Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin

Abstract

Typically, pharmacokinetic-pharmacodynamic (PK/PD) models use plasma concentration as the input that drives the PD model. However, interindividual variability in uptake transporter activity can lead to variable drug concentrations in plasma without discernible impact on the effect site organ concentration. A physiologically based PK/PD model for rosuvastatin was developed that linked the predicted liver concentration to the PD response model. The model was then applied to predict the effect of genotype-dependent uptake by the organic anion-transporting polypeptide 1B1 (OATP1B1) transporter on the pharmacological response. The area under the plasma concentration-time curve (AUC0-∞) was increased by 63 and 111% for the c.521TC and c.521CC genotypes vs. the c.521TT genotype, while the PD response remained relatively unchanged (3.1 and 5.8% reduction). Using local concentration at the effect site to drive the PD response enabled us to explain the observed disconnect between the effect of the OATP1B1 c521T>C polymorphism on rosuvastatin plasma concentration and the cholesterol synthesis response.

Figure 1

Schematic of the physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) model used in this study. The unbound concentration of rosuvastatin in the intracellular water of hepatocytes (Cu_IW) and the impact of liver uptake transporter activity are predicted by a permeability-limited liver model within a full PBPK model. This accounts for the distribution of unbound drug from the blood into the extracellular water and the passive diffusion and active transport (K_tEW-in and K_tIW-out) across the sinusoidal membrane between the intracellular and extracellular space. The impact of ionization is considered (red circles represent ionized drug and blue circles unionized drug) as well as the association of drug with extracellular proteins and intracellular acidic phospholipids and partitioning into neutral lipids and neutral phospholipids. Elimination of intracellular drug via biliary clearance and metabolism are considered. The PD response model uses a modified indirect response model input, with the drug effect resulting from inhibition of the input rate (K_in) and driven by the predicted liver Cu_IW.

Figure 2

Simulated and observed plasma rosuvastatin concentration profiles for the (a) wild-type (c.521TT), (b) heterozygous, and (c) homozygous deficient (c.521CC) organic anion-transporting polypeptide 1B1 (OATP1B1) genotypes. Gray lines represent simulated individual trials, and the solid black line represents the simulated mean of 10 trials. Circles represent data extracted from Pasanen et al.. The simulation study design was matched to that of the clinical study.

Figure 3

(a) Simulated and observed plasma rosuvastatin concentration profile after multiple daily dosing (10 mg) for 14 days. Gray lines represent simulated individual trials, the solid black line represents the simulated mean of 10 trials, and circles are mean observed data. (b) Mean simulated (lines) and observed (markers) plasma MVA profile before rosuvastatin administration (baseline) and after morning (07:00) or evening (18:00) rosuvastatin administration. The time is 06:00 at 312 h. Observed data are from Martin et al.. The simulation study design was matched to that of the clinical study. MVA, mevalonic acid.

Figure 4

The effect of the organic anion-transporting polypeptide 1B1 (OATP1B1) sequence variation on the simulated mean (a) plasma concentration and (b) liver unbound intracellular water concentration (Cu_IW) of rosuvastatin and (c) plasma mevalonic acid (MVA) concentration using plasma concentration or (d) liver Cu_IW as the driving concentration for the response. Data are the mean of 100 simulated individuals based on a population that was 50% female with an age range 20–50 years. Individuals were dosed with 10 mg oral rosuvastatin at 18:00 daily for 5 days. The time is 18:00 at 108 h.

Figure 5

Comparison of the interindividual variability of simulated (a) plasma rosuvastatin AUC_0–∞ and (b) reduction in MVA AUC from baseline for OATP1B1 c.521TT, TC, and CC genotype groups. Box and whisker plots: horizontal lines from bottom to top are the minimum, 25th percentile, median, 75th percentile, and maximum values. The diamond symbol is the mean. Distributions obtained for 100 simulated healthy volunteer individuals for each genotype. Variability was included in PBPK model parameters but not the PD model parameters.

Figure 6

Sensitivity analysis of the influence of total uptake transporter intrinsic clearance (CL_int,T) on (a) plasma area under the curve (AUC_{0–24 h}), (b) liver unbound concentration in intracellular water (Cu_IW) AUC_{0–24 h}, (c) muscle AUC_{0–24 h} of rosuvastatin, and (d) the reduction in plasma mevalonic acid (MVA) AUC relative to baseline. (e) The elasticity index allows direct comparison of the relative change of plasma, liver Cu_IW, and muscle AUC of rosuvastatin and reduction in MVA AUC ratio to the relative change in total uptake transporter CL_int,T. MVA, mevalonic acid.