DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Design and Optimization
of Dosage Regimens:
Pharmacokinetic Data
Kenneth E. Thummel, Danny D. Shen,
and Nina Isoherranen
This appendix provides a summary of basic pharmacokinetic
information pertaining to drugs that are in common
clinical use and are delivered to the systemic
circulation by parenteral or non-parenteral administration.
Because of space limitations, this list cannot be
exhaustive. Drugs designed exclusively for topical
administration and not to be significantly absorbed into
the bloodstream (e.g., ophthalmic and some dermal
applications; Chapters 64 and 65) are not included. A
few other selection criteria have influenced the makeup
of the list, but, in general, the authors have tried to
include one or more representative drugs in each of the
therapeutic areas in this text, based on distinct mechanism(s)
of action. In some instances, drugs may be
excluded because pharmacokinetics are not relevant to
their therapeutic management. An obvious case is when
drug efficacy is not apparently correlated with drug
concentration in a reversible fashion (e.g., some cytotoxic
anticancer drugs). Also, for a number of therapeutic
antibodies, the antibody is administered at a fixed dose
at prolonged intervals that allows for its near complete
clearance (e.g., infliximab).
Often, the issue comes down to deciding which of the many
drugs within a class should be selected. This is particularly problematic
when the choices are largely therapeutic equivalents. Two criteria
that have proven useful are prevalence of use and uniqueness of
mechanism of action. For the present edition, we have consulted the
“2008 Top 200 Branded Drugs by Total Prescriptions” and “2008
Top 200 Generic Drugs by Total Prescriptions” published in
the respective May 22 and 26, 2009, issues of Drug Topics
(http://drugtopics.modernmedicine.com) for usage data. Drugs that
fall into the top 200 list are selected. As mentioned above, a less used
drug may be included if it has a different mechanism of action than
the frequently used drugs, some additional actions that offer a unique
therapeutic advantage, or a more acceptable side-effects profile.
Pharmacokinetic data for many older drugs not included in
this appendix can be found in earlier editions of this book.
A major objective of this appendix is to present
pharmacokinetic data in a format that informs the clinician
of the essential characteristics of drug disposition
that form the basis of drug-dosage regimen design.
Table AII–1 contains quantitative information about the
absorption, distribution, and elimination of drugs; the
effects of disease states on these processes; and the correlation
of efficacy and toxicity with drug concentrations
in blood/plasma. The general principles that
underlie the design of appropriate maintenance dose
and dosing interval (and, where appropriate, the loading
dose) for the average patient are described in Chapter 2.
Their application using the data in Table AII–1 for individualization
of dosage regimens is presented here.
To use the data that are presented, one must
understand clearance concepts and their application to
drug-dosage regimens. One also must know average
values of clearance as well as some measures of the
extent and kinetics of drug absorption and distribution.
The text below defines the eight basic parameters that
are listed in the tabular material for each drug and key
factors that influence these values in both normal subjects
and patients with renal or liver disease. It obviously
would be more straightforward if there were a
consensus on a standard value for a given pharmacokinetic
parameter; instead, literature estimates usually
vary over a wide range, and a consensus set of pharmacokinetic
values has been reached for only a limited
number of drugs.
In Table AII–1, a single set of values for each
parameter and its variability in a relevant population