AI Summary & Key Takeaways
AI InsightTherefore, the FDC is safe for use in human subjects.
📌 3 Key Takeaways
Abstract
Objectives: The objective of this study was to establish and validate an in vitro-in vivo correlation (IVIVC). To investigate the safety of a fixed-dosecombination (FDC) versus the reference formulations (Januvia® 100 mg Filmtabletten co-administered with Glucophage® SR 1000 mg prolonged release tablets), a bioequivalence study was conducted in the fasted and fed states, and the data generated were used to establish the correlation. Materials and Methods: The formulations used in the bioequivalence study were a FDC (sitagliptin hydrochloride equivalent to 100 mg of sitagliptinand metformin hydrochloride 1000 mg prolonged release) and Januvia® 100 mg co-administered with Glucophage® SR 1000 mg. The plasmaprofiles from the bioequivalence study and respective dissolution data were then utilized to establish “level A” IVIVC. The procedure comprisespharmacokinetic modeling to derive the empirical constants for further use in deconvolution and convolution procedures. Levy plots wereconstructed to understand the relationship between in vitro and in vivo properties. The internal and external predictabilities were evaluated bycomparing the predicted pharmacokinetics with the observed values from the bioequivalence study. Results: The formulations showed approximately 91%-95% and 89%-91% dissolution, respectively in fasted and fed-state dissolution media forsitagliptin. The dissolution of metformin was 96%-98% and 89%-95%, respectively, in fasted and fed-state media. The regression coefficients ofall the Levy plots were more than 0.900, indicating a linear correlation between in vitro release and in vivo parameters. The prediction error valueof internal and external predictabilities was below 10 and met the US Food and Drug Administration criteria. Therefore, it can be stated that thecorrelation models are validated and can be used for predictions and to setting the dissolution specifications. The safety and tolerability of the FDCwas found to be superior to those of the reference formulations, as fewer adverse events occurred following administration of the FDC. Conclusion: Correlation models can be useful for the prediction of FDCs during the management life cycle of the product. The models can alsoserve as a surrogate for in vivo studies. The FDC was tolerable, and the adverse events were mild and similar to those observed with the referenceproducts. Therefore, the FDC is safe for use in human subjects.
Özet
Amaç: Bu çalışmanın amacı sabit doz kombinasyonunun (FDC) güvenliliğini araştırmak için referans formülasyonlara (Januvia® 100 mg Filmtablettenie birlikte uygulanan Glucophage® SR 1000 mg uzatılmış salınımlı tablet) karşı in vitro-in vivo korelasyonu (IVIVC) kurmak ve valide etmektir. Bunedenle, aç ve tok durumlarda bir biyoeşdeğerlik çalışması yapılmış ve elde edilen veriler korelasyon kurmak için kullanılmıştır.Gereç ve Yöntemler: Biyoeşdeğerlik çalışmalarında kullanılan formülasyonlar bir FDC (100 mg sitaglipine eş staglipin hidroklorür ve uzun salınımlımetformin hidroklorür 1000 mg) idi. Biyoeşdeğerlik çalışmasının plazma profilleri ve takip eden dissolüsyon verileri “düzey A” IVIVC kurmak içinkullanılmıştır. Bu prosedür, dekonvülüsyon ve konvülüsyon prosedürlerinde kullanılmak üzere ampirik sabiteleri derive etmek için kullanılan birfarmakokinetik modellemeden oluşmaktadır. İn vitro ve in vivo özellikler arasındaki ilişkiyi anlamak için için levy grafikleri düzenlenmiştir. İç ve dıştahmin edilebilirlikler biyoeşdeğerlik çalışmasından elde edilen tahmini gözlemlenen değerler ile farmakokinetikleri karşılaştırarak değerlendirilmiştir.