The influence of combination use of CYP450 inducers on the pharmacokinetics of voriconazole: a systematic review

Abstract

SUMMARYWhat is known and objectives: Voriconazole is a triazole antifungal agent and is extensively metabolized via cytochrome P450 (CYP450); therefore, special precautions need to be taken when co-administered with a known CYP450 inducer, which may lead to treatment failure. The influence of some CYP450 inducers on the pharmacokinetics of voriconazole has been described in previous studies, but a systematic review was lacking. In this study, we carried out a systematic review to assess the influence of CYP450 inducers on the pharmacokinetic (PK) parameters of voriconazole. Methods: Pubmed, Embase, Cochrane Library, Clinicaltrials.gov and three Chinese databases (CNKI, CBM and WanFang) were searched through January 2016. Interventional and observational studies comparing the PK parameters of voriconazole used alone or with CYP450 inducers in healthy volunteers and patients were included. The outcomes included were the area under the plasma concentration-time curve (AUC), peak plasma concentrations (C max ) and trough plasma concentrations (C min ). The quality of the included studies was assessed using Cochrane's risk of bias tool, Newcastle-Ottawa Scale (NOS) and a modified risk of bias tool for pharmacokinetic before-and-after studies. Results and discussion: Sixteen studies were included in this review: three randomized controlled trials (RCTs), five single-arm before-after studies (SBAs), six cohort studies and two case reports. All studies except case reports had moderate to high quality. Of the 11 inducers reviewed, efavirenz, ritonavir (chronic use), phenytoin, rifampin and rifabutin significantly decreased mean AUC and C max of voriconazole; St John's wort significantly decreased only mean AUC; rifampin, rifabutin, phenobarbital and carbamazepine significantly decreased mean C min . Etravirine and Ginkgo biloba did not reveal any such influence. The influence of glucocorticoids may depend on its type and dose. What is new and conclusions: To conclude, the combination use of high-dose efavirenz, high-dose ritonavir, St John's wort, rifampin, phenobarbital, or carbamazepine with voriconazole is contraindicated as instructed in the drug label. Low-dose efavirenz, low-dose ritonavir, rifabutin and phenytoin may be used together with voriconazole provided TDM and dose adjustment of voriconazole. Moreover, this study shows there is low risk of drug-drug interactions when voriconazole is co-administered with etravirine or G. biloba; however, whether the use of glucocorticoids has a clinically significant effect on voriconazole still requires more evidence. This study also highlights the lack of clinical studies and future high-quality studies assessing the influence of CYP450 inducers on voriconazole. PK parameters and dosing optimization should be designed to provide a more definitive answer regarding the necessity of TDM and the recommendations for dose adjustment of voriconazole. WHAT IS KNOWN AND OBJECTIVESVoriconazole is a second-generation broad-spectrum triazole antifungal agent with activity against a w...

Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients

“…The effect of glucocorticoids on VRC exposure remains controversial. Some studies have found that they reduced the VRC concentrations, whereas others have made contradictory findings , which may have been due to different types and doses of glucocorticoids. Similarly to our retrospective study , neither PPIs (including lansoprazole and ilaprazole) nor glucocorticoids (methylprednisolone) seemed to affect the VRC pharmacokinetic parameters in the current study.…”

Individualized Medication of Voriconazole: A Practice Guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society

“…Concomitant use of several drugs had a significant impact on VRZ PK. 23 , 24 The quality of evidence varied from high to very low. The CYP2C19 polymorphism was not associated with the rates of treatment response (low quality of evidence), hepatotoxicity (very low quality of evidence), or nervous system/psychiatric disorders (very low quality of evidence).…”

“…Summary of the evidence is shown in Refs. 23 and 24 Supplemental Digital Content 1 , http://links.lww.com/TDM/A265 . The concomitant use of CYP450 inducers or inhibitors, especially drugs inducing or inhibiting CYP3A4 or CYP2C19, is very likely to influence VRZ PK and clinical outcomes.…”

Aspergillus endocarditis diagnosed by fungemia plus serum antigen testing

“…The benefit of adding amphotericin B or an echinocandin to voriconazole is uncertain, although in a subset of patients with invasive aspergillosis and an elevated serum GM, those receiving combination therapy with voriconazole and anidulafungin had a lower 6-week mortality relative to patients who received voriconazole alone [17] . We opted to treat our patient with combination therapy because of concern that we would be unable to achieve therapeutic voriconazole levels due to the recent administration of rifampin for presumed bacterial prosthetic valve endocarditis [18] . Indeed, after 1 week of therapy, the patient's serum voriconazole level was subtherapeutic at 1.2 µg/ml.…”