p38 MAPK Signaling Pathway glycoprotein and UGT1A4 and inhibits CYP3A4 and pglycoprotein

summary on interactions between antifungals and ARVs, readers are referred to a recent review and Health Canada approved dose of 800/100 mg once daily), etravirine 200 mg twice daily, tenofovir/ emtricitabine 300 mg/200 mg daily and voriconazole JNJ 26854165 400 mg IV/PO twice daily for 6 weeks. Plasma trough concentrations were obtained after a total of 4 weeks of voriconazole therapy, and again 3 weeks after voriconazole discontinuation. Therapeutic voriconazole concentrations were achieved, while etravirine Cmin reased by 134%. Ritonavir Cmin was undetectable and darunavir Cmin was well below historical reference data. After voriconazole was discontinued, ritonavir Cmin reased to the same range as the historical control and darunavir Cmin reased by fourfold.
The combination of etravirine/ darunavir/ritonavir with voriconazole should be undertaken with caution and twice daily dosing of darunavir/ritonavir should be considered in this setting. Therapeutic drug monitoring should be utilized when available . In p38 MAPK Signaling Pathway contrast to voriconazole, posaconazole is substrate of P glycoprotein and UGT1A4, and inhibits CYP3A4 and pglycoprotein . Brüggemann , conducted a three period, cross over, open label multi dose study where healthy volunteers received either posaconazole 400 mg twice daily, fosamprenavir 700/ritonavir 100 mg twice daily, or posaconazole plus fosamprenavir 700 mg twice daily for 10 days each separated by 17 day washout periods. When posaconazole and unboosted fosamprenavir were coadministered, a dual negative interaction was observed with a 23% and 65% decrease in the AUC of posaconazole and amprenavir, respectively.
While the mechanism of the interaction is unclear, the authors postulated that fosamprenavir mediated induction of UGT1A4 and/or P glycoprotein may have played a role. The combination of posaconazole and unboosted fosamprenavir should be avoided. Optimal dosing of posaconazole and boosted fosamprenavir has not yet been determined, and fixative if concomitant therapy is required, boosted fosamprenavir is recommended and TDM should be performed for both fosamprenavir and posaconazole . Antimalarials A number of antimalarial drugs have the potential to interact with ARVs, particularly the PIs and NNRTIs. New updates on interactions with quinine, atovaquone/ proguanil and doxycycline are reviewed.
Quinine is mainly a CYP3A4 substrate, therefore with the exception of unboosted tipranavir, all PIs have the potential to rease quinine concentrations, while efavirenz, nevirapine and etravirine may decrease quinine concentrations. Soyinka , studied the impact of ritonavir 200 mg twice daily in 10 healthy volunteers who received a single dose of oral quinine 600 mg. Both the Cmax and AUC of quinine reased by about 2.8 fold and 3.4 fold respectively, and the quinine half life2 reased by 20% . The metabolism of quinine to its major active metabolite, 3 hydroxyquinine, was markedly inhibited by ritonavir. There was a 21% rease in the AUC of ritonavir, however this is not likely to be clinically significant. Although firm guidelines are not available on the correct dosing when quinine and ritonavir are coadministered, the authors concluded that a decreased dose of quinine is recommended in order to prevent cardiotoxicity and QTc prolongation .

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