Pharmacokinetic-pharmacodynamic model of fimasartan applied to predict the influence of a high fat diet on its blood pressure-lowering effect in healthy subjects.
OBJECTIVE
Fimasartan is a non-peptide angiotensin II receptor antagonist which selectively blocks the AT(1) receptor. The aim of our study was to perform a population pharmacokinetic-pharmacodynamic (PK-PD) analysis of fimasartan to evaluate the effect of food on the mechanistic PK-PD relationship.


METHODS
This was a food-drug interaction single-center study involving 24 healthy subjects that was designed as a randomized, open-label, single-dosing, two-way crossover trial. Extensive PK data was obtained on blood samples collected at 0, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 12, and 24 h post-dosing and five systolic/diastolic blood pressure (BP) measurements made at 0, 4, 8, 12 and 24 h post-dosing and used to construct a mixed effect model (NONMEM, ver. 6.2).


RESULTS
A two-compartment linear PK model with zero-order (fasted) or Weibull (fed with high-fat diet) absorption best described the PK of fimasartan. Relative bioavailability decreased by 37 % when the subjects were given a high-fat diet.


CONCLUSIONS
The turnover PK-PD model combined with pre-defined cosine function for circadian rhythm described the BP changes measured within 24 h after dosing better than the effect compartment or transduction models. To predict the influence of a high-fat diet on the blood pressure-lowering effect of fimasartan in healthy subjects, we simulated changes in BP when fimasartan was given daily for 30 days. The overlapping pattern of simulated BP curves in the fasted versus fed group demonstrated that a high-fat diet would not cause a clinically significant reduction in the BP-lowering effect of fimasartan, despite a significant reduction in bioavailability.
Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, Seoul, Korea.
Jongtae
J
Lee
Seunghoon
S
Han
Sangil
S
Jeon
Taegon
T
Hong
Dong-Seok
DS
Yim
D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000097:blood / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D059305:Diet, High-Fat; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011743:Pyrimidines / Q000097:blood / Q000494:pharmacology*; D013777:Tetrazoles / Q000097:blood / Q000494:pharmacology*; D055815:Young Adult
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D011743:Pyrimidines; D013777:Tetrazoles; C558933:fimasartan