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Time‐dependent pharmacokinetics of cyclosporine (Neoral ® ) in de novo renal transplant patients
Author(s) -
Lukas J. C.,
Suárez A. M.,
Valverde M. P.,
Calvo M. V.,
Lanao J. M.,
Calvo R.,
Suarez E.,
Gil A. D.
Publication year - 2005
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/j.1365-2710.2005.00683.x
Subject(s) - cmin , pharmacokinetics , bioavailability , nonmem , volume of distribution , population , medicine , urology , transplantation , renal function , confidence interval , pharmacology , cmax , environmental health
Summary 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− α * exp(− λ * 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 λ = 0·037/day (0·005–0·069) (120%). The absorption rate k a and the parameter α 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.