Pharmacology. Chatchai Chinpaisal, Ph.D. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Silpakorn University.

Transcription

1 Pharmacology Chatchai Chinpaisal, Ph.D. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Silpakorn University. 1

2 PHARMACODYNAMIC STUDIES A. Primary pharmacodynamics primary action in target system. B. Secondary pharmacodynamics resultant action in target systems, not related to the intended target C. Safety pharmacology pharmacodynamics in non target systems leading to side effects D. Pharmacodynamic interactions 2

3 Principles of Safety Pharmacology 2015:pp387 3

4 Principles of Safety Pharmacology 2015:pp70 4

5 PRIMARY PHARMACODYNAMICS Proof of concept (in-vitro and in-vivo) and mode of action target affinity preferably linked to functional response Availability of animal models relevant for the proposed indication/ interspecies comparison. Activity (e.g. ED 50 ) including the species used in toxicology studies. Preliminary PK (plasma concentration) in animal models if available. Duration/reversibility of effects, resistance profiles (anti-infectives). Pharmacologically active metabolites (relative contribution to pharmacodynamics). Immunological properties, including antigenic specificity for monoclonal antibodies. 5

6 International Pharmaceutical Product Registration, Second Edition 6

7 SECONDARY PHARMACODYNAMICS mab - complement binding and any unintentional reactivity and/or cytotoxicity towards human tissues distinct from the intended target a screen to identify binding at a range of other receptors, transporter proteins, ion channels, and enzymes should be summarized by organ system Erythropoietin - potential benefit postinfarct (cardioprotective effect in acute MI) Chloroquine for active rheumatoid arthritis Principles of Safety Pharmacology 2015:pp330 International Pharmaceutical Product Registration, Second Edition 7

8 MECHANISMS OF DRUG ACTION J.-P. Valentin, T. Hammond / Journal of Pharmacological and Toxicological Methods 58 (2008)

9 SAFETY EVALUATION 1) to identify an initial safe dose and subsequent dose escalation schemes in humans; 2) to identify potential target organs for toxicity and for the study of whether such toxicity is reversible; and 3) to identify safety parameters for clinical monitoring. ICH guideline S6 (R1) 9

10 SAFETY PHARMACOLOGY Integrated discipline pharmacology, physiology and toxicology Organ functions can be toxicological targets in humans exposed to novel therapeutic agents However, the drug effects on organ function (unlike organ structures) are not readily detected by standard toxicological testing. Majewski Pharmacology 10

11 SAFETY PHARMACOLOGY A useful tool in the risk assessment process that leads to the authorization to market a new drug Studies functional indices of potential toxicity Intact animals, isolated organs or other test systems Aim reveal any functional effects on the major physiological systems To identify undesirable pharmacodynamic properties - HAZARD IDENTIFICATION To evaluate adverse pharmacodynamic and/or pathophysiological effects - RISK ASSESSMENT To investigate the mechanism of the adverse pharmacodynamic effects - RISK MANAGEMENT/MITIGATION ICH guideline S6 (R1) J.-P. Valentin, T. Hammond / Journal of Pharmacological and Toxicological Methods 58 (2008)

12 SAFETY PHARMACOLOGY ICH guideline S7a (2001) Safety pharmacology those studies that investigate the potential undesirable pharmacodynamics effects of a substance on physiological functions in relation to exposure in the therapeutic range and above. Should be completed before the first trial in man A refinement of secondary pharmacodynamics A Guide to Practical Toxicology 2 nd Edition 12

13 BIOTECHNOLOGICALLY DERIVED PHARMACEUTICALS Complex structural and biological characteristics require different approaches to their safety evaluation ICH S6 was adopted by the European, Japanese, and US authorities natural proteins produced unexpected activity potential contaminants due to the manufacturing process Importance of species selection and of the case-by-case principles ICH S6(R1) 13 Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics.

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15 REGULATORY GUIDELINES 15 Modified from: Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics.

16 SAFETY PHARMACOLOGY INTEGRATED RISK ASSESSMENT MATRIX J.-P. Valentin, T. Hammond / Journal of Pharmacological and Toxicological Methods 58 (2008)

17 SPECIES SELECTION Selection of the relevant species Pharmacologically relevant expresses the relevant binding epitope (target) of the drug and in which biological (functional) activity of the biopharmaceutical can be demonstrated. ICH S6(R1) -- Modulation of a known biologic response or of a pharmacodynamic (PD) marker can provide evidence for functional activity to support species relevance. 17 Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics.

18 RELEVANT SPECIES Rodents Mice, rat Hamster, woodchuck Non-rodent, Rabbits Non-human primates typically cynomolgus monkey rhesus monkeys and the common marmoset chimpanzee Others Dog, mini-pig 18 Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics.

