Yun Kim1, Kyung-Sang Yu1, Jae-Yong Chung2
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea, 2Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea
Introduction: Rosuvastatin is one of the most hydrophilic statins (3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors) used for the treatment of hyperlipidemia. Rosuvastatin is taken up into the liver predominantly via the organic anion-transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1), and also is a substrate of the breast cancer resistance protein (BCRP, gene ABCG2), which is an efflux transporter expressed in various normal tissues. Genetic polymorphisms of OATP1B1 and BCRP are known to be associated with inter-individual variability in the pharmacokinetics (PKs)/pharmacodynamics (PDs) of rosuvastatin. However, there is currently limited information regarding how genetic polymorphisms of OATP1B1 and BCRP quantitatively affect the PK/PD of rosuvastatin using a population approach in young and especially in elderly subjects.
Objectives: This study was conducted to determine how genetic polymorphisms of OATP1B1 and BCRP quantitatively influence the PK/PD after multiple administrations of rosuvastatin, and to investigate clinical covariates in healthy young and elderly subjects.
Methods: We obtained the PK/PD data from two separate clinical trials, one of which involved 20 elderly subjects (age 65-85 years), and the other of which involved 34 young subjects (age 20-50 years). Both studies were designed as open-label, one-sequence, and multiple oral administration of 20 mg of rosuvastatin for 21 days. A population PK/PD model was developed using 468 rosuvastatin concentrations at steady state, and 220 low-density lipoprotein cholesterol (LDL-c) concentrations in 52 subjects. The First-Order Conditional Estimation with Interaction estimation method was used with NONMEM (version 7.3). A physiological indirect response model was incorporated to explain the change of LDL-c levels. PD modeling was performed after fixing all the PK parameters. The effects of demographics including class (young or elderly), baseline serum creatinine (BScr), and the phenotypes of OATP1B1 and BCRP on the PK/PD of rosuvastatin were evaluated. Transporter phenotypes were converted by genotypes at rs2231142 for ABCG2 [C/C, normal function (NF); C/A, intermediate function (IF); A/A, low function (LF)] and at rs4149056 for SLCO1B1 (T/T, NF; T/C, IF; C/C, LF).
Results: A two-compartment model with a simultaneous zero- and first-order absorption model along with lag times adequately described the time-concentration profiles of rosuvastatin. The typical values of the clearance (CL) and inter-compartmental clearance (Q) were found to 39.7 and 50.9 L/h, respectively. The absorption process of rosuvastatin was explained by first-order absorption rate constant (ka, 0.264 /h) with lag time (1.48 h), and duration of zero-order absorption (D2, 0.709 h) with lag time (0.675 h). The PK model showed that 83.7% of the administered dose of rosuvastatin was absorbed by the first-order process and the remaining 16.3% was absorbed by the zero-order process. Reduced function of BCRP, BScr, and effect of elderly were found to be significant covariates for the CL of rosuvastatin. The CL estimates in BCRP IF and LF decreased 24.2% and 50.2% compared to that in NF. We also observed the CL and Q in elderly were approximately 20% and 16% lower than young subjects, respectively. The profile of the LDL-c lowering effect of rosuvastatin was appropriately described by the physiological indirect response model. Multiple administration of rosuvastatin inhibited the LDL-c synthesis rate constant (Kin, 1.29 mg/dL/hr) along with maximum inhibitory effect (Imax, 0.966) model and concentration resulting in 50% of Imax (IC50) was shown as 0.0672 μg/L. Baseline of LDL-c was identified with significant covariates (BMI, body mass index; BScr) as the following regression equation: Baseline (mg/dL) = 113 x (BMI/23.8)0.803 x (BScr/0.96)0.494.
Conclusions: The PK/PD parameters of rosuvastatin were quantitatively described by the developed population model. This PK/PD model in the contribution of BCRP, elderly effect, and demographic data to the variability of rosuvastatin can be served as a tool to predict the PK/PD of rosuvastatin, thus providing a rationale for individualized optimal dosing to improve clinical outcome.
References:
[1] Tzeng, T.B. et al. Population pharmacokinetics of rosuvastatin: implications of renal impairment, race, and dyslipidaemia. Curr Med Res Opin 24, 2575-85 (2008).
[2] Aoyama, T. et al. Pharmacokinetic/pharmacodynamic modeling and simulation of rosuvastatin using an extension of the indirect response model by incorporating a circadian rhythm. Biol Pharm Bull 33, 1082-7 (2010).
[3] Kakara, M. et al. Population pharmacodynamic analysis of LDL-cholesterol lowering effects by statins and co-medications based on electronic medical records. Br J Clin Pharmacol 78, 824-35 (2014).
[4] Kim, J. et al. A population pharmacokinetic-pharmacodynamic model for simvastatin that predicts low-density lipoprotein-cholesterol reduction in patients with primary hyperlipidaemia. Basic Clin Pharmacol Toxicol 109, 156-63 (2011).
Reference: PAGE 28 (2019) Abstr 9024 [www.page-meeting.org/?abstract=9024]
Poster: Drug/Disease Modelling - Endocrine