Key result
Ticagrelor co-administration requires up to a ~4-fold rosuvastatin dose reduction to maintain target exposure.
Why the study?
Ticagrelor inhibits BCRP/ABCG2, increasing rosuvastatin exposure and potentially the risk of rhabdomyolysis in patients with acute coronary syndrome. This risk may be further influenced by age and the ABCG2 c.421C>A variant, creating uncertainty about optimal rosuvastatin dosing with ticagrelor in elderly patients.
Does half- or quarter-dose reduction of rosuvastatin achieve comparable steady-state plasma exposure to monotherapy when co-administered with ticagrelor in young and elderly patients stratified by ABCG2 c.421C>A genotype?
Does half- or quarter-dose reduction of rosuvastatin achieve comparable steady-state plasma exposure to monotherapy when co-administered with ticagrelor in young and elderly patients stratified by ABCG2 c.421C>A genotype?
Physiologically based pharmacokinetic modeling suggests that when co-administered with ticagrelor, rosuvastatin requires a four-fold dose reduction in elderly patients with the wild-type ABCG2 genotype and a half-dose reduction in elderly homozygous ABCG2 c.421C>A variant carriers to match monotherapy exposure and minimize toxicity risk.
Answers are grounded in this paper and cite their sources.
PBPK modeling suggests genotype-specific rosuvastatin dose reductions with ticagrelor in elderly patients; leaves open prospective validation before clinical adoption.
Aims Rosuvastatin is commonly co-administered with ticagrelor in patients with acute coronary syndrome. Ticagrelor inhibits breast cancer resistance protein (BCRP/ABCG2), increasing rosuvastatin exposure and potentially the risk of rhabdomyolysis. This risk may be further influenced by age and the ABCG2 c.421C>A variant. We aimed to predict optimal rosuvastatin dosing with ticagrelor in elderly patients stratified by ABCG2 genotype using physiologically based pharmacokinetic (PBPK) modelling Methods PBPK models for rosuvastatin and ticagrelor were developed and validated in PK-Sim® using clinical data from healthy adults, elderly patients, and individuals with wild-type or homozygous ABCG2 c.421C>A genotypes. Key parameters, including BCRP catalytic activity and age-dependent declines in CYP2C9 and CYP3A4 activity, were optimized. The drug–drug interaction model incorporated competitive BCRP inhibition by ticagrelor. Rosuvastatin steady-state exposure was simulated with half or quarter standard doses during ticagrelor co-administration, and exposure matching approach was used to identify optimal dosing. Results The PBPK models demonstrated good predictive performance across populations and genotypes. In young adults with the wild-type genotype, halving the rosuvastatin dose resulted in an AUC fold change of 1.44, supporting a half-dose strategy. In young homozygous variant carriers, half-dose co-administration produced comparable exposure (AUC fold change 0.78). In elderly wild-type individuals, a four-fold dose reduction achieved comparable exposure (AUC fold change 1.06), whereas elderly variant carriers required only a half-dose reduction (1.12). Conclusions PBPK modelling supported age- and ABCG2 genotype-specific rosuvastatin dosing with ticagrelor. Elderly wild-type patients may require a further dose reduction to minimise toxicity while maintaining therapeutic exposure.
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Nguyen et al. (2026) studied Acute coronary syndrome and hypercholesterolemia requiring concomitant rosuvastatin and ticagrelor (n=400). Rosuvastatin co-administered with ticagrelor vs. Rosuvastatin monotherapy (5, 10, 20, or 40 mg QD) was evaluated on Simulated steady-state rosuvastatin area under the concentration-time curve (AUC) fold change compared to monotherapy. PBPK modeling predicted that concomitant ticagrelor requires a four-fold rosuvastatin dose reduction in elderly ABCG2 wild-type patients (AUC fold change 1.06) and a half-dose in variant carriers (1.12).
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