Full Text PA-95-001

FACTORS THAT DETERMINE THERAPEUTIC DRUG BIOAVAILABILITY

NIH GUIDE, Volume 23, Number 35, September 30, 1994

PA NUMBER:  PA-95-001

P.T. 34

Keywords: 
  Chemotherapeutic Agents 
  Drug Design 


National Institute of General Medical Sciences

PURPOSE

The purpose of this program announcement (PA) is to encourage basic
research in the areas that are fundamental to understanding the factors
that determine therapeutic drug bioavailability, with emphasis on the
oral route of delivery.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and
not-for-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, eligible agencies of the Federal government, and small
businesses.  Applications from minority individuals and women are
particularly encouraged.  Foreign institutions are not eligible to
receive First Independent Research Support and Transition (FIRST)
awards (R29) or program project grants (P01).

For-profit applicants for the Small Business Innovation Research (SBIR)
program (R43, R44) and the Small Business Technology Transfer Research
(STTR) program (R41, R42) must qualify as a small business concern in
accordance with the definition given in the latest edition of the
Omnibus Solicitation of the Public Health Service for Small Business
Innovation (SBIR) Grant and Cooperative Agreement Applications, and the
Omnibus Solicitation of the National Institutes of Health for Small
Business Technology Transfer Research (STTR) Applications.  Additional
eligibility requirements for SBIR and STTR applicants, including
organizational, principal investigator, and performance site criteria
are described in these Omnibus Solicitations.

MECHANISMS OF SUPPORT

Support of this program announcement will be through individual
research project grants (R01), FIRST awards (R29), program project
(P01) grants, and awards to small businesses under the Small Business
Innovation Research (SBIR) program (R43, R44) and the Small Business
Technology Transfer Research (STTR) program (R41, R42).  Investigators
with ongoing R01, R37 (Method to Extend Research in Time (MERIT)) and
P01 awards who are expanding the scope of their work and would have at
least one year of support remaining from the anticipated date of award
may apply for competing supplement awards.

RESEARCH OBJECTIVES

Bioavailability represents an area of basic research that has received
little emphasis to date.  The economic consequences of problems with
drug bioavailability are enormous.  Many potential drug candidates have
failed as a result of difficulties in penetrating barriers or not
arriving or remaining in active form at the site of action.  Drug
candidates can be tested for their desired therapeutic activity, but it
is not yet possible to predict whether or not a compound will have
sufficient bioavailability to be useful and practical.  The National
Institute of General Medical Sciences (NIGMS) wants to encourage
research in several different fundamental areas in order to optimize
the bioavailability of newly designed therapeutic entities, and to
develop strategies to predict how a drug candidate will perform based
on its chemical structure.  Because comprehensive understanding of the
basic biology of how a drug gets to the site of action and overcomes
the obstacles it encounters is currently quite limited, mechanistic
research is encouraged in the areas that determine the physiological,
pharmacological, biological, and chemical processes that contribute to
drug absorption, metabolism, transport, or clearance.  Overall, these
studies may include, but are not limited to studies on:

o  integrating information useful for maximizing drug bioavailability
at the drug design stage

o  generating strategies to predict the bioavailability of drug
candidates intended for use in humans

Basic research is encouraged in the areas of mechanisms determination,
models validation, structure-activity relationships, formulations,
methods development, and determining intra-/interindividual
differences.  Emphasis will be placed on, but not limited to, the oral
route of drug delivery.  Investigations that involve the interactions
of physical and biological scientists (e.g., chemists, biologists,
clinicians) are particularly encouraged.  Liaisons between academic,
industrial, and eligible government laboratories are also encouraged.
Possible example research areas include:

o  investigation of the molecular mechanisms of active and passive
transport processes of the gastrointestinal tract, liver, kidney, and
lung, that determine drug absorption, metabolism, transport, or
clearance

o  characterization of human metabolic enzymes, their isoforms and
their heterogeneous distribution, that determine drug absorption,
metabolism, transport, or clearance

