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Limited-sampling strategy models for itraconazole and hydroxy-itraconazole based on data from a bioequivalence study
G Suarez-Kurtz1, F A Bozza, F L Vicente
1Instituto Nacional de Câncer, Coordenação de Pesquisa, Programa de Farmacologia, Rio de Janeiro, Brazil. kurtz@inca.org.br
Antimicrobial Agents and Chemotherapy
|December 31, 1998
Summary
Two itraconazole formulations, Sporanox and Traconal, were not bioequivalent in healthy volunteers. Limited-sampling models accurately predicted drug levels, proving useful for pharmacokinetic studies.
Area of Science:
- Pharmacology
- Pharmaceutical Sciences
- Clinical Pharmacy
Background:
- Interindividual variability in itraconazole oral bioavailability necessitates bioequivalence studies.
- Assessing generic drug formulations against reference standards is crucial for therapeutic equivalence.
Purpose of the Study:
- To evaluate the bioequivalence of Traconal (test) versus Sporanox (reference) itraconazole formulations in Brazil.
- To develop and validate limited-sampling strategy models for estimating itraconazole pharmacokinetics.
Main Methods:
- A randomized, crossover study involving 18 healthy volunteers receiving single 200-mg oral doses.
- High-performance liquid chromatography (HPLC) for measuring itraconazole and hydroxy-itraconazole plasma concentrations.
- Development and validation of limited-sampling models to estimate area under the curve (AUC).
Main Results:
- The 90% confidence intervals for key pharmacokinetic parameters (Cmax, AUC0-48h, AUC0-infinity) fell outside the 80-125% range, indicating non-bioequivalence.
- Three-point limited-sampling models accurately predicted AUC0-infinity (R2 > 0.98, bias < 3%) for both itraconazole and hydroxy-itraconazole.
- Increasing sampling points beyond three offered minimal improvement in AUC estimation accuracy.
Conclusions:
- The Traconal and Sporanox formulations are not bioequivalent based on single-dose administration.
- Limited-sampling strategy models with three data points are accurate and efficient tools for pharmacokinetic and bioequivalence assessments of itraconazole.