Investigating the Discriminatory Power of BCS-Biowaiver in Vitro Methodology to Detect Bioavailability Differences between Immediate Release Products Containing a Class I Drug.
The purpose of this work is to investigate the discriminatory power of the Biopharmaceutics Classification System (BCS)-biowaiver in vitro methodology, i.e., to investigate if a BCS-biowaiver approach would have detected the Cmax differences observed between two zolpidem tablets and to identify the cause of the in vivo difference. Several dissolution conditions were tested with three zolpidem formulations: the reference (Stilnox), a bioequivalent formulation (BE), and a nonbioequivalent formulation (N-BE). Zolpidem is highly soluble at pH 1.2, 4.5, and 6.8. Its permeability in Caco-2 cells is higher than that of metoprolol and its transport mechanism is passive diffusion. None of the excipients (alone or in combination) showed any effect on permeability. All formulations dissolved more than 85% in 15 min in the paddle apparatus at 50 rpm in all dissolution media. However, at 30 rpm the nonbioequivalent formulation exhibited a slower dissolution rate. A slower gastric emptying rate was also observed in rats for the nonbioequivalent formulation. A slower disintegration and dissolution or a delay in gastric emptying might explain the Cmax infra-bioavailability for a highly permeable drug with short half-life. The BCS-biowaiver approach would have declared bioequivalence, although the in vivo study was not conclusive but detected a 14% mean difference in Cmax that precluded the bioequivalence demonstration. Nonetheless, these findings suggest that a slower dissolution rate is more discriminatory and that rotation speeds higher than 50 rpm should not be used in BCS-biowaivers, even if a coning effect occurs.
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University , 03550 Alicante, Spain.|Pharmacokinetics and Pharmaceutical Technology, Complutense University of Madrid , 28040 Madrid, Spain.|Analysis and Control Department, University of Los Andes , Mérida, Venezuela.
Sarin
S
Colón-Useche
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University , 03550 Alicante, Spain.
Isabel
I
González-Álvarez
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University , 03550 Alicante, Spain.
Victor
V
Mangas-Sanjuan
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University , 03550 Alicante, Spain.
Marta
M
González-Álvarez
Pharmacokinetics and Pharmaceutical Technology, Complutense University of Madrid , 28040 Madrid, Spain.
Pilar
P
Pastoriza
Pharmacokinetics and Pharmaceutical Technology, Complutense University of Madrid , 28040 Madrid, Spain.
Irene
I
Molina-Martínez
Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University , 03550 Alicante, Spain.
Marival
M
Bermejo
Service on Pharmacokinetics and Generic Medicines, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products , 28022 Madrid, Spain.
Alfredo
A
García-Arieta
D000818:Animals; D001682:Biological Availability; D001702:Biopharmaceutics / Q000379:methods*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical; D005079:Excipients / Q000737:chemistry*; D058785:GABA-A Receptor Agonists / Q000378:metabolism*; D005746:Gastric Emptying / Q000502:physiology; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D011725:Pyridines / Q000378:metabolism*; D051381:Rats; D013810:Therapeutic Equivalency; D000077334:Zolpidem
D005079:Excipients; D058785:GABA-A Receptor Agonists; D011725:Pyridines; D000077334:Zolpidem
Biopharmaceutics Classification System; bioequivalence; dissolution test; gastric emptying; in vitro; zolpidem