Elucidating the Role of Dose in the Biopharmaceutics Classification of Drugs: The Concepts of Critical Dose, Effective In Vivo Solubility, and Dose-Dependent BCS

• Published in: Pharmaceutical research Vol. 29; no. 11; pp. 3188 - 3198
• Main Authors: Charkoftaki, Georgia, Dokoumetzidis, Aristides, Valsami, Georgia, Macheras, Panos
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.11.2012; Springer; Springer Nature B.V
• Subjects: Aqueous solutions; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Biopharmaceutics - methods; Classification; Dose-Response Relationship, Drug; Drug delivery systems; Efficiency; General pharmacology; Intestinal Absorption; Medical Law; Medical sciences; Models, Biological; Permeability; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - classification; Pharmaceutical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Research Paper; Solubility; effective; solubility; dose; BCS; DDBCS; critical dose; Drug; effective in vivo solubility; Pharmaceutical technology; Solubility; Biopharmaceutics; In vivo; Classification; Effective dose; Physicochemical properties
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-012-0815-4

Purpose To develop a dose dependent version of BCS and identify a critical dose after which the amount absorbed is independent from the dose. Methods We utilized a mathematical model of drug absorption in order to produce simulations of the fraction of dose absorbed ( F ) and the amount absorbed as function of the dose for the various classes of BCS and the marginal cases in between classes. Results Simulations based on the mathematical model of F versus dose produced patterns of a constant F throughout a wide range of doses for drugs of Classes I, II and III, justifying biowaiver claim. For Classes I and III the pattern of a constant F stops at a critical dose Dose cr after which the amount of drug absorbed, is independent from the dose. For doses higher than Dose cr , Class I drugs become Class II and Class III drugs become Class IV. Dose cr was used to define an in vivo effective solubility as S eff  = Dose cr /250 ml. Literature data were used to support our simulation results. Conclusions A new biopharmaceutic classification of drugs is proposed, based on F , separating drugs into three regions, taking into account the dose, and Dose cr , while the regions for claiming biowaiver are clearly defined.