Toxicokinetic studies screening of pre clinical models .pptx

screening of pre clincal models

1. TOXICOKINETICS , EVALUATION OF PRECLINICAL STUDIES ,SATURATION KINETICS IMPORTANCE, APPLICATIONS OF TOXICOKINETIC STUDIES, By : SRINIDHI IRAVATTUR 1 st year M pharm Dept : Pharmacology

2. TOXICOKINETICS Toxicokinetics deals with absorption, distribution biotransformation (biotransformation) and excretion of chemicals. Toxicokinetics (TK) is defined by The International Conference on Harmonization (ICH) as ‘the generation of pharmacokinetic data, either as an integral component in the conduct of non-clinical toxicity studies.   In these studies a minimum of two animal species are employed, as per regulation of FDA. I. Rodents(rat and mice) II. Non-rodents(dog)

3. Need of toxicokinetic studies Generation of kinetic data for systemic exposure and toxicity assessment of the drug. • Safety/risk ratio • Important in drug development stages especially in preclinical stage. • Useful for the setting safe dose level in clinical phases.

4. O bjective of the toxicokinetic studies  To describe the systemic exposure achieved in animals and its relationship to dose level and the time course of the toxicity study. To relate the exposure achieved in toxicity studies to toxicological findings and contribute to the assessment of human safety clinically. To provide information which, in conjunction with the toxicity findings contributes to the design of subsequent non-clinical toxicity studies.

5. Toxicokinetic evaluation is both a regulatory and scientific requirement in the drug development process. Toxicokinetics is the generation of kinetic data to assess systemic exposure, either as an integral component of preclinical toxicity studies, or in specially designed supportive studies. These data help to understand the relationship between observed toxicity and administered dose. They also play a role in the clinical setting, assisting in the setting of plasma limits for early human exposure and in the calculation of safety margins.

6. Toxicokinetic studies in Preclinical stage : Safety assessment Single dose and rising dose studies Repeated-dose toxicity studies Repeated-dose toxicity studies d. Genotoxicity studies e. Reproduction toxicity studies i . Studies of fertility ii. In pregnant and lactating animals f . Carcinogenicity studies:

7. Safety assessment •Generally safety of a molecule can be performed in in-vivo systems. •This step is not included in the guidelines but it is very useful for the researchers to assess the systemic exposure of the molecule and its effect on it. •This safety study is integral part in the central nervous system (CNS), cardio vascular system (CVS) and respiratory assessments. 

8. b. Single dose and rising dose studies •These studies are often performed in a very early phase 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.

9. c. Repeated-dose toxicity studies •To give support for phase 1 studies this study is carried out for four weeks in both rodents as well as non-rodents. •The treatment regimen (Note 11) and species should be selected whenever possible with regard to pharmacodynamic and pharmacokinetic principles. • This may not be achievable for the very first studies, at a time when neither animal nor human pharmacokinetic data are normally available.

10. 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.

11. 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). Studies of fertility Assessment of fertility toxicity has very important, because most of the drugs used in fertility conditions so has to strengthen at that time. Usually this can be done in rats.

12. In pregnant and lactating animals: There is a regulatory expectation for toxicokinetic data in pregnant animals, although no specific guidance is given1,16. Data from non-pregnant animals is useful to set dose levels, and the limitation of exposure is usually governed by maternal toxicity. Toxicokinetics may involve exposure assessment of dams, embryos, foetuses or newborn at specified days. Secretion in milk may be assessed to define its role in the exposure of newborns..

13. 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 pharmaceuticals17 and non-rodents can also be used. •Dose selection is usually determined as the maximum tolerated dose (MTD)

14. • 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 not essential for monitoring to occur beyond six months. • However, pharmaceutical companies use various strategies for such monitoring times

15. Protocol for toxicokinetic validation Rationale Selection of animal Preliminary study Method of Evaluation Main study Chronic Study Statistical Analysis Results and Reporting

16. Improved strategy assessment. The fewer animals used and provide superior data for risk assessment purposes. In preclinical/early clinical development risk programs at rescue. At early stages proactively screen/ evaluate leads using predictive tools for toxicity and mechanism of action. A pre-clinical biomarkers of toxicity & drug response developed. In safety of preclinical drug evaluation and biomarkers identification. Application of toxicokinetics studies.

