Study On The Interactions Of Voriconazole With Commonly Used Drugs In Clinical

OBJECTIVE:1.To explore the drug-drug interactions?DDIs?between voriconazole and commonly used clinical drugs in patients with hematological diseases2.To explore the DDIs between voriconazole and proton pump inhibitors?PPIs?.3.To explore the DDIs between voriconazole and Non-steroidal anti-inflammatory drugs?NSAIDs?.METHODS:1.Study on the interactions of voriconazole with commonly used clinical drugs in patients with hematologyPatients who were hospitalized in Department of Hematology,Tianjin First Central Hospital from December 2015 to December 2017 and prevented or treated IFI by voriconazole were selected.Blood samples were collected to determine the concentration.PPK model of voriconazole was established to study the interaction of voriconazole with commonly used clinical drugs in patients with hematology.2.Study on the interactions of voriconazole with PPIsUsing adjusted physicochemical parameters and enzymatic kinetic parameters in vitro of voriconazole and PPIs,the physiologically based pharmacokinetic?PBPK?models were built and verified in healthy subjects to predict the plasma concentration-time profiles of voriconazole and PPIs.A DDI model of single-dose voriconazole and omeprazole was then established and validated.Then the validated model was used to predict DDIs when voriconazole was used in combination with multi-dose PPIs.3.Study on the interactions of voriconazole with NSAIDsUsing adjusted physicochemical parameters and in vitro enzymatic kinetic parameters of voriconazole and NSAIDs,the PBPK models were built and verified in healthy subjects to predict the plasma concentration-time profiles of voriconazole and NSAIDs.A DDI model of voriconazole and diclofenac was then established and validated.Then the validated model was used to predict DDI when voriconazole was combined with other NSAIDs.RESULTS:1.Study on the interactions of voriconazole with commonly used clinical drugs in patients with hematologyThe apparent clearance?CL?and apparent volume of distribution?Vd?of voriconazole were 8.24 L/h and 163 L,respectively.The alkaline phosphatase?ALP?has a significant impact on CL.When combined with lansoprazole,cyclosporine,or dexamethasone,the interaction was obvious.Lansoprazole reduced the voriconazole CL by 33.4%.Cyclosporine reduced the voriconazole CL by 32.8%.Dexamethasone increase the voriconazole clearance by 41.0%.2.Study on the interactions of voriconazole with PPIsThe basic PBPK model and DDI model of voriconazole and PPIs are stable and reliable.DDI simulations showed that when combined with multiple doses of omeprazole,esomeprazole,lansoprazole,and rabeprazole,the pharmacokinetics of voriconazole changed to varying degrees.The AUC_0-t increased by 39%,18%,12%and 1%,respectively.Omeprazole showed the strongest inhibitory effect,and rabeprazole did not interact with voriconazole.3.Study on the interactions of voriconazole with NSAIDsThe PBPK and DDI models of voriconazole and NSAIDs are stable and reliable.DDI simulations showed that when combinated with voriconazole,diclofenac,celecoxib,ibuprofen,tenoxicam,and piroxicam,the AUC_0-inf of celecoxib,ibuprofen,tenoxicam and piroxicam increased by 51%,7%,2%and 1%respectively and the Cmax of celecoxib,ibuprofen,tenoxicam and piroxicam increased by 21%,1%,1%and 1%,respectively.CONCLUSION:1.The use of drugs is complex in patients with hematology.The CL of voriconazole reduces significantly when combined with lansoprazole or cyclosporine.Dexamethasone significantly increases the CL of voriconazole.So when voriconazole is used in combination with lansoprazole,cyclosporine,or dexamethasone,attention should be given to the interactions and to a reasonable adjustment of the dose.2.When voriconazole is combined with PPI,there is different degree of interaction:omeprazole>esomeprazole>lansoprazole>rabeprazole.A PPI with less interaction is selected when voriconazole is used in combination with a PPI in clinical.3.There are different degrees of interactions between diclofenac,celecoxib,ibuprofen,tenoxicam,and piroxicam with voriconazole.The adverse events and toxic reactions related to NSAIDs should be closely monitored.It is necessary to properly select or adjust medications.