This document discusses toxicokinetics evaluation and saturation kinetics in preclinical studies. It defines toxicokinetics and its primary and secondary objectives in preclinical testing according to ICH guidelines. It outlines the general principles and types of toxicokinetic studies conducted at different stages of preclinical development, including safety assessment studies, single/rising dose studies, repeated dose toxicity studies, genotoxicity studies, reproduction toxicity studies, and carcinogenicity studies. It also discusses saturation kinetics, how non-linear pharmacokinetics can occur due to saturation of absorption, distribution, metabolism or excretion processes, and how non-linearity is detected.

1. TOXICOKINETICS EVALUATION IN PRECLINICAL STUDIES
& SATURATION KINETICS
Noida Institute of Engineering and Technology
(Pharmacy Institute)
Greater Noida
Presented by :-
ANMOL KANDA(2ND SEM )
M . Pharm (Pharmacology)
Submitted to :-
Dr. Saumya Das
Associate Professor
NIET (Pharmacy Institute)
Greater Noida

2. WHAT IS TOXICOKINETIC
 Toxicokinetics deals with absorption , distribution , biotransformation and
excretion of chemicals
 According to ICH S3A guidance on the assessment of systemic exposure in
toxicity studies , toxicokinetics is defined as the generation of
pharmacokinetics data , either as an integral component in the conduct of
non-clinical toxicity studies or in specially designed supportive studies , in
order to assess systemic exposure
 Toxicokinetics is the science to understand what the body does with a drug
when the drug is given at a relatively high dose . Toxicokinetics play a major
role in interpreting the histopathological finding in a toxicological study .

3. PRIMARY AND SECONDARY OBJECTIVE OF TOXICOKINETICS
STUDIES
 According to ICH , the primary objective of the toxicokinetic studies is to describe the
systemic exposure achieved in animals and its relationship to dose level and the time of
course of the toxicity study .
 Seconadary objectives includes :
1) Assessing the clinical safety of a drug molecule by creating a relation between the exposure
achieved in toxicity studies and toxicological findings .
2) Choosing the right animal species and proper treatment regimen during pre-clinical studies.
3) To provide relevant data that helps in preparing the non-clinical toxicity study report .

4. GENERAL PRINCIPLES TO BE CONSIDERED
1. QUANTIFICATION OF EXPOSURE
2. Extent of exposure assessment on toxicity studies .
3. Sampling point
4. Dose level setting
5. Rectifying factor on study to be considered
6. Route of administration .
7. Determination of metabolities
8. Statistical evaluation of data
9. Analytical methods
10. Reporting

5. TOXICOKINETIC STUDDIES IN PRE-CLINICAL STAGES
A. SAFETY ASSESSMENT :
 generally safety of molecule can be performed in in-vivo system .
 This step is not included in guidelines but it is very useful for rsearchers since it give effect
it .
 This safety study is integral part in the CNS,CVS, and respiratory assessment .
B. SINGLE DOSE AND RISING DOSE STUDIES :
 These studies performed in very early stage of drug development before a bioanalytical
method has been developed .
 These studies are usually performed in rodents .
 Plasma samples may be taken in such studies and stored for later analysis

6. TOXICOKINETIC STUDDIES IN PRE-CLINICAL STAGES
C. REPEATED-DOSE TOXICITY STUDIES :
 To give support for phase 1 studies this study is carried out for four weeks on both rodents as
well as non-rodents.
 The treatment regimen and species should be selected whenever possible with regard to
pharmacodynamic and pharmacokinetics principles.
 This may not be achievable for the very first studies , at a time when neither animal nor
human pharmacokinetic data are normally available .
D. GENOTOXICITY STUDIES :
 Two in vitro studies and one in vivo study is essential to support development of drug .
 In vivo investigations usually use a rodent micronucleus (bone marrow or peripheral
erythrocytes) test or chromosome aberration (bone marrow cells) test .
 These are the well established studies for the genotoxicity evaluation .

7. TOXICOKINETIC STUDDIES IN PRE-CLINICAL STAGES
 E. REPRODUCTION TOXICITY STUDIES :
 Reproduction toxicity measurements are taken in studies of fertility (rat) , embryo-foetal
development ( rat and rabbit) and peri- or post-natal development (rat) .
a. STUDIES OF FERTILITY ( Mainly done in rats )
Assessment of fertility toxicity has very important , because most of the drugs used in fertility conditions
has to strengthen at that time .
a. IN PREGNANT AND LACTATING ANIMALS
( no specific guidance is given 1,16. , data from non-pregnant animals is useful to set dose levels )
Toxicokinetics may involve exposure assessment of , embryos , foetus or newborn at specified days .
Secretion in milk may be assessed to define its role in the exposure of newborns .

8. TOXICOKINETIC STUDDIES IN PRE-CLINICAL STAGES
 F. CARCINOGENICITY STUDIES :
 Sometimes drugs are used for longtime for curing purposes , this may lead to the toxicity or
carcinogenicity .
 So lifetime studies in the rodent are needed to support the long-term clinical use of pharmaceuticals
and non-rodents can also be used
 Dose selection is usually determined as the maximum tolerated dose (MTD) .
 Selection based on AUC is less common as a 25-fold ratio is often not feasible .
 It is recommended that monitoring should occur on a few occasions during the study , although it is
essential for monitoring to occur beyond six months .
 However , pharmaceutical companies use various strategies for such monitoring times .

9. SATURATION KINETICS
 Also known as nonlinear pharmacokinetics .
 The rate process of a drugs ADME are dependent upon carrier or enzymes that are substrate-specific .
 Have definite capacities and susceptible to saturationate high drug concentration .
 In such cases , an essentially first-order kinetics transform into a mixture of first-order and zero-order rate processes
and Pk parameters changes with size of the administered dose .
 DETECTION OF NON-LINEARITY IN PHAMRMACOKINETICS
 Determination of steady state plasma concentration at diff. doses
 Determination of some imp. Pk parameters such as
 1. fraction bioavailability
 2. elimination half-life or total systemic clearance .
 https://derangedphysiology.com/main/cicm-primary-exam/required-reading/pharmacokinetics/Chapter%20337/first-
order-zero-order-and-non-linear-elimination-kinetics

10. CAUSES OF NON-LINEARITY
A.DRUG ABSORPTION .
B. DRUG DISTRIBUTION .
C.DRUG METABOLISM .
D.DRUG EXCRETION .

11. REFERENCES :
 Baldrick P. Toxicokinetics in preclinical evaluation. Drug discovery today. 2003 Jan 21;8(3):127-33.
 Tang S, Ma X, Lu J, Zhang Y, Liu M, Wang X. Preclinical toxicology and toxicokinetic evaluation of ailanthone, a
natural product against castration-resistant prostate cancer, in mice. Fitoterapia. 2019 Jul 1;136:104161.
 Ploemen JP, Kramer H, Krajnc EI, Martin I. The use of toxicokinetic data in preclinical safety assessment: A
toxicologic pathologist perspective. Toxicologic pathology. 2007 Oct;35(6):834-7.