Does the choice of applied physiologically-based pharmacokinetics platform matter? A case study on simvastatin disposition and drug-drug interaction

Abstract

Physiologically-based pharmacokinetic (PBPK) models have an important role in drug discovery/development and decision making in regulatory submissions. This is facilitated by predefined PBPK platforms with user-friendly graphical interface, such as Simcyp and PK-Sim. However, evaluations of platform differences and the potential implications for disposition-related applications are still lacking. The aim of this study was to assess how PBPK model development, input parameters, and model output are affected by the selection of PBPK platform. This is exemplified via the establishment of simvastatin PBPK models (workflow, final models, and output) in PK-Sim and Simcyp as representatives of established whole-body PBPK platforms. The major finding was that the choice of PBPK platform influenced the model development strategy and the final model input parameters, however, the predictive performance of the simvastatin models was still comparable between the platforms. The main differences between the structure and implementation of Simcyp and PK-Sim were found in the absorption and distribution models. Both platforms predicted equally well the observed simvastatin (lactone and acid) pharmacokinetics (20-80 mg), BCRP and OATP1B1 drug-gene interactions (DGIs), and drug-drug interactions (DDIs) when co-administered with CYP3A4 and OATP1B1 inhibitors/inducers. This study illustrates that in-depth knowledge of established PBPK platforms is needed to enable an assessment of the consequences of PBPK platform selection. Specifically, this work provides insights on software differences and potential implications when bridging PBPK knowledge between Simcyp and PK-Sim users. Finally, it provides a simvastatin model implemented in both platforms for risk assessment of metabolism- and transporter-mediated DGIs and DDIs.

FIGURE 1

Metabolism and transport pathways included in the PBPK models.

FIGURE 2

Modeling strategy of simvastatin lactone (SVL) and acid (SVA) in the selected platforms. ADME, absorption, distribution, metabolism, and excretion; DDI, drug–drug interaction; DGI, drug–gene interaction; J_max, unbound maximum concentration; PBPK, physiologically‐based pharmacokinetic; PK, pharmacokinetic; SVA, simvastatin acid; SVL, simvastatin lactone; V_max, maximal rate of metabolism.

FIGURE 3

Predicted simvastatin lactone PK profiles (lines) in Simcyp (a) and PK‐Sim (b) versus clinical observations reported as mean (circles) for BCRP CC (dark colors) and AA (light colors) genotypes (31). Predicted simvastatin acid PK profiles (lines) in Simcyp (c) and PK‐Sim (d) versus observed (circles) for OATP1B1 TT and CC genotypes (25). The solid lines represent the predicted geometric mean and the shaded area the predicted 5%–95% quantiles for virtual populations. The normal genotypes (BCRP‐CC and OATP1B1‐TT) are represented with dark colors and the genotypes with reduced function of transporter (BCRP‐AA and OATP1B1‐CC) with light colors. PK, pharmacokinetic.

FIGURE 4

Predicted simvastatin lactone (a, b) and acid (c, d) PK profiles in Simcyp (pink/left) and PK‐Sim (blue/right) versus clinical observations reported as study mean (dots) for 40 mg dose (S19–S37). The black line represents the predicted geometric mean and the shaded area represents the predicted 5%–95% quantiles for virtual populations. AUC, area under the curve; C_max, maximum plasma concentration; Obs, observed; PK, pharmacokinetic; Pred, predicted.

FIGURE 5

Predicted versus observed simvastatin lactone and acid AUC and C_max for different datasets at a dose range 20–80 mg (S15–S44). Each study is represented by a dot. The solid line represents the line of unity, the dashed lines represent the 1.25‐fold error and the shaded area represents the twofold error in Simcyp (pink/left) and PK‐Sim (blue/right). AUC, area under the curve; C_max, maximum plasma concentration; DDI, drug–drug interaction; DGI, drug–gene interaction.

FIGURE 6

Predicted versus observed simvastatin lactone and acid AUC and C_max ratio when coadministered with CYP3A4 and OATP1B1 inhibitors for nine clinical DDI studies (S17;S25;S28;S45‐S48) and for different BCRP and OATP1B1 genotypes for three clinical DGI studies (S1–S3). Each study is represented by a circle (lactone) or triangle (acid); details of the study design can be found in Table S2 in Appendix S2. The solid line represents the line of unity, the dashed lines represent the 1.25‐fold error and the shaded area represents the twofold error in Simcyp (pink/left) and PK‐Sim (blue/right). AUC, area under the curve; C_max, maximum plasma concentration