Effect of posaconazole on the pharmacokinetics of simvastatin and midazolam in healthy volunteers

Krishna, Gopal; Ma, Lei; Prasad, Pallavi; Moton, Allen; Martinho, Monika; O’Mara, Edward

doi:10.1517/17425255.2012.639360

Cited by 35 publications

(30 citation statements)

References 38 publications

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“…The antifungal azole derivatives intraconazole, ketoconazole and posaconazole are very potent and effective inhibitors of CYP3A4 4. All have been shown to cause an at least fivefold increase in the plasma concentration of simvastatin in drug–drug interaction studies performed in healthy volunteers,3 5 6 and rhabdomyolysis in the context of concomitant use of simvastatin and itraconazole has been described in case reports similar to the present one 7–10. The present case contributes by further confirming the clinical relevance of the drug–drug interaction in younger patients, as the prior reported cases have been in elderly patients with several comorbidities and comedications 7–10…”

Section: Discussionsupporting

confidence: 70%

Statin-associated rhabdomyolysis triggered by drug–drug interaction with itraconazole

et al. 2016

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A 47-year-old woman had been treated with high-dose simvastatin for several years. After systemic treatment with the antifungal agent itraconazole, she developed muscle pain and highly elevated levels of creatine kinase and myoglobin. Muscle biopsy was compatible with statin-associated rhabdomyolysis, probably caused by a drug-drug interaction between simvastatin and itraconazole. The patient made full recovery. Three commonly used statins-simvastatin, atorvastatin and lovastatin-are metabolised by the liver enzyme CYP3A4. Several potent inhibitors of this enzyme are known, for example, azole antifungal agents such as itraconazole and posaconazole. If antifungal treatment is indicated in a patient using a CYP3A4-metabolised statin, we recommend (1) topical administration of the antifungal agent if possible, (2) the use of a non-CYP3A4-inhibiting antifungal drug such as terbinafine or (3) temporary discontinuation of statin treatment.

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Section: Discussionsupporting

confidence: 70%

Statin-associated rhabdomyolysis triggered by drug–drug interaction with itraconazole

et al. 2016

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“…For rifampin, a systematic search identified three PK studies [26][27][28] assessing the impact of single dose and four PK studies [29][30][31][32] assessing the impact of multiple doses. Eight [33][34][35][36][37][38][39][40] PK studies were identified for azole antifungals.…”

Section: Literature Reviewmentioning

confidence: 99%

“…Posaconazole is a strong CYP3A4 inhibitor and increases the AUC of simvastatin acid by approximately 7-8 times its original value [40]. Per prescribing information, its administration is contraindicated with simvastatin, lovastatin, and atorvastatin [58].…”

Section: Statins Interactions With Azole Antifungalsmentioning

confidence: 99%

An updated review of interactions of statins with antibacterial and antifungal agents

Eljaaly¹,

Alshehri²

2017

J Transl Sci

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Numerous antimicrobial agents interact with statins. It is important to prevent these drug interactions and resulting statin toxicity and/or reduced efficacy. We review and highlight major drug-drug interactions between statins and antibacterial and antifungal agents; interactions with antiviral agents were not considered. Daptomycin interacts with statins via additive skeletal muscle toxicity. One possibility is to discontinue statins during daptomycin therapy, though no retrospective studies to date have shown a statistically significant elevation of adverse outcome risk. Multiple doses of rifampin induce cytochrome P450 (CYP), particularly 3A4 and 2C9, resulting in reduced systemic exposures to all statins, except rosuvastatin, for which the response was variable. Macrolide antibiotics are inhibitors of CYP3A4 and organic anion-transporting polypeptide-1B1. Azithromycin has the fewest drug interactions, while clarithromycin and erythromycin increase systemic exposure to all statins except rosuvastatin and fluvastatin. Azole antifungals are CYP450 inhibitors. Itraconazole and posaconazole are strong CYP3A4 inhibitors and mainly affect simvastatin, lovastatin, and atorvastatin, while fluconazole is an inhibitor of CYP2C9 and potentially CYP2C19 and mainly affects fluvastatin; however, risk cannot be ruled out with rosuvastatin.

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“…However, simvastatin is a substrate of cytochrome P450 3A4 and as a consequence coadministration with potent inhibitors of cytochrome P450 3A4 increases the concentration of HMG-CoA reductase inhibitory activity in plasma and the risk of myopathy and rhabdomyolysis. Hence, the coadministration of simvastatin with ketoconazole, itraconazole, posaconazole, clarithromycin, telithromycin, erythromycin, HIV protease inhibitors (e.g., nelfinavir), danazol and nefazodone is contraindicated [142][143][144][145][146][147][148][149][150][151][152][153][154][155][156][157]. If the administration of a CYP3A4 inhibitor is needed then simvastatin treatment should be at least temporarily stopped.…”

Section: Brief Description Of Drug Interactionsmentioning

confidence: 99%

Safety considerations with fenofibrate/simvastatin combination

Filippatos

Elisaf

2015

Expert Opinion on Drug Safety

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Large randomized clinical trials show that the combined administration of fenofibrate with simvastatin is not associated with significantly increased incidence of serious adverse events compared with simvastatin monotherapy. The incidence of rhabdomyolysis is slightly increased with fibrate/statin combination compared with monotherapy but the actual risk is very low. Although fenofibrate increases creatinine and homocysteine serum levels, the incidence of diabetic nephropathy and thrombotic events was not significantly increased with fenofibrate/simvastatin combination compared with simvastatin monotherapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial. Furthermore, a decrease in albuminuria was observed with fenofibrate in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and ACCORD Lipid trials. Overall, the combined administration of fenofibrate with simvastatin appears to be safe, unless clinicians give fenofibrate/simvastatin combination to patients with predisposing risk factors for the occurrence of adverse events.

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Effect of posaconazole on the pharmacokinetics of simvastatin and midazolam in healthy volunteers

Cited by 35 publications

References 38 publications

Statin-associated rhabdomyolysis triggered by drug–drug interaction with itraconazole

Statin-associated rhabdomyolysis triggered by drug–drug interaction with itraconazole

An updated review of interactions of statins with antibacterial and antifungal agents

Safety considerations with fenofibrate/simvastatin combination

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