Concepts of non-linear pharmacokinetics and KMD

Alan R BoobisImperial College London a.boobis@imperial.ac.uk

NICEATM, US EPA OPP & HESIKinetically-Derived Maximum Dose (KMD) Workshop

30 September 2020

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

3

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%

4

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

5

Absorption, distribution, metabolism, excretion (ADME) determine exposure

Absorption Distribution Metabolism Excretion

6

Human drug transporters

Giacomini & Huang (2013)

Tmax

Km

7

Xenobiotic biotransformation

Yeung et al, 2013

• Specificity

• Maximum rate (Vmax)

• Affinity (Km)

UGTsGSTs

CYPs

SULTs

Hepatocytes

8

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

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)

11

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

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

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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