Pharmacokinetics model for Nifedipine administered to Healthy Volunteers.
C. Hoyo-Vadillo(1), H. González(2), E. Romero(2) and J. Pérez Urízar(3)
(1)Cinvestav, Mexico; (2)University of Guadalajara, Mexico; (3)University of San Luis Potosí, Mexico
Objectives: Nifedipine pharmacokinetics a great variability on clearance due to genetic polymorphisms and food-drug interaction. In Mexicans [1] the clearance is significantly lower than in Caucasian populations. The purpose of this study was to fit a pharmacokinetic population model for a population of young healthy volunteers.
Results: Eighty six healthy young volunteers of both genders participated. After signing consent they received the 10 mg gelatin capsule of Bayer nifedipine. Ten blood samples were taken from cubital vein. Nifedipine was analyzed with a validated hplc method. Nonmem version 6 was used with ADVAN4 TRANS1.
The $PK section was tested with combinations for exponential etas. Best fit was achieved with:
TVCL=THETA(1)
CL=TVCL *EXP(ETA(1))
TVKA=THETA(2)
KA=TVKA*EXP(ETA(2))
TVK23=THETA(3)
K23=TVK23 *EXP(ETA(3))
TVK32=THETA(4)
K32=TVK32*EXP(ETA(4))
TVV2=THETA(5)
V2=TVV2*EXP(ETA(5))
K=CL/V2
$ERROR was: Y=F*EXP(ERR(1)). Xpose2 was used to analyze the goodness of fit. Best model had an objective function of 5931.334. Mean values and standard deviation (SD) were:
|
|
Mean |
SD |
|
Cl |
56.2 |
3.7 |
|
Ka |
6.35 |
0.91 |
|
k23 |
0.481 |
0.126 |
|
k32 |
0.266 |
0.054 |
|
V |
128.0 |
21.4 |
|
Epsilon |
0.124 |
|
Conclusions: Nifedipine pharmacokinetics showed greater variability in absorption besides a tlag parameter was clear for most subjects it did not improve the fit, and so was not included. No covariables were included at this time.
References:
[1] Hoyo-Vadillo C, Castaneda-Hernandez G, Herrera JE, Vidal-Garate J, Salazar LA, Moreno-Ramos A, Chavez F, Tena I, Hong E. 1989. Pharmacokinetics of oral nifedipine: relevance of the distribution phase. J Clin Pharmacol 29(3):251-6.