17.   TK evaluation is useful in selection of dose dosing form alternative dosing route evaluatiaon of toxicological mechanism used for the setting safe dose level in clinical phases TK data are practically used for the purpose of drug discovery such as lead-optimization and candidate-selection The role of toxicokinetics in pharmacokinetics and modified medicine .

18. To improve the theraupetic outcomes adoption of toxicity management approaches. The studies of pre-clinical or clinical studies that are focused on research of mechanism of drug toxicity and adverse drug reactions using toxicokinetics will be of high interest. The toxicokinetics purpose of dosage selection, each toxic expression should be seperately analyzed and a correlation sought between each amount of exposure that best reflects the mechanism af the related the mechanism of the related toxic effect & pathogenesis.

19. Saturation kinetics are also known as Nonlinear pharmacokinetics can arise from factors associated with absorption, first-pass metabolism, binding, excretion and biotransformation. Saturable elimination: above a certain drug concentration, the elimination rate tends to reach a maximal value. Once this maximum capacity is reached, there is no further increase in the elimination rate when plasma drug concentration increases. Therefore, in nonlinear elimination kinetics, the drug clearance decreases with increasing drug concentration. Saturation kinetics

20. Saturable binding or reabsorption : above a certain drug concentration, drug protein binding or drug reabsorption in kidney tubules tends to reach maximal capacity. This leads to a disproportionate increase in the rate of elimination with increasing drug concentrations (e.g. with high doses of vitamin). Saturable absorption: above a certain drug concentration at the absorption site, there is no further increase in the absorption rate. Therefore, absorption rate constant and possibly bioavailability decrease with doses leading to concentrations at the absorption site above the maximal absorption capacity.

21. Clinical implications: For drugs with saturable elimination, an increase in dosage or dosage frequency can lead to a disproportionate increase in plasma drug concentration when the rate of elimination tends to reach its maximum capacity. Therefore, changing dose is difficult and unpredictable. Special caution should be taken when deciding to change the dosage regimen of such drugs, particularly if elevated plasma concentrations are associated with toxicity (e.g.  phenytoin ). On the other hand, for drugs with saturable absorption or tubular reabsorption , a change in dosage may lead to a less than proportional change in plasma concentration. This is important in evaluating the efficiency of a drug dosage regimen.

22. Detection of non-linearity in pharmacokinetics • Determination of steady state plasma concentration at different doses • Determination of some important PK parameters such as Fraction bioavailability Elimination half life or total systemic clearance

23. CAUSES OF NON LINEARITY Drug absorption • When absorption is solubility or dissolution rate limited e.g. griseofulvin • When absorption involve carrier mediated transport system. e.g. absorption of the riboflavin, ascorbic acid, cyanocobalamine , etc. • When presystemic gut wall or hepatic metabolism attains saturation. e.g. propranolol, hydralazine and verapamil

24. B) Drug distribution Non-linearity in drug distribution of drugs administered at high doses may be due to- • Saturation of binding sites on plasma proteins. e.g. phenylbutazone and naproxen • Saturation of tissue binding sites. e.g. thiopental and fentanyl C) Drug metabolism Two important causes of non-linearity in metabolism are- • Capacity limited metabolism due to enzyme and cofactor saturation. e.g. phenytoin, alcohol, theophylline • Enzyme induction. e.g. carbamazepine

25. D) Drug excretion The two active processes in renal excretion of a drug that are saturable are- • Active tubular secretion. e.g. penicillin G • Active tubular reabsorption. e.g. water soluble vitamins and glucose Note: other sources of non-linearity in renal excretion include forced diuresis, change in urine pH, nephrotoxicity.

26. REFERENCE 1)Kate, R., Case, D.E., Hakes, H., Nod, K., Salami, F., Horii,I ., Mayahara , H., Cayeb n, M.N., Marriott, T.B., Igarashi, T., Toxicokinetics : its significance and practical problems.J.Toxicol.Sci.18:211-238;( 1993). 2)CPMP/ICH/286/95, modification: operational November 2000. Nonclinical safety studies for the conduct of human clinical trials for pharmaceuticals. Also known as ICH Topic M3 (seehttp://www.emea.eu.int) 4)CPMP/ICH/384/95: Operational June 1995. Toxicokinetics : guidance for assessing systemic exposure in toxicology studies. Also known asICH Topic S3A (see http :// www. emea.eu.int) 5) Baldrick, Paul. (2003). Toxicokinetics in preclinical evaluation. Drug discovery today. 8. 127-33. 10.1016/S1359-6446(02)02568-0.

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