Intracystic concentrations of albendazolesulphox

Authors: Felix Lötsch Judith Naderer Tomislava Skuhala Mirjam Groger Herbert Auer Klaus Kaczirek Fredrik Waneck Michael Ramharter

Publish Date: 2016/04/16

Volume: 115, Issue: 8, Pages: 2995-3001

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Abstract

Cystic echinococcosis CE is a widespread zoonosis caused by the species complex Echinococcus granulosus Albendazole ABZ—the firstline anthelminthic drug for medical treatment of CE—is metabolized in vivo to the active derivative ABZsulphoxide ABZSO Targetsite ABZSO concentrations in the hydatid cyst mediate the anthelminthic effect in CE Primary outcome of this systematic review of individual patient data was the intracystic ABZSO concentration stratified by cyst size location calcification status and use of praziquantel Studies reporting intracystic ABZSO concentrations in humans were identified by a systematic search A pooled analysis of individual patient data was performed to assess intracystic concentrations Pharmacokinetic data of 121 individual cysts were analysed There was no correlation between plasma and intracystic ABZSO concentrations rho = −003 p = 076 Intracystic drug concentrations were also not associated with sex and treatment duration Use of praziquantel in combination with ABZ was associated with higher plasma median 540 vs 240 μg/L p = 004 but not intracystic ABZSO concentrations median 220 vs 199 μg/L p = 036 Relative drug concentrations in hepatic cysts were higher than in other cysts 08 vs 04 p = 005 Intracystic concentrations were higher in calcified than noncalcified cysts median 897 vs 245 μg/L p = 003 There was a trend towards higher intracystic concentrations in smaller sized cysts β = −172 μg/L/cm 95th CI −359 to 16 p = 007 This study demonstrates that mean intracystic drug concentrations are similar to plasma concentrations on a population level However in individual patients plasma concentrations are not directly predictive for intracystic concentrations The use of booster drugs was not associated with higher intracystic ABZSO concentrations in this analysisCystic echinococcosis is a parasitic zoonosis caused by the larval stage of tapeworms of the speciescomplex Echinococcus granulosus Humans serve as aberrant intermediate host The disease is characterised by an almost worldwide distribution causing significant morbidity and considerable socioeconomic impact in highly endemic regions Budke et al 2013 2006Humans infected with E granulosus present with cystic lesions in virtually any organ with liver 60  and lungs 20  being the most commonly affected Twenty to forty percent of individuals have multiple cysts or multiple organs involved McManus et al 2003 Moro and Schantz 2009 Cysts may vary remarkably in size but are usually between 1 and 15 cm Eckert and Deplazes 2004 Cysts may persist grow progressively collapse calcify and degrade spontaneously or rupture and release parasitic material The stage of the disease is defined by radiologic criteria issued by WHO’s informal working group on echinococcosis WHOIWGE Brunetti et al 2010 In this classification cysts of the stages CE1 and CE2 are classified as active CE3a and CE3b as transitional and CE4 and CE5 as inactiveAntiparasitic treatment with albendazole ABZ was introduced into clinical practice almost three decades ago Davis et al 1986 1989 and is still one of the cornerstones of management of cystic echinococcosis It may be used alone or in combination with surgical or interventional techniques ABZ is a benzimidazole derivative with poor bioavailability when administered without fatty food Certain drugs eg praziquantel or cimetidine—when coadministered with ABZ—were reported to increase serum and potentially intracystic drug concentrations Wen et al 1994 Cobo et al 1998 However these drugs are not yet routinely recommended as it is unknown whether the administration of a booster drug translates into improved clinical outcomeABZSO acts mainly on the germinal layer of the cyst and only to a lesser extent on protoscolices Liu et al 2015 Cure rates of medical treatment were shown to depend on cyst size and stage Although it is not known whether higher intracystic drug concentrations are associated with improved clinical outcome the mode of action at the target site strongly supports this hypothesis Similarly monitoring of ABZSO serum levels is recommended but data are lacking whether serum levels are predictive for intracystic drug concentrations Measurement of intracystic target site concentrations is therefore currently the best surrogate pharmacokinetic marker for medical treatment of human echinococcosisTo improve our knowledge on intracystic drug concentrations of ABZSO in human cystic echinococcosis and to describe its potential determinants this systematic review and a pooled analysis of collected data was performed Primary outcome was the intracystic ABZSO concentration stratified by cyst size location calcification status and use of booster drugs This review provides a systematic collation of all available evidence on intracystic concentrations of ABZSO in the treatment of cystic echinococcosis in humans and its determinantsA systematic search strategy identifying all relevant information on intracystic ABZ and ABZSO concentrations in echinococcosis was conceived To identify eligible publications “PubMed” and “Cochrane” databases were searched with the search terms “albendazole AND echinococc OR hydatid” for references published until August 2014 with all publications being considered before this date There were no predefined language restrictions and nonEnglish papers were translated for further analysis Inclusion criteria were 1 human patients ie no animal studies 2 reporting of intracystic drug concentrations of ABZ or ABZSO for individual patients

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