Pharmacokinetics, Safety and Efficacy of Voriconazole in Pediatric Patients: An Update

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1. 1.
   Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol. 1998;44:343–500.PubMedCrossRefGoogle Scholar
2. 2.
   Wiederhold NP. Pharmacology, in vitro activity, and in vivo efficacy of new antifungal agents. Curr Fungal Infect Rep. 2009;3:77–85.CrossRefGoogle Scholar
3. 3.
   Groll AH, Gea-Banacloche JC, Glasmacher A, et al. Clinical pharmacology of antifungal compounds. Infect Dis Clin North Am. 2003;17:159–91.PubMedCrossRefGoogle Scholar
4. 4.
   Thompson 3rd GR, Lewis 2nd JS. Pharmacology and clinical use of voriconazole. Expert Opin Drug Metab Toxicol. 2010;6:83–94.PubMedCrossRefGoogle Scholar
5. 5.
   Weiss J, Ten Hoevel MM, Burhenne J, et al. CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol. 2009;49:196–204.PubMedCrossRefGoogle Scholar
6. 6.
   Trifilio S. Update on antifungal drug dosing and therapeutic drug monitoring. Curr Fungal Infect Rep. 2011;5:92–102.CrossRefGoogle Scholar
7. 7.
   Brueggemann RJM, Alffenaar JWC, Blijlevens NMA, et al. Pharmacokinetic drug interactions of azoles. Curr Fungal Infect Rep. 2008;2:20–7.CrossRefGoogle Scholar
8. 8.
   Hegener P, Troke PF, Fakenheuer G, et al. Treatment of fluconazole-resistant candidiasis with voriconazole in patients with AIDS. AIDS. 1998;12:2227–8.PubMedGoogle Scholar
9. 9.
   Ally R, Schurmann D, Kreisel W, et al. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis. 2001;33:1447–54.PubMedCrossRefGoogle Scholar
10. 10.
    Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408–15.PubMedCrossRefGoogle Scholar
11. 11.
    Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet. 2005;366:1435–42.PubMedCrossRefGoogle Scholar
12. 12.
    Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346:225–34.PubMedCrossRefGoogle Scholar
13. 13.
    Wingard JR, Carter SL, Walsh TJ, et al. Blood and Marrow Transplant Clinical, Trials Network. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010;116:5111–8.PubMedCrossRefGoogle Scholar
14. 14.
    Marks DI, Pagliuca A, Kibbler CC, IMPROVIT Study Group, et al. Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation. Br J Haematol. 2011;155:318–27.PubMedCrossRefGoogle Scholar
15. 15.
    Europen Medicines Agency. Vfend : EPAR - product information, EMEA. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000387/WC500049756.pdf (21. August 2011, date last accessed).
16. 16.
    US Food and Drug Administration. Label information for VFEND, NDA no. 021266, highlights of prescribing information FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021266s033,021267s037,021630s024lbl.pdf (20. August 2011, date last accessed).
17. 17.
    Doby EH, Benjamin DK Jr, Blaschke AJ, et al. Therapeutic monitoring of voriconazole in children less than 3 years of age: a case report and summary of voriconazole concentrations for 10 children. Pediatr Infect Dis J. 2012 Feb 1. [Epub ahead of print].Google Scholar
18. 18.
    •• Walsh TJ, Karlsson MO, Driscoll T, Arguedas AG, et al. Pharmacokinetics and safety of intravenous voriconazole in children after singe- or multiple-dose administration. Antimicrob Agents Chemother. 2004;48:2166–72. Pharmacokinetic study revealing a higher capacity for elimination of voriconazole per kilogram of body weight in children relative to adult healthy volunteers and the need for higher doses to achieve exposures consistent with those in adults. PubMedCrossRefGoogle Scholar
19. 19.
    •• Driscoll TA, Yu LC, Frangoul HL, et al. Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised adolescents and healthy adults. Αntimicrob Agents Chemother. 2011;55(12):5770–9. Pharmacokinetic study demonstrating that young adolescents with low body weight (<0 kg) during the transitioning period from childhood to adolescence (e.g., 12 to 14 years old) may need to receive higher doses (i.e., the children’s dose) to match the adult exposures. CrossRefGoogle Scholar
20. 20.
    • Karlsson MO, Lutsar I, Milligan PA. Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies. Antimicrob Agents Chemother. 2009;53:935–44. Population pharmacokinetic analysis in children 2 to 11 years of age suggesting that an intravenous dosage of 7 mg/kg twice daily and an oral dosage of 200 mg twice daily given as oral suspension without loading provided exposures comparable to those observed in adult healthy volunteers receiving the approved adult dose regimen. PubMedCrossRefGoogle Scholar
21. 21.
    • Walsh TJ, Lutsar I, Driscoll T, Dupont B, et al. Voriconazole in the treatment of aspergillosis, scedosporiosis, and other invasive fungal infections in children. Pediatr Infect Dis J. 2002;21:240–8. Early phase II compassionate use trial in 58 children with proven or probable invasive fungal infections that first demonstrated both safety and efficacy of voriconazole in pediatric patients. PubMedCrossRefGoogle Scholar
22. 22.
