Byungjeong Song, Hyunmoon Back, Younghoon You, Eben Jung, Nayoung Han, Hwi-yeol Yun, Kwang-il Kwon
College of pharmacy, Chungnam National University, Daejeon, Korea
Objectives: Physiological changes during pregnancy are well known and these have various effects on drug pharmacokinetics (PK). The objective of this study was to compare methodologies which could explain pharmacokinetic variabilities of sulindac in pregnant women.
Method: Blood samples from 69 patients with preterm labor whose gestational age was between 17 and 37 weeks were collected 1.5 hr, 4 hr, 10 hr after oral administration of 200 mg sulindac. Three methods were applicated to explain pharmacokinetic variability in preterm labor patients, (1) dividing gestational age into three trimesters, (2) insertion of covariate related to pregnancy status such as gestational age to PK parameters, (3) applicate gestational age functions. Pharmacokinetics of sulindac and variability was evaluated using the nonlinear-mixed-effect modeling program (NONMEM® 7.3.0). Goodness of fit plots and visual predictive checks were conducted to confirm concordance with observed data.
Results: Population pharmacokinetic parameters were estimated based on 196 plasma samples. Data were adequately described by a one-compartment model. Vd/F and CL/F of sulindac was estimated 47.6 L, 6.09 L/hr, respectively. The third method which applicate gestational age functions described the observed variability well in PK data from preterm labor patients.
Conclusion: Population pharmacokinetic models were developed which can adequately describe the plasma concentrations of sulindac in patients with preterm labor. The gestational age function was a good tools to predict pharmacokinetics in pregnant women. We plan to expland this model to include an active and an inactive metabolites of sulindac. This methodology appears to be promising, therefore its application in other drugs used in pregnancy should be further explored.
References:
[1] Charles O. Odongo, Keteesa R. Bisaso, Mugammad Nitale et al., Trimester-specific population pharmacokinetics and other correlates of variability in Sulphadoxine-Pyrimethamine disposition among Uganda pregnant women. Drugs R D 15:351-362
[2] Berg AK, Mandrekar SJ, Ziegler KL, et al., Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects. J Clin Pharmacol 53(4):403-12
Reference: PAGE 25 () Abstr 5826 [www.page-meeting.org/?abstract=5826]
Poster: Methodology - Covariate/Variability Models