title: Pediatric Clinical Pharmacology of Voriconazole: Role of Pharmacokinetic/Pharmacodynamic Modeling in Pharmacotherapy.
abstract: Voriconazole is a potent antifungal agent used for the treatment of invasive fungal infections caused by Aspergillus and Candida species in adult and pediatric patients. Voriconazole has a narrow therapeutic index and a large intra- and inter-individual pharmacokinetics (PK) variability. Several factors including non-linear PK, age, body weight, cytochrome P450 2C19 genotype, concomitant drugs, liver function, and food are responsible for the large variability in voriconazole PK. A combination of a narrow therapeutic index with a large PK variability results in treatment failure in many patients at clinically recommended doses. There is an urgent need to establish an optimal dosing regimen for pediatric patients <2 years of age because of a lack of recommended dosing guidelines and high (>60 %) treatment failure rates. Therapeutic drug monitoring is commonly used in clinical practice to optimize the voriconazole dosing regimens in pediatric patients, but it is associated with several practical limitations. Implementation of a PK model-guided individualized dose selection will help in reducing the PK variability and will improve therapeutic outcomes. In this review, we have summarized the covariates influencing the PK of voriconazole in adult and pediatric patients, emphasizing that the clearance of voriconazole is significantly different between adult and pediatric patients owing to developmental changes in the major clearance pathways. Moreover, we have provided the limitations of the current dosing regimens and have proposed a new dosing method using a PK model-guided dose individualization of voriconazole in pediatric patients.
authors.affiliation: Clinical Pharmacology, InnoPharma, Inc., a Pfizer Company, 10 Knightsbridge Road, Piscataway, NJ, 08854, USA. rajendra.kadam1981@gmail.com.
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Kadam
authors.affiliation: Division of Pediatric Clinical Pharmacology, Children's National Health System, Washington, DC, USA.|Division of Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, Basel, Switzerland.|Intensive Care and Department of Surgery, Erasmus MC-Sophia Hospital, Rotterdam, The Netherlands.
authors.forename: Johannes N
authors.initials: JN
authors.lastname: Van Den Anker
mesh_terms: D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001230:Aspergillus / Q000187:drug effects; D002175:Candida / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000072742:Invasive Fungal Infections / Q000188:drug therapy* / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010601:Pharmacology, Clinical / Q000379:methods*; D012189:Retrospective Studies; D065819:Voriconazole / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole