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Pharmaceutics
2019 May 05;115:. doi: 10.3390/pharmaceutics11050215.
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In Silico Prediction of Plasma Concentrations of Fluconazole Capsules with Different Dissolution Profiles and Bioequivalence Study Using Population Simulation.
Duque MD
,
Silva DA
,
Issa MG
,
Porta V
,
Löbenberg R
,
Ferraz HG
.
Abstract
A biowaiver is accepted by the Brazilian Health Surveillance Agency (ANVISA) for immediate-release solid oral products containing Biopharmaceutics Classification System (BCS) class I drugs showing rapid drug dissolution. This study aimed to simulate plasma concentrations of fluconazole capsules with different dissolution profiles and run population simulation to evaluate their bioequivalence. The dissolution profiles of two batches of the reference product Zoltec® 150 mg capsules, A1 and A2, and two batches of other products (B1 and B2; C1 and C2), as well as plasma concentration-time data of the reference product from the literature, were used for the simulations. Although products C1 and C2 had drug dissolutions < 85% in 30 min at 0.1 M HCl, simulation results demonstrated that these products would show the same in vivo performance as products A1, A2, B1, and B2. Population simulation results of the ln-transformed 90% confidence interval for the ratio of Cmax and AUC0-t values for all products were within the 80-125% interval, showing to be bioequivalent. Thus, even though the in vitro dissolution behavior of products C1 and C2 was not equivalent to a rapid dissolution profile, the computer simulations proved to be an important tool to show the possibility of bioequivalence for these products.
400455/2014-5 Conselho Nacional de Desenvolvimento Científico e Tecnológico, Finance Code 001 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Figure 1. Dissolution profiles of products A1, A2, B1, B2, C1, and C2, obtained in USP Apparatus 1 (basket) with 900 mL of 0.1 M HCl at 37 ± 0.5 °C and 100 rpm for 30 min (adapted from [29], with permission from Brazilian Journal of Pharmaceutical Sciences, 2019).
Figure 2. Plasma concentration-time curve of reference product (Ref) based on experimental values and of products A1, A2, B1, B2, C1, and C2 created using simulated values given by GastroPlus™; error bars represent the standard deviation for the reference plot. A zoom in of the time period 0–48 h is highlighted for better visualization.
Figure 3. Amount of fluconazole dissolved in vivo (AmtDiss), amount absorbed to the portal vein (AmtPV), total amount absorbed (AmtAbs), and the amount in the systemic circulation (AmtSC) for products (A1–C2) calculated by GastroPlus™. Simulation time displayed is 8 h instead of the total simulation time (96 h) to provide better visualization.
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