Concepts of non-linear pharmacokinetics and KMD · 2021. 2. 8. · Concepts of non-linear...
Transcript of Concepts of non-linear pharmacokinetics and KMD · 2021. 2. 8. · Concepts of non-linear...
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Concepts of non-linear pharmacokinetics and KMD
Alan R BoobisImperial College London [email protected]
NICEATM, US EPA OPP & HESIKinetically-Derived Maximum Dose (KMD) Workshop
30 September 2020
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Disclosure Statement• Member of several science advisory boards (public and private
sector) [non-remunerated] (e.g. ILSI, HESI, Owlstone Medical, Cosmetics Europe LRSS, Swiss Centre for Applied Human Toxicology, MSU Center for Research on Ingredient Safety, A*STAR Food and Chemical Safety Programme Singapore)
• Member/chair of several national and international scientific advisory committees (UK COT, UK COMEAP, JMPR, JECFA, TobReg, ISO TC126 WG10 Intense Smoking Regime)
• I have no financial interests in the subject matter of the session
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Risk characterization
Uncertaintyfactor
Hazard IDHazard characterisation POD
MOE = POD/Exposure
HBGV (e.g. ADI) HBGV = POD/UF
Exposure assessment
Risk characterisation(Exposure cf HBGV)
0 0.1 1 10 100
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Bioavailability
Griseofulvin
Yu, 1999
Solubility Permeation & pre-systemic metabolism
External dose Bioaccessible dose Bioavailable dose
500
5
50
0.5
0.05
0 5 10 15 20Time (h)
Control
+ Furafylline
Plas
ma
phen
acet
in (n
g/m
l)
CLi = 178 ± 118 l/min
CLi = 0.82 ± 0.83 l/min
Frel = 0.5 ± 0.3%
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Dose-dependency of systemic exposure
Fractional absorption independent of dose
Species Durat.Dose
(mg/kg)
Plasma concentration (µg/ml)
AUC(0-24) (µg·h/ml)
Male Female Male Female
Rat 2 Week
Gavage500
12502500Diet
50012502500
13.527.647.4
11.525.950.7
9.9225.240.7
10.719.032.4
120332626
199491921
102334602
181336606
Fractional absorption dependent on dose
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Absorption, distribution, metabolism, excretion (ADME) determine exposure
Absorption Distribution Metabolism Excretion
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Human drug transporters
Giacomini & Huang (2013)
Tmax
Km
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Xenobiotic biotransformation
Yeung et al, 2013
• Specificity
• Maximum rate (Vmax)
• Affinity (Km)
UGTsGSTs
CYPs
SULTs
Hepatocytes
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Kinetics of metabolism
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑜𝑜𝑜𝑜 𝑚𝑚𝑅𝑅𝑅𝑅𝑅𝑅𝑚𝑚𝑜𝑜𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 =𝑉𝑉𝑚𝑚𝑚𝑚𝑚𝑚 × 𝐶𝐶𝐾𝐾𝑚𝑚 + 𝐶𝐶
When C << Km
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑜𝑜𝑜𝑜 𝑚𝑚𝑅𝑅𝑅𝑅𝑅𝑅𝑚𝑚𝑜𝑜𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 ≈𝑉𝑉𝑚𝑚𝑚𝑚𝑚𝑚 × 𝐶𝐶
𝐾𝐾𝑚𝑚𝑚𝑚. 𝑅𝑅. 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑜𝑜𝑜𝑜 𝑚𝑚𝑅𝑅𝑅𝑅𝑅𝑅𝑚𝑚𝑜𝑜𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 ∝ 𝐶𝐶
When C > Km
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑜𝑜𝑜𝑜 𝑚𝑚𝑅𝑅𝑅𝑅𝑅𝑅𝑚𝑚𝑜𝑜𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 ≈𝑉𝑉𝑚𝑚𝑚𝑚𝑚𝑚 × 𝐶𝐶
𝐶𝐶𝑚𝑚. 𝑅𝑅. 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝑜𝑜𝑜𝑜 𝑚𝑚𝑅𝑅𝑅𝑅𝑅𝑅𝑚𝑚𝑜𝑜𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 → 𝑉𝑉𝑚𝑚𝑚𝑚𝑚𝑚
From Winter & Tozer, 1986 9
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Normal vs. saturating kinetics
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Effects of furafylline on caffeine kinetics
Furafylline(90 mg p.o.)
[Fur
afyl
line]
(mg/
l)
0
1
2
0 2 4 8
4
8
12
Time (days)
[Caf
fein
e] (m
g/l)
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Point of departure
NOAEL
LOAEL
Uncertaintyfactor
Hazard IDHazard characterisation POD
MOE = POD/Exposure
HBGV (e.g. ADI) HBGV = POD/UF
Exposure assessment
Risk characterisation(Exposure cf HBGV)
0 0.1 1 10 100
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Major and minor routes of elimination
Cl = ClR + Clm1 + Clm2 + Clm3 + Clother
Parent
Metabolite 1Metabolite 2
Metabolite 3Other
Renal
Metabolite 1 conj
Plas
ma
conc
(ng/
ml)
4′-OH-PROPRANOLOL
Propranolol and metoprolol are both cleared > 90% by CYP-dependent oxidation
Time (h)
Urinary metoprolol and metabolites (% dose)
EMPM
Data from Tucker, Lennard, Wood et al 13
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Acetaminophen hepatotoxicity
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HNCOCH3
OHP450
NCOCH3
O
Protein arylation TOXICITYGSH
GSH conjugate Excretion
Acetaminophen
NABQI
GSSG
2GSH
GSH-reductase
Oxidation ofcellular constituents
Loss of cellularfunctions
GSH depletion
Oxidative damage
UGT, SULT Sulphate andglucuronide conjugates
Excretion
TOXICITY
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GSH depletion and acetaminophen toxicity
Dose of acetaminophen
100
50
00 250 500 750 1000
GSH
(% c
ontro
l)
Mic
e w
ith li
ver
necr
osis
(%)
100
50
0
Data of Gillette, Mitchell, et al
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Quantitative Adverse Outcome Pathway (AOP)
Exposure
KE2 Adverse outcomeKE1 KE3ADME/TK
Adverse Outcome Pathway
Dose-MIE (KE1)
KE1-KE2 KE2-KE3 KE3-AO
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Conclusions• The maximum dose used in toxicity testing is often many orders of
magnitude greater than worst-case human exposure
• Limited solubility and/or saturation of processes of absorption, distribution, metabolism and excretion can lead to marked non-linearity between dose and plasma/active-site concentration
• This confounds interpretation of dose-effect relationships and extrapolation to human relevant exposures; hence, substantial over- or under-estimation of risk to exposed populations is possible
• Kinetic considerations are therefore essential in both study design and data interpretation
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