Overview: Value of ADME/PK Studies in Safety Assessment

31 Pages·2015·1.49 MB·English

Overview: Value of ADME/PK Studies
in Safety Assessment

Harvey J. Clewell, PhD, DABT, FATS
Director, Center for Human Health Assessment
The Hamner Institutes for Health Sciences
Research Triangle Park, NC
Overview
 Background on Biokinetics (ADME/PK)
 Applications of Biokinetics
The Past: Safety Assessments based on in vivo data
–
 Methylene Chloride
 Methylmercury
 Perchlorate
The Future: Safety Assessments based on in vitro data
–
 Toxicity Testing in the 21st Century
 In vitro to in vivo extrapolation (IVIVE)
 In vitro based risk assessment approaches
Biokinetics
 Also referred to as pharmacokinetics or toxicokinetics
 Describes the change in chemical distribution over time in the body
 Explores the quantitative relationship between Absorption, Distribution,
Metabolism, and Excretion of a given chemical
 Classical compartmental/non-compartmental modeling
‘Data-based’, empirical descriptions
–
Describes chemical time-course with fitted parameters
–
 Physiologically-based modeling:
Compartments are based on real tissue volumes, physiological structure
–
Mechanistically based description of chemical movement using tissue
–
blood flow and simulation of in vivo transport processes.
The Traditional Role of Biokinetics:
Relating Animal Doses to Equivalent Human Exposures
Physiologically Based Pharmacokinetic
(PBPK) Modeling
 The purpose of a PBPK model is to
define the relationship between an
external measure of (administered)
exposure/dose and an internal
measure of (biologically effective)
exposure/dose in both the
experimental animal and the human
Methylene Chloride: Using a PBPK Model in
Risk Assessment
 First use of a PBPK model in an agency
risk assessment
 Used by EPA, OSHA, and Health
Canada, but not FDA, to estimate lung
cancer risk from a 2-yr mouse bioassay
 Predicted substantially lower risk in
humans compared to default
approaches
Alternative Risk Assessment Approaches for
Methylene Chloride
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SSppeecciieess ttoo HHuummaann 55..6644ee--55
00..22
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PPBB--PPKK GGSSTT
11..4455ee--66
00..77 00..77
BBooddyy SSuurrffaaccee DDCCMM
SSppeecciieess 11..4455ee--66
00..33 00..11
BBiiookkiinneettiiccss
AApppplliieedd
33..4488ee--66 Old EPA
00..33
AApppplliieedd MMFFOO
44..4466ee--66
00..22 00..22
PPBB--PPKK GGSSTT
11..1155ee--77
00..77 00..77
BBooddyy WWeeiigghhtt DDCCMM
11..1155ee--77
00..77 00..11
AApppplliieedd
22..7755ee--77 FDA
00..33
WWeeiigghhtteedd aavveerraaggee MMFFOO
11..0066ee--55
ooff uunniitt rriisskk == 22..11xx1100--77 00..22
PPBB--PPKK GGSSTT 55..5555ee--77 New EPA
11..00 00..77
BBooddyy SSuurrffaaccee DDCCMM
66..3388ee--66
00..22 00..11
AApppplliieedd
nn//aa
00..00
PPBB--PPKK MMFFOO
88..44ee--77
00..88 00..22
PPBB--PPKK GGSSTT 44..3388ee--88 HC
11..00 00..77
BBooddyy WWeeiigghhtt DDCCMM
55..0044ee--77
00..88 00..11
AApppplliieedd
nn//aa
00..00
Methylmercury: Using a PBPK Model to
Reconstruct Accidental Exposure in Iraq
(Shipp et al. 2000)
Using the PBPK Model to Estimate the Impact
of Population Variability on Safe Exposure
Distribution of daily methylmercury ingestion rates for women
of childbearing age in the U.S. corresponding to the NOAEL
hair concentration derived by USEPA from the study of the
Iraqi poisoning incident.
RfD = 0.1
(Clewell et al. 1999)
Perchlorate: Using a PBPK model to link
urinary concentrations to dietary exposure
Predicted (in blue) vs. measured (in red) creatinine-
adjusted urinary perchlorate concentrations (in lg
perchlorate g1 creatinine) for 340 non-pregnant
women, age 15–45, in NHANES 2001–2002.
(Yang et al. 2012)