Co-administration of Fluvastatin and CYP3A4 and CYP2C8 Inhibitors May Increase the Exposure to Fluvastatin in Carriers of CYP2C9 Genetic Variants

Fluvastatin, which is one of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins), is primarily metabolized by CYP2C9 and to a lesser extent by CYP3A4 and CYP2C8. Predictions of drug-drug interactions (DDI) are important for the safety of combination therapies with statins, in particular drugs that are metabolized by CYP3A4. Little information is available regarding drug interactions with fluvastatin. Since CYP2C9 is a polymorphic enzyme, we investigated the effect of DDI via CYP2C9, CYP3A4, and CYP2C8 on fluvastatin pharmacokinetics by using a validated prediction method in relation to CYP2C9 variants. The predicted increases in the area under the concentration-time curve (AUC) ratios of fluvastatin in carriers with CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3 versus that found in carriers with CYP2C9*1/*1 were 1.16, 1.35, 1.37, 1.65, and 2.06, respectively. Our in silico model predicted that administration of fluvastatin in conjunction with the potent inhibitors that completely inhibited CYP3A4 and CYP2C8 in carriers with the CYP2C9*3/*3 variant would cause a 3.23- and 2.60-fold increase in the AUC ratios, respectively, when compared to that for the carriers with the CYP2C9*1/*1 taking fluvastatin alone. We also predicted the effect of telmisartan when coadministered with fluvastatin. Our prediction results showed that the interaction between telmisartan and fluvastatin via CYP enzymes were negligible in clinical situations.