    •• Walsh T, Driscoll T, Milligan P, et al. Pharmacokinetics, Safety, and tolerability of voriconazole in immunocompromised children. Antimicrob Agents Chemother. 2010;48:4116–23. Pharmacokinetic study of higher doses of voriconazole in immunocompromised children aged 2 to <12 years that showed the mean plasma AUCτ for 8 mg/kg intraveously in children approached that for 4 mg/kg intravenously in adults and that the bioavailability of oral voriconazole in children is lower (65%) than that reported in adults. CrossRefGoogle Scholar
23. 23.
    •• Driscoll TA, Yu LC, Frangoul H, et al. Pharmacokinetics and safety of intravenous voriconazole to oral switch in immunocompromised children compared to adults. Antimicrob Agents Chemother. 2011;55:5770–9. Pharmacokinetic study that showed that voriconazole intravenous doses higher than 7 mg/kg are needed in children to closely match adult exposures, and that a weight-based oral dose may be more appropriate for children than a fixed dose. PubMedCrossRefGoogle Scholar
24. 24.
    Voriconazole Summary of Product Characteristics. Update 21-March-2012. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000387/WC500049756.pdf.
25. 25.
    ClinicalTrials.gov. A study to evaluate the safety of voriconazole as treatment of invasive aspergillosis (fungal infection) and other rare molds in children. http://clinicaltrials.gov/ct2/show/NCT00836875?term=Voriconazole+AND+Children&rank=7 (17. January 2012, date last accessed).
26. 26.
    ClinicalTrials.gov. A study of the safety, tolerability and effective of voriconazole for the treatment of serious candida infection and candida infection of the throat in pediatric patients. http://clinicaltrials.gov/ct2/show/NCT01092832?term=Voriconazole+AND+Children&rank=9 (17. January 2012, date last accessed).
27. 27.
    Pieper S, Kolve H, Gumbinger HG, Würthwein G, Groll AH. Safety, tolerance and outcome of treatment with voriconazole in immunocompromised pediatric patients. Mycoses. 2011;54(Suppl2):125.Google Scholar
28. 28.
    Gerin M, Mahlaoui N, Elie C, et al. Therapeutic drug monitoring of voriconazole after intravenous administration in infants and children with primary immunodeficiency. Ther Drug Monit. 2011;33:464–6.PubMedCrossRefGoogle Scholar
29. 29.
    Molina JR, Serrano J, Sánchez-García J et al. Voriconazole as primary antifungal prophylaxis in children undergoing allo-SCT. Bone Marrow Transplant. 2011 May 16. [Epub ahead of print].Google Scholar
30. 30.
    • Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis. 2010;50:27–36. Important pediatric study whose results suggested a pharmacodynamic association between a voriconazole trough >1000 ng/mL and survival. PubMedCrossRefGoogle Scholar
31. 31.
    Bruggemann RJ, van der Linden JW, Verweij PE, et al. Impact of therapeutic drug monitoring of voriconazole in a pediatric population. Pediatr Infect Dis J. 2010;30:533–4.Google Scholar
32. 32.
    Soler-Palacin P, Frick MA, Martin-Nalda A, et al. Voriconazole drug monitoring in the management of invasive fungal infection in immunocompromised children: a prospective study. J Antimicrob Chemother. 2012;67(3):700–6.PubMedCrossRefGoogle Scholar
33. 33.
    Cowen EW, Nguyen JC, Miller DD, et al. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol. 2010;62(1):31–7.PubMedCrossRefGoogle Scholar
34. 34.
    Mandhaniya S, Swaroop C, Thulkar S, et al. Oral voriconazole versus intravenous low dose amphotericin B for primary antifungal prophylaxis in pediatric acute leukemia induction: a prospective, randomized, clinical study. J Pediatr Hematol Oncol. 2011;33(8):e333–41.PubMedCrossRefGoogle Scholar
35. 35.
    Panagopoulou P, Fragandrea-Sidi F, Roilides E, et al. Antifungal prophylaxis with voriconazole in paediatric patients treated for hematological malignancies. Haematologica. 2010;95 Suppl 2:363.Google Scholar
36. 36.••
    Pascual A, Nieth V, Calandra T, et al. Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods. Antimicrob Agents Chemother. 2007;51:137–43. First prospective cohort study that showed that voriconazole therapeutic drug monitoring improves the efficacy and safety of therapy in patients with invasive mycoses. PubMedCrossRefGoogle Scholar
37. 37.
    •• Troke PF, Hockey HP, Hope WW. Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients. Antimicrob Agents Chemother. 2011;55:4782–8. Comprehensive analysis of the voriconazole exposure-response relationships for patients from nine published clinical trials suggesting that a trough/MIC ratio of 2 to 5 is associated with a near-maximal probability of response and that a trough/MIC ratio of 2 to 5 may be used as a target for therapeutic drug monitoring. PubMedCrossRefGoogle Scholar
38. 38.
    • Tragiannidis A, Dokos C, Lehrnbecher T, Groll AH. Antifungal chemo-prophylaxis in children and adolescents with haematological malignancies and following allogeneic haematopoietic stem cell transplantation: review of the literature and options for clinical practice. Drugs. 2012;72(5):685–704. Comprehensive review of antifungal chemoprophylaxis in children and adolescents with haematological malignancies and following allogeneic haematopoietic stem cell transplantation. PubMedCrossRefGoogle Scholar
39. 39.
    Groll AH. Drug therapy in paediatric patients. Lancet. 2001;357(9257):719.PubMedCrossRefGoogle Scholar