4-5 years. The doses varied between 100 and 538 mg with an apparent hyperbolic trend in C(2)/dose vs. PTD. A nonlinear mixed effects modelling (NONMEM) approach was used to obtain population and individual patient one-compartment pharmacokinetic (PK) parameters for oral CsA, which carry implicit the bioavailability (F). RESULTS: In the final PK model (PK-f) the F was modelled via a simple function for the temporal (days) trend of the bioavailability after transplantation as, F(f) = 1-alpha * exp(-lambda * PTD) resulting in a 28% reduction in the unexplained intra-individual variability. The population PK-f parameters were, for apparent clearance [mean, 95% confidence interval (interindividual CV%)] Cl/F(f) = 17.0 (13.8-20.2) L/h (27%), apparent central compartment volume of distribution, V/F(f) = 134 L (108-160) (28%), and lambda = 0.037/day (0.005-0.069) (120%). The absorption rate k(a) and the parameter alpha were approximated iteratively as 4/h and 0.62 respectively. The PK-f was structurally superior to the base model in explaining part of the within subject (occasion) variability and predicting the exposure surrogates C(2) and C(3). Also, the PK-f was better than the base model with Bayesian fitting of individual profiles in that group. CONCLUSION: The PTD-dependent relative bioavailability model provides a rational means of steering dose titration of CsA in de novo renal transplantation patients by removing the large scale PK adjustment signal, either through nomograms or as a Bayesian prior.
J C Lukas; A M Su?rez; M P Valverde; M V Calvo; J M Lanao; R Calvo; E Suarez; A D Gil
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of clinical pharmacy and therapeutics     Volume:  30     ISSN:  0269-4727     ISO Abbreviation:  J Clin Pharm Ther     Publication Date:  2005 Dec 
Date Detail:
Created Date:  2005-12-12     Completed Date:  2006-03-17     Revised Date:  2008-05-28    
Medline Journal Info:
Nlm Unique ID:  8704308     Medline TA:  J Clin Pharm Ther     Country:  England    
Other Details:
Languages:  eng     Pagination:  549-57     Citation Subset:  IM    
Resource Facility for Population Kinetics, Department of Bioengineering, University of Washington, Seattle, WA, USA.
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MeSH Terms
Biological Availability
Cyclosporine / blood,  pharmacokinetics*
Immunosuppressive Agents / blood,  pharmacokinetics*
Kidney Transplantation*
Middle Aged
Models, Biological*
Time Factors
Grant Support
5 P41 RR-12609/RR/NCRR NIH HHS
Reg. No./Substance:
0/Emulsions; 0/Immunosuppressive Agents; 59865-13-3/Cyclosporine

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