| Time-dependent pharmacokinetics of cyclosporine (Neoral) in de novo renal transplant patients. | |
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MedLine Citation:
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PMID: 16336287 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of clinical pharmacy and therapeutics Volume: 30 ISSN: 0269-4727 ISO Abbreviation: J Clin Pharm Ther Publication Date: 2005 Dec |
Date Detail:
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Created Date: 2005-12-12 Completed Date: 2006-03-17 Revised Date: 2008-05-28 |
Medline Journal Info:
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Nlm Unique ID: 8704308 Medline TA: J Clin Pharm Ther Country: England |
Other Details:
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Languages: eng Pagination: 549-57 Citation Subset: IM |
Affiliation:
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Resource Facility for Population Kinetics, Department of Bioengineering, University of Washington, Seattle, WA, USA. jlukas@pharsight.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Biological Availability Cyclosporine / blood, pharmacokinetics* Emulsions Humans Immunosuppressive Agents / blood, pharmacokinetics* Kidney Transplantation* Middle Aged Models, Biological* Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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5 P41 RR-12609/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Emulsions; 0/Immunosuppressive Agents; 59865-13-3/Cyclosporine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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