2011 Anniversary Yearbook - EUFEPS today and history

EUFEPS Newsletter, 1997, vol. 6, issue 3
Biopharmaceutical
Classification System (BCS)
for Oral Immediate-release
Drug Products
Anders Grahnen, Assoc. Professor
EUFEPS Vice–President and Quintiles AB
A biopharmaceutical classification
system (BCS) for immediate release
(IR) drug products has recently been
proposed (I) and is under consideration
by regulatory authorities. The new
classification system is a result of basic
research into the mechanistics of drug
absorption. Advances in physiology,
molecular biology and pharmacokinetics
have revealed crucial new information
regarding physiological mechanisms
involved in the absorption process.
Although drug absorption has been
investigated for more than four decades,
predictive models (such as the pH-
partition hypothesis) for absorption
have so far been of limited value due
to the complexity of the physiological/
physiochemical events involved in the
intestinal absorption process of drugs.
Theoretical considerations of the
BCS
Drug dissolution is a prerequisite to drug
absorption and clinical response for most
drugs given orally. Amidon and co-workers
have developed a microscopic approach
to drug absorption and demonstrated
a good correlation between the extent
of drug absorption and the intestinal
membrane permeability in both animals
and man (1). In addition they developed
a drug dissolution and absorption model
for water insoluble drugs that limits to
the previous microscopic results under
appropriate conditions. These models
show that the key parameters controlling
drug absorption are three dimensionless
numbers: Absorption number (An);
Dissolution number (Dn); Dose number
(Do); representing the fundamental
processes of membrane permeation, drug
dissolution and dose respectively.
The rate of absorption from the
intestinal lumen (assuming no luminal
reactions) at any time is:
Absorption rate = ʃʃ A P eff C lumen dA
(double integral is over the entire gastrointestinal surface)
where A is available intestinal surface area.
P eff is the effective membrane permeability
and C lumen is the drug concentration at the
membrane (intestinal) surface.
The total mass (M) of drug absorbed
at time t is thus:
M(t) / Dose = ʃ ʃʃ 0
t
P C dAdt
A eff lumen
These relations are general since the
surface can be of any arbitrary shape
and the concentration at the lumen and
permeability can have any dependence
on position and time. It is thus important
to point out that P eff is both position
dependent and time dependent.
Based on these general mass balance
equations, it follows that: If two drug
products, containing the same drug,
have the same concentration time profile
at the intestinal membrane surface then
XVII
Anders Grahnen, Assoc. Professor
they will have the same rate and extent
of absorption. In addition, if two drug
products have the same in vivo dissolution
profile under all luminal conditions they
will have the same rate and extent of drug
absorption. Furthermore, the relationship
between in vivo drug dissolution and
the luminal concentration as well as the
relations hip between in vivo dissolution
and in vitro dissolution become crucial for
the prediction of absorption.
As shown above, membrane
permeability and solubility are the
primary determinant for predicting drug
absorption in man. Pioneer work of
Lennernäs and co-workers utilizing a multi
channel tube system with double balloons
has enabled segmental perfusion of the
gastrointestinal tract (preferably jejunum)
in man (2). Through this experimental
technique it is possible to determine the
effective membrane permeability (P err )
in man for any type of drug including
carrier mediated transported compounds
(using scaling factors) throughout the
entire gastrointestinal channel (including
the rectum). The experimental procedure
has been validated and extensively tested.