o  identification of regional differences or site-specific processes
within an organ system, that contribute to drug absorption, metabolism,
transport, or clearance

o  investigation of interactions between the organ systems in humans,
that contribute to drug absorption, metabolism, transport, or clearance

o  design and validation of predictive in vitro tests, based upon human
information and comparison to existing established models

o  integrated modelling of all processes that in concert determine drug
absorption, metabolism, transport, or clearance in humans

o  establishment of compound libraries to examine drug absorption,
metabolism, transport, or clearance, that can be used to provide drug
structural/functional predictive information

o  identification of pro-drug strategies that harness or circumvent
carriers or enzymes of drug absorption, metabolism, transport, or
clearance

o  identification of formulation approaches that take advantage of
known routes for drug absorption, metabolism, transport, or clearance
or devise new methods for delivery

o  development of analytical techniques with increased sensitivity,
accuracy, speed, and simplicity for measuring drug absorption,
metabolism, transport, or clearance

o  influence of age-based, sex-based, racially-based, disease-based, or
other interindividual differences in drug absorption, metabolism,
transport, or clearance

o  influence of polytherapy, food intake, nutritional status, or other
intraindividual differences in drug absorption, metabolism, transport,
or clearance

APPLICATION PROCEDURES

Applicants for research project grants (R01, R29), program project
grants (P01), and supplemental awards are to use the regular grant
application form PHS 398 (rev. 9/91).  Application receipt dates are
listed in the PHS 398.  Application kits are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grants Information, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892,
telephone (301) 710-0267.

Applications for the SBIR program will be accepted for the usual
receipt dates:  April 15, August 15, and December 15.  Applications for
the STTR program, phase I (R41) will be accepted for December 1, 1994.
Applicants should consult future publications of the Omnibus
Solicitation of the NIH for STTR Applications for additional receipt
dates.   Application kits are available from MTL, Inc., 13687 Baltimore
Avenue, Laurel, MD 20707-5096, telephone (301) 206-9385; FAX (301)
206-9722; Internet [email protected].

All individuals applying under this announcement must cite this program
announcement by title and number.  The application should clearly state
how the scientific objectives of the proposed research will enhance the
basic understanding of the factors that determine drug bioavailability
in humans.

On the face page of the application form PHS 398, item 2a, the word
"YES" must be checked, and the title and number of this program
announcement must be inserted in the space provided.  FIRST
applications must include the three sealed letters of reference
attached to the face page of the original application, or the
applications will be considered incomplete and will be returned to the
applicant.  The completed original application and five copies must be
sent or delivered to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

REVIEW CONSIDERATIONS

Applications will be assigned to an initial review group (IRG) and to
a funding component (institute) based upon established Public Health
Service referral guidelines.  IRGs will review the applications for
scientific and technical merit in accordance with the usual NIH peer
review procedures.  Following the IRG reviews, applications will
receive a second level of review by the appropriate National Advisory
Council.

AWARD CRITERIA

Applications will compete for funds with other approved applications.
The following criteria will be considered when making funding
decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Significance of the proposed research to the aims of this program
announcement
o  Program diversity and balance

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Rochelle M. Long, Ph.D.
Pharmacology and Biorelated Chemistry Program
National Institute of General Medical Sciences
45 Center Drive, Box 6200
Bethesda, MD  20892
Telephone:  (301) 594-7808
FAX:  (301) 594-7728
Email:  [email protected]

Direct inquiries regarding financial matters to:

Ms. Toni Holland
National Institute of General Medical Sciences
45 Center Drive, Box 6200
Bethesda, MD  20892
Telephone:  (301) 594-7819
FAX:  (301) 594-8891
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
number 93.859 (Pharmacology and Biorelated Chemistry).  Awards will be
made under the Public Health Service Act, Titles III and IV (Public Law
78-410, as amended by Public Law 99-158, 42 USC 241 and 287) and
administered under PHS grants policies and Federal Regulations 42 CFR
part 52 and 45 CFR Part 92.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use of
all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

.

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