Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis

Andreas H. Groll, Lauren Wood, Maureen Roden, Diana Mickiene, Christine C. Chiou, Ellen Townley, Luqman Dad, Stephen C. Piscitelli, Thomas J. Walsh

Research output: Contribution to journalArticle

Abstract

The safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension were investigated in an open sequential dose escalation study with 26 human immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old; mean CD4+-cell count, 128/μl) with oropharyngeal candidiasis (OPC). Patients received CD-ITRA at either 2.5 mg/kg of body weight once a day (QD) or 2.5 mg/kg twice a day (BID) for a total of 15 days. Pharmacokinetic sampling was performed after the first dose and for up to 120 h after the last dose, and antifungal efficacy was evaluated by standardized scoring of the oropharynx. Apart from mild to moderate gastrointestinal disturbances in three patients (11.5%), CD-ITRA was well tolerated. Two patients (7.6%) discontinued treatment prematurely due to study drug-related adverse events. After 15 days of treatment, the peak concentration of drug in plasma (Cmax, the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC0-24), the concentration in plasma at the end of the dosing interval (predose) (Cmin), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 ± 0.53 μg/ml, 6.80 ± 7.4 μg · h/ml, 0.192 ± 0.06 μg/ml, and 56.48 ± 44 h, respectively, for the QD regimen and 1.340 ± 0.75 μg/ml, 23.04 ± 14.5 μh/ml, 0.782 ± 0.19 μg/ml, and 104.22 ± 94 h, respectively, for the BID regimen. The mean AUC-based accumulation factors for ITRA on day 15 were 4.14 ± 0.9 and 3.53 ± 0.6, respectively. A comparison of the dose-normalized median AUC of the two dosage regimens revealed a trend toward nonlinear drug disposition (P = 0.05). The mean metabolic ratios (AUC of hydroxy-itraconazole/AUC of ITRA) at day 15 were 1.96 ± 0.1 for the QD regimen and 1.29 ± 0.2 for the BID regimen, respectively (P <0.05). The OPC score (range, 0 to 13) for all 26 patients decreased from a mean of 7.46 ± 0.8 at baseline to 2.8 ± 0.7 at the end of therapy (P <0.001), demonstrating antifungal efficacy in this setting. The relationships among Cmax, Cmin, AUC0-12, Cmax/MIC, Cmin/MIC, AUC0-12/MIC, time during the dosing interval when the plasma drug concentrations were above the MIC for the infecting isolate, and the residual OPC score at day 15 for the entire study population fit inhibitory effect pharmacodynamic models (r, 0.595 to 0.421; P,

Original languageEnglish (US)
Pages (from-to)2554-2563
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume46
Issue number8
DOIs
StatePublished - 2002
Externally publishedYes

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Candidiasis
Itraconazole
Area Under Curve
Pharmacokinetics
Pediatrics
Safety
Pharmaceutical Preparations
Oropharynx
CD4 Lymphocyte Count
Drug-Related Side Effects and Adverse Reactions
Half-Life
Suspensions
Therapeutics
Body Weight
cyclodextrin itraconazole
HIV
Population

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis. / Groll, Andreas H.; Wood, Lauren; Roden, Maureen; Mickiene, Diana; Chiou, Christine C.; Townley, Ellen; Dad, Luqman; Piscitelli, Stephen C.; Walsh, Thomas J.

In: Antimicrobial Agents and Chemotherapy, Vol. 46, No. 8, 2002, p. 2554-2563.

