Abstract:Aims
The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin.
Methods
We conducted a genome‐wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88).
Results
In a genome‐wide association meta‐analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide… Show more
“…In a previous clinical study, the BCRP‐inhibiting drug febuxostat increased the C max and AUC of rosuvastatin 2.1‐fold and 1.9‐fold 17 . Similarly, the ABCG2 c.421A/A genotype that predicts poor BCRP function has been associated with a 2.0–2.2‐increased AUC of rosuvastatin 22,37 . The effect size of ticagrelor on rosuvastatin pharmacokinetics in this study was in the vicinity of these previous findings.…”
Section: Discussionsupporting
confidence: 75%
“…Furthermore, a single oral dose of the OATP‐ and BCRP‐inhibitor rifampicin has increased rosuvastatin concentrations more than fourfold 19 . Similarly, genetically poor BCRP or OATP1B1 function associate with markedly increased rosuvastatin concentrations 20–23 …”
Ticagrelor and rosuvastatin are often used concomitantly after atherothrombotic events. Several cases of rhabdomyolysis during concomitant ticagrelor and rosuvastatin have been reported, suggesting a drug‐drug interaction. We showed recently that ticagrelor inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1 ‐mediated rosuvastatin transport in vitro. The aim of this study was to investigate the effects of ticagrelor on rosuvastatin pharmacokinetics in humans. In a randomized, cross‐over study, nine healthy volunteers ingested a single dose of 90 mg ticagrelor or placebo, followed by a single 10 mg dose of rosuvastatin 1 hour later. Ticagrelor 90 mg or placebo were additionally administered 12, 24, and 36 hours after their first dose. Ticagrelor increased rosuvastatin area under the plasma concentration‐time curve (AUC) and peak plasma concentration 2.6‐fold (90% confidence intervals 1.8‐3.8 and 1.7‐4.0, P=0.001 and P=0.003), and prolonged its half‐life from 3.1 to 6.6 hours (P=0.009). Ticagrelor also decreased the renal clearance of rosuvastatin by 11% (3‐19%, P=0.032). The N‐desmethylrosuvastatin:rosuvastatin AUC0‐10 h ratio remained unaffected by ticagrelor. Ticagrelor had no effect on the plasma concentrations of the endogenous OATP1B substrates glycodeoxycholate 3‐O‐glucuronide, glycochenodeoxycholate 3‐O‐glucuronide, glycodeoxycholate 3‐O‐sulfate, and glycochenodeoxycholate 3‐O‐sulfate, or the sodium‐taurocholate cotransporting polypeptide substrate taurocholic acid. These data indicate that ticagrelor increases rosuvastatin concentrations more than two‐fold in humans, probably mainly by inhibiting intestinal BCRP. Since the risk for rosuvastatin‐induced myotoxicity increases along with rosuvastatin plasma concentrations, using ticagrelor concomitantly with high doses of rosuvastatin should be avoided.
“…In a previous clinical study, the BCRP‐inhibiting drug febuxostat increased the C max and AUC of rosuvastatin 2.1‐fold and 1.9‐fold 17 . Similarly, the ABCG2 c.421A/A genotype that predicts poor BCRP function has been associated with a 2.0–2.2‐increased AUC of rosuvastatin 22,37 . The effect size of ticagrelor on rosuvastatin pharmacokinetics in this study was in the vicinity of these previous findings.…”
Section: Discussionsupporting
confidence: 75%
“…Furthermore, a single oral dose of the OATP‐ and BCRP‐inhibitor rifampicin has increased rosuvastatin concentrations more than fourfold 19 . Similarly, genetically poor BCRP or OATP1B1 function associate with markedly increased rosuvastatin concentrations 20–23 …”
Ticagrelor and rosuvastatin are often used concomitantly after atherothrombotic events. Several cases of rhabdomyolysis during concomitant ticagrelor and rosuvastatin have been reported, suggesting a drug‐drug interaction. We showed recently that ticagrelor inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1 ‐mediated rosuvastatin transport in vitro. The aim of this study was to investigate the effects of ticagrelor on rosuvastatin pharmacokinetics in humans. In a randomized, cross‐over study, nine healthy volunteers ingested a single dose of 90 mg ticagrelor or placebo, followed by a single 10 mg dose of rosuvastatin 1 hour later. Ticagrelor 90 mg or placebo were additionally administered 12, 24, and 36 hours after their first dose. Ticagrelor increased rosuvastatin area under the plasma concentration‐time curve (AUC) and peak plasma concentration 2.6‐fold (90% confidence intervals 1.8‐3.8 and 1.7‐4.0, P=0.001 and P=0.003), and prolonged its half‐life from 3.1 to 6.6 hours (P=0.009). Ticagrelor also decreased the renal clearance of rosuvastatin by 11% (3‐19%, P=0.032). The N‐desmethylrosuvastatin:rosuvastatin AUC0‐10 h ratio remained unaffected by ticagrelor. Ticagrelor had no effect on the plasma concentrations of the endogenous OATP1B substrates glycodeoxycholate 3‐O‐glucuronide, glycochenodeoxycholate 3‐O‐glucuronide, glycodeoxycholate 3‐O‐sulfate, and glycochenodeoxycholate 3‐O‐sulfate, or the sodium‐taurocholate cotransporting polypeptide substrate taurocholic acid. These data indicate that ticagrelor increases rosuvastatin concentrations more than two‐fold in humans, probably mainly by inhibiting intestinal BCRP. Since the risk for rosuvastatin‐induced myotoxicity increases along with rosuvastatin plasma concentrations, using ticagrelor concomitantly with high doses of rosuvastatin should be avoided.
“…Impaired OATP1B1 function should theoretically reduce the clearance and increase the plasma exposure (AUC 0–∞ ) of rosuvastatin because it decreases its entry into the liver, its main site of elimination. Previous studies have shown reduced OATP1B1‐mediated uptake of statins into hepatocytes caused by genetic polymorphism or drug interactions 47 . This study shows that HCV infection may also decrease the activity of OATP1B1.…”
Section: Discussionsupporting
confidence: 52%
“…Previous studies have shown reduced OATP1B1-mediated uptake of statins into hepatocytes caused by genetic polymorphism or drug interactions. 47 This study shows that HCV infection may also decrease the activity of OATP1B1. Although plasma concentrations of proinflammatory cytokines are not available in this study, the lower activity of OATP1B1 observed before the treatment with DAAs (Phase 1) may be related to the intense inflammatory response previously reported in infection by HCV, 3,4,[8][9][10] which could impact the regulation of transporter activity.…”
The activity of the membrane transporters organic anion-transporting polypeptide 1B1 (OATP1B1) & breast cancer resistance protein (BCRP) (rosuvastatin) and P-glycoprotein (P-gp) (fexofenadine) was evaluated in patients with chronic hepatitis C virus (HCV) infection (n = 28), genotypes 1 and 3, investigated before the treatment with directacting antiviral agents (Phase 1) and up to 30 days after the assessment of the virologic response (Phase 2). Participants allocated in Groups 1 (n = 15; F0/F1 and F2, mild to moderate liver fibrosis) and 2 (n = 13; F3 and F4, advanced course of liver fibrosis/cirrhosis) received in both phases fexofenadine (10 mg) and rosuvastatin (2 mg). OATP1B1 & BCRP activity (rosuvastatin area under the plasma concentration-time curve of rosuvastatin from time zero to infinity (AUC 0-∞ )) was reduced in Groups 1 and 2, respectively, by 25% (ratio 0.75 (0.53-0.82), P < 0.01) and 31% (ratio 0.69 (0.46-0.85), P < 0.05) in Phase 1 compared with Phase 2. OATP1B1 & BCRP activity was reduced in Phases 1 and 2, respectively, by 49% (median ratio 1.51 (1.17-2.20), P < 0.05) and 61% (ratio 1.39 (1.16-2.02), P < 0.01) in Group 2 compared with Group 1. P-gp activity (fexofenadine AUC 0-∞ ) was also reduced in Phase 1 compared with Phase 2 (ratio Phase2/Phase1 0.79 (0.66-0.96) in Group 1 and 0.81 (0.69-0.96) in Group 2) as well as in Group 2 compared with Group 1 in both Phases (ratio Group2/Group1 1.47 (1.08-2.01) in Phase 1 and 1.51 (1.10-2.07) in Phase 2). Thus, clinicians administering OATP1B1 & BCRP and P-gp substrates with low therapeutic indexes should consider the evolution of the treatment and the stage of HCV infection.
“…Otherwise, possible associations could be diluted by differences in metabolic and disposition pathways of different statins. For example, common SLCO1B1 and ABCG2 variants differentially affect pharmacokinetics of specific statins [6,[21][22][23][24][25][26][27][28]. Moreover, simvastatin and atorvastatin are metabolized by CYP3A4/5, and fluvastatin is metabolized by the genetically polymorphic CYP2C9 [9,25,[28][29][30][31].…”
Objective
The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport also by other proteins exhibiting clinically meaningful genetic variation. Our aim was to investigate associations of SLCO1B1 c.521T>C with intolerance to atorvastatin, fluvastatin, pravastatin, rosuvastatin, or simvastatin, those of ABCG2 c.421C>A with intolerance to atorvastatin, fluvastatin, or rosuvastatin, and that of CYP2C9*2 and *3 alleles with intolerance to fluvastatin.
Methods
We studied the associations of these variants with statin intolerance in 2042 patients initiating statin therapy by combining genetic data from samples from the Helsinki Biobank to clinical chemistry and statin purchase data.
Results
We confirmed the association of SLCO1B1 c.521C/C genotype with simvastatin intolerance both by using phenotype of switching initial statin to another as a marker of statin intolerance [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.08–3.25, P = 0.025] and statin switching along with creatine kinase measurement (HR 5.44, 95% CI 1.49–19.9, P = 0.011). No significant association was observed with atorvastatin and rosuvastatin. The sample sizes for fluvastatin and pravastatin were relatively small, but SLCO1B1 c.521T>C carriers had an increased risk of pravastatin intolerance defined by statin switching when compared to homozygous reference T/T genotype (HR 2.11, 95% CI 1.01–4.39, P = 0.047).
Conclusion
The current results can inform pharmacogenetic statin prescribing guidelines and show feasibility for the methodology to be used in larger future studies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.