Method Profile
A whole-body PBPK workflow evaluates a transporter-mediated drug interaction across age and ABCG2 genotype strata, then compares simulated rosuvastatin exposure with a monotherapy reference.
Research assessment of how ticagrelor-related BCRP inhibition, older age and the ABCG2 c.421C>A homozygous variant could change rosuvastatin exposure.
Separate rosuvastatin and ticagrelor PBPK models were developed and combined with competitive BCRP inhibition. The workflow includes genotype-specific transporter activity and an age-related 40% reduction in CYP2C9 activity for the older group.
Four virtual groups of 100 people: younger and 65–85-year-old adults, each wild type or homozygous for ABCG2 c.421C>A. Simulations compare rosuvastatin alone with coadministration at full, half or quarter doses; the stated exposure-matching AUC ratio interval is 0.80–1.25.
Model inputs
Clinical concentration–time and exposure data for both drugs, available interaction data, ABCG2 genotype, age-related physiology, transporter expression and enzyme activity.
Software and scenarios
PK-Sim version 12.0; observed-study characteristics were aligned with virtual populations where available. Study-specific rosuvastatin and ticagrelor regimens were simulated over two weeks.
Assess model fit using mean relative deviation, geometric mean fold error, AUC and Cmax; compare simulated and observed drug-interaction ratios; report each age–genotype group against the 0.80–1.25 exposure-matching target.
Component models compared with available clinical pharmacokinetic data; interaction model compared with observed coadministration data; separate age–genotype dose scenarios simulated afterward.
Four simulated groups of 100 virtual subjects each; older group aged 65–85 years. The relevant elderly, variant and coadministration clinical scenarios relied on a single study and did not provide an independent scenario validation.
Observed versus simulated interaction exposure ratios; simulated coadministration AUC versus monotherapy AUC.
Interaction AUC ratio 2.25 simulated versus 2.47 observed; Cmax ratio 1.92 versus 2.58. The exposure-matching scenarios yielded AUC ratios 1.44 and 0.78 for younger wild-type and homozygous-variant groups at half dose, 1.06 for older wild-type at quarter dose, and 1.12 for older homozygous-variant at half dose.
A medRxiv preprint simulated rosuvastatin exposure during ticagrelor coadministration in four age–ABCG2 genotype groups. Exposure-matching results differed by group, but the proposed dose scenarios were not clinically tested.
