Oral Voriconazole Dose in Children - Semantic Scholar

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2010 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2010/5107-0021$15.00. DOI: 10.1086/656292. Oral Voriconazole Dose.
netii within free-living amoebae Acanthamoeba castellanii. Clin Microbiol Infect 2001; 7:75–79. 5. Moliner C, Fournier PE, Raoult D. Genome analysis of microorganisms living in amoebae reveals a melting pot of evolution. FEMS Microbiol Rev 2010; 34:281–294. 6. Raoult D, Boyer M. Amoebae as genitors and reservoirs of giant viruses. Intervirology 2010; 53:321–329. 7. Berger P, Papazian L, Drancourt M, La Scola B, Auffray JP, Raoult D. Ameba-associated microorganisms and diagnosis of nosocomial pneumonia. Emerg Infect Dis 2006; 12:248– 255. Reprints or correspondence: Prof Didier Raoult, URMITE, CNRS, IRD, UMR 6236, Faculte´ de Me´decine, Unite´ des Rickettsies, Marseille, France ([email protected]). Clinical Infectious Diseases 2010; 51(7):869–870  2010 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2010/5107-0021$15.00 DOI: 10.1086/656292

Oral Voriconazole Dose in Children: One Size Does Not Fit All To the Editor—We read with interest the article by Neely et al [1], who reported their clinical pharmacokinetic and pharmacodynamic experience with voriconazole in pediatric patients. The article raises interesting issues about the pharmacologic rationale for the approved oral dose of voriconazole in children. According to European recommendations, a fixed 200-mg oral dose should be given twice daily in all children 2–12 years old, irrespective of age or weight. As a consequence, children with a low weight would receive a higher dose on a milligram per kilogram basis than would those with a high weight. This is bewildering given that voriconazole dosing on the basis of body weight is recommended for the intravenous route, because previous results showed that weight significantly influenced the pharmacokinetics of intravenous voriconazole in children [2]. Because the pediatric reference study [3] found that oral bioavailability in children was markedly reduced relative to that in adults (44.6% vs 96%), a possible justification for a fixed dose could lie in a correlation between bioavailability and age or weight. However, this study did not demonstrate any significant influence of

weight or age on oral bioavailability, and no covariate was included in the final model. In fact, the fixed 200-mg dose of oral voriconazole was based on a single pharmacokinetic study that did not include a pharmacodynamic end point [3]. In the study by Neely and colleagues, an effect of age or weight on bioavailability was not observed either. The estimated oral bioavailability was higher (∼80%), with no significant difference between children aged !12 years and those aged ⭓12 years [1]. Neely and colleagues state that use of the fixed 200-mg dose may result in many concentrations considerably above or below a target trough of 1 mg/mL, and they question the tolerability of such a dose in the youngest children. The fixed dose also raises concerns about possible underdosing in the oldest children. We examined 35 trough concentrations obtained from routine therapeutic drug monitoring in 21 hospitalized pediatric patients (age range, 7–18 years; mean age, 13.3 years) who received 200 mg of oral voriconazole twice daily between 2002 and 2008 (unpublished data from a multicenter French and Swiss database). Concentrations were measured at least 4 days after the dose was changed to 200 mg given twice daily or after therapy with this regimen was initiated. Trough concentration data were as follows: mean  standard deviation, 1.66  1.62 mg/mL; median, 1.29 mg/mL; range, !0.2 to 5.7 mg/mL. Seventeen levels (48.6%) were ⭐1 mg/mL and may be considered suboptimal [4, 5]. Two levels were 15.5 mg/mL. Although limited, these data suggest that the fixed 200-mg dose is likely to expose a significant proportion of children to suboptimal voriconazole concentrations. There is increasing evidence for exposure-effect relationships in patients treated with voriconazole [1, 4, 6]. Because voriconazole pharmacokinetics is highly variable, we agree with Neely and colleagues’ support of the need for therapeutic drug monitoring in children. We also believe that optimal dosage regimens of voricon-

870 • CID 2010:51 (1 October) • CORRESPONDENCE

azole, based on pharmacokinetic and pharmacodynamic end points, are still to be developed. Acknowledgments Potential conflicts of interest. All authors: no conflicts. Sylvain Goutelle,1,3 Romaric Larcher,4 Christophe Padoin,5 Vale´rie Mialou,2 and Nathalie Bleyzac2,3 1

Department of Pharmacy and ADCAPT, Pierre Garraud Hospital, and 2Institute of Pediatric Hematology and Oncology, University Hospitals of Lyon, Lyon, 3Unite´ Mixte de Recherche 5558, “Biome´trie et Biologie Evolutive,” Centre National de la Recherche Scientifique, University Lyon 1, Villeurbanne, 4University Hospital of Montpellier and Montpellier 1 University, Montpellier, and 5Avicenne Hospital, University Hospitals of Paris (Assistance Publique–Hoˆpitaux de Paris), Paris, France

References 1. Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis 2010; 50:27–36. 2. Walsh TJ, Karlsson MO, Driscoll T, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multipledose administration. Antimicrob Agents Chemother 2004; 48:2166–2172. 3. Karlsson MO, Lutsar I, Milligan PA. Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies. Antimicrob Agents Chemother 2009; 53: 935–944. 4. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 2008; 46:201–211. 5. Bruggemann RJ, Donnelly JP, Aarnoutse RE, et al. Therapeutic drug monitoring of voriconazole. Ther Drug Monit 2008; 30:403–411. 6. Csajka C, Pascual A, Bolay S, et al. Population pharmacokinetics of voriconazole in patients with invasive mycoses. Presented at: 2009 Population Approach Group in Europe Annual Meeting. Abstract 1564. http://www.page -meeting.org/default.asp?abstractp1564. Accessed 30 April 2010. Reprints or correspondence: Sylvain Goutelle, Hospices Civils de Lyon, Groupement Hospitalier de Ge´riatrie, Service Pharmaceutique, Hoˆpital Pierre Garraud, 136 rue du Commandant Charcot, 69005 Lyon, France ([email protected]). Clinical Infectious Diseases 2010; 51(7):870  2010 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2010/5107-0022$15.00 DOI: 10.1086/656293