Research output: Contribution to journalArticle

Groll, AH, Wood, L, Roden, M, Mickiene, D, Chiou, CC, Townley, E, Dad, L, Piscitelli, SC & Walsh, TJ 2002, 'Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis', Antimicrobial Agents and Chemotherapy, vol. 46, no. 8, pp. 2554-2563. https://doi.org/10.1128/AAC.46.8.2554-2563.2002
Groll, Andreas H. ; Wood, Lauren ; Roden, Maureen ; Mickiene, Diana ; Chiou, Christine C. ; Townley, Ellen ; Dad, Luqman ; Piscitelli, Stephen C. ; Walsh, Thomas J. / Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis. In: Antimicrobial Agents and Chemotherapy. 2002 ; Vol. 46, No. 8. pp. 2554-2563.
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abstract = "The safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension were investigated in an open sequential dose escalation study with 26 human immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old; mean CD4+-cell count, 128/μl) with oropharyngeal candidiasis (OPC). Patients received CD-ITRA at either 2.5 mg/kg of body weight once a day (QD) or 2.5 mg/kg twice a day (BID) for a total of 15 days. Pharmacokinetic sampling was performed after the first dose and for up to 120 h after the last dose, and antifungal efficacy was evaluated by standardized scoring of the oropharynx. Apart from mild to moderate gastrointestinal disturbances in three patients (11.5{\%}), CD-ITRA was well tolerated. Two patients (7.6{\%}) discontinued treatment prematurely due to study drug-related adverse events. After 15 days of treatment, the peak concentration of drug in plasma (Cmax, the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC0-24), the concentration in plasma at the end of the dosing interval (predose) (Cmin), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 ± 0.53 μg/ml, 6.80 ± 7.4 μg · h/ml, 0.192 ± 0.06 μg/ml, and 56.48 ± 44 h, respectively, for the QD regimen and 1.340 ± 0.75 μg/ml, 23.04 ± 14.5 μh/ml, 0.782 ± 0.19 μg/ml, and 104.22 ± 94 h, respectively, for the BID regimen. The mean AUC-based accumulation factors for ITRA on day 15 were 4.14 ± 0.9 and 3.53 ± 0.6, respectively. A comparison of the dose-normalized median AUC of the two dosage regimens revealed a trend toward nonlinear drug disposition (P = 0.05). The mean metabolic ratios (AUC of hydroxy-itraconazole/AUC of ITRA) at day 15 were 1.96 ± 0.1 for the QD regimen and 1.29 ± 0.2 for the BID regimen, respectively (P <0.05). The OPC score (range, 0 to 13) for all 26 patients decreased from a mean of 7.46 ± 0.8 at baseline to 2.8 ± 0.7 at the end of therapy (P <0.001), demonstrating antifungal efficacy in this setting. The relationships among Cmax, Cmin, AUC0-12, Cmax/MIC, Cmin/MIC, AUC0-12/MIC, time during the dosing interval when the plasma drug concentrations were above the MIC for the infecting isolate, and the residual OPC score at day 15 for the entire study population fit inhibitory effect pharmacodynamic models (r, 0.595 to 0.421; P,",
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AU - Mickiene, Diana

AU - Chiou, Christine C.

AU - Townley, Ellen

AU - Dad, Luqman

AU - Piscitelli, Stephen C.

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N2 - The safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension were investigated in an open sequential dose escalation study with 26 human immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old; mean CD4+-cell count, 128/μl) with oropharyngeal candidiasis (OPC). Patients received CD-ITRA at either 2.5 mg/kg of body weight once a day (QD) or 2.5 mg/kg twice a day (BID) for a total of 15 days. Pharmacokinetic sampling was performed after the first dose and for up to 120 h after the last dose, and antifungal efficacy was evaluated by standardized scoring of the oropharynx. Apart from mild to moderate gastrointestinal disturbances in three patients (11.5%), CD-ITRA was well tolerated. Two patients (7.6%) discontinued treatment prematurely due to study drug-related adverse events. After 15 days of treatment, the peak concentration of drug in plasma (Cmax, the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC0-24), the concentration in plasma at the end of the dosing interval (predose) (Cmin), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 ± 0.53 μg/ml, 6.80 ± 7.4 μg · h/ml, 0.192 ± 0.06 μg/ml, and 56.48 ± 44 h, respectively, for the QD regimen and 1.340 ± 0.75 μg/ml, 23.04 ± 14.5 μh/ml, 0.782 ± 0.19 μg/ml, and 104.22 ± 94 h, respectively, for the BID regimen. The mean AUC-based accumulation factors for ITRA on day 15 were 4.14 ± 0.9 and 3.53 ± 0.6, respectively. A comparison of the dose-normalized median AUC of the two dosage regimens revealed a trend toward nonlinear drug disposition (P = 0.05). The mean metabolic ratios (AUC of hydroxy-itraconazole/AUC of ITRA) at day 15 were 1.96 ± 0.1 for the QD regimen and 1.29 ± 0.2 for the BID regimen, respectively (P <0.05). The OPC score (range, 0 to 13) for all 26 patients decreased from a mean of 7.46 ± 0.8 at baseline to 2.8 ± 0.7 at the end of therapy (P <0.001), demonstrating antifungal efficacy in this setting. The relationships among Cmax, Cmin, AUC0-12, Cmax/MIC, Cmin/MIC, AUC0-12/MIC, time during the dosing interval when the plasma drug concentrations were above the MIC for the infecting isolate, and the residual OPC score at day 15 for the entire study population fit inhibitory effect pharmacodynamic models (r, 0.595 to 0.421; P,

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