Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents

Clinical Infectious Diseases, May 2009

There are currently a number of licensed azole antifungal drugs; however; only 4 (namely, fluconazole, itraconazole, posaconazole, and voriconazole) are used frequently in a clinical setting for prophylaxis or treatment of systemic fungal infections. In this article, we review the pharmacokinetic interactions of these azole antifungal drugs with other coadministered agents. We describe these (2-way) interactions and the extent to which metabolic pathways and/or other supposed mechanisms are involved in these interactions. This article provides an overview of all published drug-drug interactions in humans (either healthy volunteers or patients), and on the basis of these findings, we have developed recommendations for managing the specific interactions.

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Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents

Roger J. M. Bru ggemann ([email protected]) 1 4 Jan-Willem C. Alffenaar 3 Nicole M. A. Blijlevens 4 Eliane M. Billaud 2 Jos G. W. Kosterink 3 Paul E. Verweij 0 4 David M. Burger 1 4 0 Medical Microbiology, Radboud University Nijmegen Medical Centre 1 Departments of Clinical Pharmacy 2 Department of Pharmacology, University Medical Center , l'Hopital Europeen Georges Pompidou, Universite Paris Descartes , Paris, France 3 Department of Hospital and Clinical Pharmacy, University Medical Centre Groningen , Groningen, The Netherlands 4 Nijmegen Institute for Infection, Inflammation and Immunology , Nijmegen There are currently a number of licensed azole antifungal drugs; however; only 4 (namely, fluconazole, itraconazole, posaconazole, and voriconazole) are used frequently in a clinical setting for prophylaxis or treatment of systemic fungal infections. In this article, we review the pharmacokinetic interactions of these azole antifungal drugs with other coadministered agents. We describe these (2-way) interactions and the extent to which metabolic pathways and/or other supposed mechanisms are involved in these interactions. This article provides an overview of all published drug-drug interactions in humans (either healthy volunteers or patients), and on the basis of these findings, we have developed recommendations for managing the specific interactions. - METHODS PHARMACOKINETICS OF AZOLE ANTIFUNGAL DRUGS Drug Absorption Metabolism ; i-n M ion se icx lseu i,ve TeD tyne race tro sp Z ta ita hp in fo IacZT IfTo lrtane iitndn iftyo irsew irtono ithw TDM ifon aZ icxo teho ;Zm I I % % e % 0 0 d ; 50 10 10 ; ax % 1 1 % m 0 y y 0% 0% 00 C 100% y5 ydb edb edb 1y5 1y5 1 and 1y db ase ase ase db db yb % b se re rc rc se se ed 50 d a c in in a a s 1 rsaee rceed deaxm Caxm Cxam rceed rceed iracen ybde % icnss Caxm dnC and and CU Caxm CU rase 50 A l 4A ian 4A 4A ase 4A 3PY ttse 3PY 3PY rcen 3YP n C in C C i C w fo fo 4 fo fo pH fo kno n n A n n h n n iito iito 3P iito iito ca itco U ib ib Y ib ib m u h h C h h to d In In In In S In s s s s s s t r r r r r r n e e e e e e la te te te te te te p ts n n n n n n s n lu lu lu lu lu lu an ie o o o o o o p v v v v v v tr i c y y y y y y g e h h h h h h n r lt lt lt lt lt lt u a a a a a a L e e e e e e e o n o b l eg re eg om ]57 []58 ]28 b e ta c [ [ Z Z Z Z Z Z Z PS VR VR IT IT IT IT ] 2 8 ] ] ] ] ] ] 8 9 0 1 2 3 4 [2 [6 [7 [7 [7 [7 [7 H H H H H H H H H H pe iz epn od pe iz ou iz ou iz H R C O O D C d d ; D n n e T a a ly ry ly ry ilin i,r t v n sa n a p a lftaen csee lftaen cssee itrym tzaan a n a n a a f if f f f f o l o i o o y y y il y y iitc tan iitc tan iitc iitc x n x n x x to lfe to lfe to ien to r r a r a r li r i o t o v fo fo fo fo f p f a r r r y r n ito se ito se ito itr ito za n o n o n m n ta o d o d o a o a i d s d 0% yb CU ase ilte se % 10 d rA re bo rae e i c ta c as av in e in 0 0 1 y y 1y bd rce itno axm em axm b b e in r C iv C ed ed ase axm lsu nd tac and s s r p a a a c C r d c c and iavn 010% re re in an 0% in in C C 01 U In In In Z Z Z Z L R L S F V F P r e t liltfanenA liltfanenA iilitrtypnem ii(rtvaaneh irtohhouw ii)trravno irtttsavaon A za it A P P t P Y Y u Y C P C C g m C fo -g fo fo fo ils fo P I I I I s D re t t t n n n P te la la la ithw luno sapn itsne sapn itsne tsen sapn itsne tsn vy ltr icp ltr icp ita lrt icp itae ltah ane re ane re P ane re P e R R R H I I Z Z Z Z Z Z IT IT L L L T F F F I M M M M R M M M M M A A A A C C C C C C 2 12 16 6 6 8 D O C N C O D O O O y th c fi ro r i e d ] ] ] ] g d o 3 4 5 8 tae is m [8 [8 [8 [2 ] ] ] ] ] ] 9 0 1 2 3 4 [8 [9 [9 [9 [9 [9 P In d C R C n U V U a A ; I P V sedb ydb yb1 icnaxm anCU saed ased race saee 50% sde ndC oneA ircne ircne in rc y a a r ax x e b re d C m Cam dC ed icn ACU ithn 00% AU dC d U s ax l re 1 dn an n A ae m io o a a A C z % ixn AU iren 100 05% ire 10 dn igo ZS fav 1 fav a D P E Z rc x C C R e andC trsaed ;0n yeb am U A a A znAU ;0V% dCaxm CU lyn 10% rasde iinepC 0% ittsanA 00% iirpede ircneax adone ZA ithe yb icn lod 110 av 1 m th R e lu lim C e E V F F In In In In In a m se zn il;y zn il;y fo lasp rcae irvae ade irvae ade iitcy ixn i,n fe ic fe ic txo itve o Z y g tw g tw r p ig S ra m Z Z m Z Z o e itrod foP csse 300 gVR dVR 300 gVR dVR itrfo tracn o M en se m a se m a o c n n n n o D M T U U M 2 2 3 9 1 1 2 I F e irv ine lzo Z Z Z Z Z Z Z Z Z Z a p a a r DM DM DM DM DM DM DM DM DM DM lnfie irv pe N e m In In In fo ne ine in o a m x M ird ac la fa D e iv zo la ;T isp op ira en Z r r t v L f f f f F o o o o f y y y y o it it it it y ic ic ic ic c x x x x a o o o o c t t t t fi r r r r f o o o o e f f f f r r r r r ito ito ito ito ito n n n n n o o o o o % 0 y 5 b ed % cn d s 0 i d e a 5 x e yb sa re am sa de rc icn yb d rc e C e s in in a CU sed an rce Css A a C CU e d e e re U A n in c A n C do ca de am 00% ix AU ire iav axm lzo 1 lfaa Z sp op C ia n L i r e F R R T V s t n rs rs rs ie e e e ts ta te te te n p n n n itaep ircne lvy (...truncated)


This is a preview of a remote PDF: https://cid.oxfordjournals.org/content/48/10/1441.full.pdf

Roger J. M. Brüggemann, Jan-Willem C. Alffenaar, Nicole M. A. Blijlevens, Eliane M. Billaud, Jos G. W. Kosterink, Paul E. Verweij, David M. Burger, Louis D. Saravolatz. Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents, Clinical Infectious Diseases, 2009, pp. 1441-1458, 48/10, DOI: 10.1086/598327