19 RELEVANCY (S6 ADDENDUM 2012) Comparison of target sequence homology b/w species However, a high degree of structural homology between humans and animals does not necessarily imply the same pharmacological effects. Followed by in vitro assays qualitative and quantitative cross-species comparisons of relative target binding affinities and receptor/ligand occupancy and kinetics Assessments of functional activity species-specific cell-based systems and/or in vivo pharmacology or toxicology studies modulation of a known biologic response or of a pharmacodynamic (PD) marker Nonbinding Recommendations Bussiere JL (2008) Species selection considerations for preclinical toxicology studies for biotherapeutics. Expert Opin Drug Metab Toxicol 4(7):

20 RELEVANCY (S6 ADDENDUM 2012) No relevant species - homologous molecules or transgenic models mab and others for foreign targets - a short-term safety study (see ICH S6) in one species can be considered Bussiere et al (2009) Alternative strategies for toxicity testing of species-specific biopharmaceuticals. Int J Toxicol. 28(3):

21 SPECIES SELECTION One or Two Species If two pharmacologically relevant species (one rodent and one nonrodent), then both species should be used for short-term (up to 1 month duration) general toxicology studies. If tox similar longer term tox studies in one spp. Rodent considered unless Homologous Proteins ICH S6 section IIIc hazard detection and potential for ARDs due to exaggerated pharmacology Not for quantitative risk assessment S6 addendum

22 USE OF TISSUE CROSS-REACTIVITY ASSAYS mab and or other molecules that contain a CDR limited value for species selection and should not be used as a primary selection criterion recommended component of the safety assessment target distribution and potential unexpected binding not indicate biological activity in vivo ICH guideline S6 (R1) Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics. 22

23 STUDY DESIGN CONSIDERATIONS FOR REPEAT- DOSE STUDIES ICH M3(R2) should be the same length or longer than clinical trials six months duration are generally appropriate dosing interval - the same or more frequent, and exposure greater in the nonclinical studies as compared to the clinical 23 Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics.

24 SAFETY PHARMACOLOGY ENDPOINTS ICH S6(R1), ICH S7B NHP-only programs CVS, respiratory, and CNS endpoints can be incorporated directly into the repeat-dose toxicity studies mab - in vitro herg testing is generally not warranted 24 Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics.

25 ROUTE OF ADMINISTRATION one route is sufficient - based on the proposed clinical route if the final clinical route has not yet been determined, an educated guess as to the commercial clinical route is appropriate 25 Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics.

26 SAFETY PHARMACOLOGY Core battery (GLP): Cardiovascular system (including QT prolongation in vitro/in vivo) Central nervous system Respiratory system Other e.g. Renal and GI system For similar biological medicinal products Normally other routine toxicological studies such, as safety pharmacology studies are not required for similar biological medicinal products, unless indicated of results of repeat dose studies 26

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28 REVIEW:FRONTIERS IN PHARMACOLOGY Principles of Safety Pharmacology British Journal of Pharmacology (2008) 154,

29 CARDIOVASCULAR SYSTEM SAFETY PHARMACOLOGY herg assay with BPs is considered irrelevant and is not recommended Jacket-based external telemetry (JET ) HR, ECG Implant telemetry BPs, hemodynamic parameters Echocardiographic imaging (noninvasive) cardiac functions Trastuzumab - long-term telemetry study in the cynomolgus monkey QTc prolongation Pasireotide no nonclinical evidence of herg channel inhibition, or change in Purkinje fiber APD QTc prolongation potential for drug drug interactions with other therapeutics Principles of Safety Pharmacology

30 RESPIRATORY SYSTEM SAFETY PHARMACOLOGY Head-out, whole body plethysmography RR, tidal and minute volume etc. 30

31 CNS SAFETY PHARMACOLOGY Functional observation battery (FOB) tests (rats, dogs, and monkeys) Modified Irwin s test (mice and rats) Neurobehavioral effects spontaneous locomotor activity BPs are not expected to enter CNS under normal circumstances Maybe secondary due to general toxicity or CV effects Principles of Safety Pharmacology

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33 physicochemical characterization, proof-of-concept testing in animals, and toxicity testing, WHO Technical Report Series No. 987,

34 ANIMALS-NONCLINICAL PHARMACOLOGY ability of the adjuvanted vaccine to induce and/or modify an immune response (a) an immune response to the vaccine antigen is developed; and (b) the immune response to the antigen is enhanced by the adjuvant through a mechanism similar to that expected in humansnse in an animal species most commonly are conducted in several animal species, including both naive and pre-exposed animals mechanism of action of the adjuvant in the absence of the vaccine antigen should also be evaluated WHO Technical Report Series No. 987,

35 ANIMALS-NONCLINICAL SAFETY STUDIES GLP compliance recommended not necessary, however, to conduct the nonclinical safety study in the same animal species used for proof-of-concept or nonclinical pharmacology NHP should be used only if no other relevant animal species is available choice of the animal species should be justified route of admin a single species is generally acceptable WHO Technical Report Series No. 987,

36 SAFETY PHARMACOLOGY STUDIES investigate the effects of the candidate vaccine on vital functions not usually required, but may be recommended by the NRA studies suggest that the adjuvanted vaccine may affect physiological functions other than the immune 36 WHO Technical Report Series No. 987, 2014

37 PHARMACODYNAMIC DRUG INTERACTIONS Interactions at receptor level Possible co-medications in the clinical setting Alerts from safety pharmacology, PK/metabolism or toxicology studies 37

38 2006 FDA DRAFT DDI GUIDANCE 38

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40 CliniCal pharmacology & TherapeuTiCs VOLUME 87 NUMBER 4 APRIL