Average bioequivalence of single 500 mg doses of two oral formulations of levofloxacin: a randomized, open-label, two-period crossover study in healthy adult Brazilian volunteers

Abstract

Average bioequivalence of two 500 mg levofloxacin formulations available in Brazil, Tavanic © (SanofiAventis Farmacêutica Ltda, Brazil, reference product) and Levaquin © (Janssen-Cilag Farmacêutica Ltda, Brazil, test product) was evaluated by means of a randomized, open-label, 2-way crossover study performed in 26 healthy Brazilian volunteers under fasting conditions. A single dose of 500 mg levofloxacin tablets was orally administered, and blood samples were collected over a period of 48 hours. Levofloxacin plasmatic concentrations were determined using a validated HPLC method. Pharmacokinetic parameters C max , T max , K el , T 1/2el , AUC 0-t and AUC 0-inf were calculated using noncompartmental analysis. Bioequivalence was determined by calculating 90% confidence intervals (90% CI) for the ratio of C max , AUC 0-t and AUC 0-inf values for test and reference products, using logarithmic transformed data. Tolerability was assessed by monitoring vital signs and laboratory analysis results, by subject interviews and by spontaneous report of adverse events. 90% CIs for C max , AUC 0-t and AUC 0-inf were 92.1% -108.2%, 90.7% -98.0%, and 94.8% -100.0%, respectively. Observed adverse events were nausea and headache. It was concluded that Tavanic © and Levaquin © are bioequivalent, since 90% CIs are within the 80% -125% interval proposed by regulatory agencies. A bioequivalência média de duas formulações de levofloxacino disponíveis no Brasil, Tavanic © (SanofiAventis Farmacêutica Ltda, Brasil, produto referência) e Levaquin © (Janssen-Cilag Farmacêutica Ltda, Brasil, produto teste) foi determinada por meio da realização de ensaio aleatório, aberto, cruzado, com dois períodos e duas sequências, em 26 voluntários sadios em condições de jejum. Amostras de sangue dos voluntários foram obtidas ao longo de um período de 48 horas após administração de dose única de 500 mg de levofloxacino. As concentrações plasmáticas do fármaco foram determinadas por método cromatográfico validado. Os parâmetros farmacocinéticos C max , T max , K el , T 1/2el , AUC 0-t e AUC 0-inf foram calculados por análise não compartimental. A bioequivalência foi determinada pelo cálculo de intervalos de confiança 90% (IC 90%) para as razões entre os valores de C max , AUC 0-t e AUC 0-inf obtidos para os produtos teste e referência, usando dados transformados logaritmicamente. A tolerabilidade foi avaliada pelo acompanhamento dos sinais vitais e resultados de exames laboratoriais, por consultas e por relato espontâneo dos voluntários. ICs 90% para C max , AUC 0-t e AUC 0-inf foram 92.1% -108.2%, 90.7% -98.0%, e 94.8% -100.0%, respectivamente. Os eventos adversos observados foram náusea e cefaleia. Concluiuse que os produtos Tavanic © e Levaquin © são bioequivalentes, uma vez que os ICs 90% estão dentro da faixa de 80%-125% proposta pelas agências reguladoras.Unitermos: Levofloxacino/bioequivalência. Farmacocinética. Cromatografia líquida de alta eficiência/ análise qualitativa. Tavanic

In Silico Prediction of Plasma Concentrations of Fluconazole Capsules with Different Dissolution Profiles and Bioequivalence Study Using Population Simulation

“…Drug products that are pharmaceutical equivalents are considered bioequivalent and, therefore, interchangeable when BA is not statistically different between the two products after administration at the same dose and under similar experimental conditions in a bioequivalence (BE) study. For purposes of establishing BE, a test product must be compared to a reference product [1,2,3].…”

Determination of absorption curves, dissolution profiles and establishment of <i>in vitro-in vivo</i> correlation by <i>in silico</i> methods using GastroPlus^TM and DDDPlus^TM

“…Area under the plasma concentration-time curve (AUC) is an important pharmacokinetic indicator related to bioavailability because it represents the fraction of drug absorbed (KANO et al, 2015). Acceptable internal predictability values for %PE in convolution must be less than 15% for each formulation .…”

“…Drug products that are pharmaceutical equivalents are considered bioequivalent and, therefore, interchangeable, when BA is not statistically different between two products after administration at the same dose and under similar experimental conditions in a bioequivalence (BE) study. For purposes of establishing BE, a test product must be compared to a reference product (SILVA et al, 2010;KANO et al, 2015;FDA, 2014).…”