465
14 Quantitative Structure-Property Relationship Analysis …
Low and variable absorption for class 4 drugs is anticipated because of the combined limitation of solubility and permeability.
Experience gained through development of traditional in vitro–in vivo correlations, IVIVC (level A, B, or C correlations) for IR products containing poorly soluble
drugs and for extended release products suggests a significant degree of formulation
dependency or specificity associated with such correlations. Therefore, for products
that are likely to exhibit slow in vivo dissolution, IVIVC need to be established and
their predictive performance verified through experimentation. Future research in
this area should address how to a priori identify dissolution test conditions that
yield robust IVIVC that are applicable to a wide range of formulations [14].
In recent years; the validity and broad applicability of the BCS have been the
subject of extensive research and discussion [4–6, 15]. It has been adopted by
the US Food and Drug Administration (FDA), the European Medicines Agency
(EMEA), and the World Health Organization (WHO) for setting bioavailability/
bioequivalence standards for IR oral drug product approval; and the BCS principles
are extensively used by the pharmaceutical industry throughout drug discovery and
development [7, 16–18].
The introduction of the simplification of the BCS in FDA guidelines represents a
major step forward in the regulation of oral drug products. The FDA guideline suggests internal standards and marker substances to characterize the permeability of
drug substances in vitro and in vivo. The BCS is used to set drug product dissolution
standards to reduce the in vivo bioequivalence requirements [1, 19]. Knowledge of
the BCS can also help the formulation scientist to develop a dosage form based on
mechanistic, rather than empirical, approaches [20]. This allows one to determine
the potential for IVIVC, and can significantly reduce in vivo studies.
According to the current FDA guidance [17, 18], drug API is considered highly
permeable when the extent of absorption in humans is determined to be 90 % or
more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose. The solubility classification of a given
drug is based on the highest dose strength in an IR product. In this guidance, an IR
drug product is considered rapidly dissolving when no less than 85 % of the labeled
amount of the drug substance dissolves within 30 min, using U.S. Pharmacopeia
(USP) apparatus I at 100 rpm (or apparatus II at 50 rpm) in a volume of 900 ml or
less in each of the following media: (1) 0.1 N HCl or simulated gastric fluid USP
without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or simulated intestinal
fluid USP without enzymes.
14.3 Pharmacokinetic Characteristics of Absorption
and Bioavailability
Bioavailability is based on the physiological process of absorption, which include
three stages: (1) transfer an API through apical plasma membrane inside cells; (2)
intracellular transport of substances followed by their possible metabolism; (3)
transfer of the transported and transformed API from cells into blood or lymph.
14 Quantitative Structure-Property Relationship Analysis …
Low and variable absorption for class 4 drugs is anticipated because of the combined limitation of solubility and permeability.
Experience gained through development of traditional in vitro–in vivo correlations, IVIVC (level A, B, or C correlations) for IR products containing poorly soluble
drugs and for extended release products suggests a significant degree of formulation
dependency or specificity associated with such correlations. Therefore, for products
that are likely to exhibit slow in vivo dissolution, IVIVC need to be established and
their predictive performance verified through experimentation. Future research in
this area should address how to a priori identify dissolution test conditions that
yield robust IVIVC that are applicable to a wide range of formulations [14].
In recent years; the validity and broad applicability of the BCS have been the
subject of extensive research and discussion [4–6, 15]. It has been adopted by
the US Food and Drug Administration (FDA), the European Medicines Agency
(EMEA), and the World Health Organization (WHO) for setting bioavailability/
bioequivalence standards for IR oral drug product approval; and the BCS principles
are extensively used by the pharmaceutical industry throughout drug discovery and
development [7, 16–18].
The introduction of the simplification of the BCS in FDA guidelines represents a
major step forward in the regulation of oral drug products. The FDA guideline suggests internal standards and marker substances to characterize the permeability of
drug substances in vitro and in vivo. The BCS is used to set drug product dissolution
standards to reduce the in vivo bioequivalence requirements [1, 19]. Knowledge of
the BCS can also help the formulation scientist to develop a dosage form based on
mechanistic, rather than empirical, approaches [20]. This allows one to determine
the potential for IVIVC, and can significantly reduce in vivo studies.
According to the current FDA guidance [17, 18], drug API is considered highly
permeable when the extent of absorption in humans is determined to be 90 % or
more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose. The solubility classification of a given
drug is based on the highest dose strength in an IR product. In this guidance, an IR
drug product is considered rapidly dissolving when no less than 85 % of the labeled
amount of the drug substance dissolves within 30 min, using U.S. Pharmacopeia
(USP) apparatus I at 100 rpm (or apparatus II at 50 rpm) in a volume of 900 ml or
less in each of the following media: (1) 0.1 N HCl or simulated gastric fluid USP
without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or simulated intestinal
fluid USP without enzymes.
14.3 Pharmacokinetic Characteristics of Absorption
and Bioavailability
Bioavailability is based on the physiological process of absorption, which include
three stages: (1) transfer an API through apical plasma membrane inside cells; (2)
intracellular transport of substances followed by their possible metabolism; (3)
transfer of the transported and transformed API from cells into blood or lymph.