PMID- 33928146
OWN - NLM
STAT- MEDLINE
DCOM- 20210525
LR  - 20220422
IS  - 2314-6141 (Electronic)
IS  - 2314-6133 (Print)
VI  - 2021
DP  - 2021
TI  - Development of a Population Pharmacokinetic Model for Cyclosporine from 
      Therapeutic Drug Monitoring Data.
PG  - 3108749
LID - 10.1155/2021/3108749 [doi]
LID - 3108749
AB  - AIM: To develop a population pharmacokinetic model for Uruguayan patients under 
      treatment with cyclosporine (CsA) that can be applied to TDM. Patients and 
      Methods. A total of 53 patients under treatment with CsA were included. 37 
      patients with at least one pharmacokinetic profile described with four samples 
      were considered for model building, while the remaining 16 were considered for 
      the assessments of predictive performances. Pharmacokinetic parameter estimation 
      was performed using a nonlinear mixed effect modelling implemented in the 
      Monolix(R) software (version 2019R1, Lixoft, France); meanwhile, simulations were 
      performed in R v.3.6.0 with the mlxR package. RESULTS: A two-compartment model 
      with a first-order disposition model including lag time was used as a structural 
      model. The final model was internally validated using prediction corrected visual 
      predictive check (pcVPC) and other graphical diagnostics. A total of 621 CsA 
      steady-state concentrations were analyzed for model development. Population 
      estimates for the absorption constant (ka) and lag time were 0.523 h(-1) and 
      0.512 h, respectively; apparent clearance (CL/F) was 30.3 L/h 
      (relative standard error [RSE] +/- 8.25%) with an interindividual variability of 
      39.8% and interoccasion variability of 38.0%; meanwhile, apparent clearance of 
      distribution (Q/F) was 17.0 L/h (RSE +/- 12.1%) with and interindividual 
      variability of 53.2%. The covariate analysis identified creatinine clearance 
      (ClCrea) as an individual factor influencing the Cl of CsA. The predictive 
      capacity of the population model was demonstrated to be effective since 
      predictions made for new patients were accurate for C1 and C2 (MPPEs below 50%). 
      Bayesian forecasting improved significantly in the second and third occasions. 
      CONCLUSION: A population pharmacokinetic model was developed to reasonably 
      estimate the individual cyclosporine clearance for patients. Hence, it can be 
      utilized to individualize CsA doses for prompt and adequate achievement of target 
      blood concentrations of CsA.
CI  - Copyright (c) 2021 Martin Umpierrez et al.
FAU - Umpierrez, Martin
AU  - Umpierrez M
AUID- ORCID: 0000-0002-1457-0894
AD  - Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la 
      Republica, Uruguay, General Flores, 2124 Montevideo, Uruguay.
FAU - Guevara, Natalia
AU  - Guevara N
AUID- ORCID: 0000-0002-5541-6316
AD  - Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la 
      Republica, Uruguay, General Flores, 2124 Montevideo, Uruguay.
FAU - Ibarra, Manuel
AU  - Ibarra M
AUID- ORCID: 0000-0002-0484-6367
AD  - Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la 
      Republica, Uruguay, General Flores, 2124 Montevideo, Uruguay.
FAU - Fagiolino, Pietro
AU  - Fagiolino P
AUID- ORCID: 0000-0001-6756-1601
AD  - Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la 
      Republica, Uruguay, General Flores, 2124 Montevideo, Uruguay.
FAU - Vazquez, Marta
AU  - Vazquez M
AUID- ORCID: 0000-0002-8459-4859
AD  - Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la 
      Republica, Uruguay, General Flores, 2124 Montevideo, Uruguay.
FAU - Maldonado, Cecilia
AU  - Maldonado C
AUID- ORCID: 0000-0002-9452-2111
AD  - Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la 
      Republica, Uruguay, General Flores, 2124 Montevideo, Uruguay.
LA  - eng
PT  - Journal Article
DEP - 20210408
PL  - United States
TA  - Biomed Res Int
JT  - BioMed research international
JID - 101600173
RN  - 83HN0GTJ6D (Cyclosporine)
SB  - IM
MH  - Adult
MH  - Cyclosporine/blood/*pharmacokinetics
MH  - *Drug Monitoring
MH  - Female
MH  - Humans
MH  - Male
MH  - *Models, Biological
PMC - PMC8052134
COIS- The authors declare that there is no conflict of interest regarding the 
      publication of this article.
EDAT- 2021/05/01 06:00
MHDA- 2021/05/26 06:00
PMCR- 2021/04/08
CRDT- 2021/04/30 06:56
PHST- 2020/06/08 00:00 [received]
PHST- 2021/03/05 00:00 [revised]
PHST- 2021/03/17 00:00 [accepted]
PHST- 2021/04/30 06:56 [entrez]
PHST- 2021/05/01 06:00 [pubmed]
PHST- 2021/05/26 06:00 [medline]
PHST- 2021/04/08 00:00 [pmc-release]
AID - 10.1155/2021/3108749 [doi]
PST - epublish
SO  - Biomed Res Int. 2021 Apr 8;2021:3108749. doi: 10.1155/2021/3108749. eCollection 
      2021.