Simvastatin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of simvastatin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aspirin, ASA; Omeprazole: Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
Atazanavir: The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvast |
