Pharmacotherapy, Toxicodynamics, and Regulatory Science 11

2 Pharmacotherapy, Toxicodynamics, and CopyrightedRegulatory Science – Divergent Objectives

Introduction Materials Pharmacodynamics (PD) and toxicodynamics (TD), while related to pharmacokinetics (PK) and toxicokinetics (TK), are quite different from them. PD and TD are the studies characterizing the dynamic interaction of molecules with one or more biologic targets (proteins acting as receptors) and the resulting biologic effects, be they desirable (PD) or undesirable (TD). Upon entry into a patient or an animal model, a molecule must travel to its therapeutic target in order to hopefully achieve therapeutically effective levels of action. The desired therapeutic- effect is the result of the test article attaining sufciently high (effective) levelsTaylor for a long enough period of time at a meaningful population of the target in order to elicit the desired phar- macotherapeutic effect (Copeland, 2016; Blass, 2015; Boroujerdi, 2015; Ehlert, 2015). These interactions usually involve interactions with target receptors to bring about required functional and/or structural alterations in the target tissue. This desired PD interaction is the sole objective ofand pharmacotherapy, whether we are considering a small molecule or a large biologic entity, such as a monoclonal antibody (Mab). Everything else which occurs is at best a waste of valuable molecules and, of more concern, a potentialFrancis hazard to the patient and a potential risk which may prevent the drug from reaching the marketplace and meaningful clinical use or cause unintended harm in patients (Jameson and Collins, 1998). Indeed, the target receptor occupancy has to be at a sufcient level to achieve the desired therapeutic effect in a large portion of the desired patient population but there must not be too much or excessive receptor occupancy. Consider the case of TGN-412, where too many of the “right” receptors are occupied or activated or, alternatively, target receptors that happen to be in the wrong place (such as the brain, as is the case with progressive multifocal leukoencephalopathy [PML], a viral disease in the brain associated with the use of immunosuppressing monoclonal antibod- ies) are activated.

9 10 Nonclinical Drug Administration

To achieve the effect that is desired, the drug entering the body must tran- sit to the therapeutic structure or receptor site and not be transformed into an ineffective structure or reduced to a concentration that is either ineffective or below the optimal therapeutic level, that is to say, a level that is not at the OPTIMALCRO (optimal cumulative receptor occupancy). These receptors Copyrightedmay be on cell surfaces, but more frequently are within cells, thus intracellular drug delivery (and concentrations) is the critical concern (Brouwer et al., 2015). Both cell surfaces and intracellular targets may be located within dif- cult, but possible-to-reach organs such as the brain (Hammarlund-Udenaes et al., 2014). At the same time, a molecule or a metabolite of it may go places that are not intended, that is, achieve an off-target hit by either interacting with a receptor other than the one we want it to or with our desired receptor in a different location of the body than where we want to elicit a change*, resulting in an “adverse event.” This is the regional specicity challenge of PD. The receptor specicity,Materials whether in a microbe or a mammal, is a subset of the selective toxicity challenge (Albert, 1965), but one much harder to parse out for drugs than for pesticides (Hill and Rang, 2013; Ng, 2015). We have generally advanced our technology to improve this aspect of limiting the toxicity of our therapeutic molecules, and we can now readily screen molecules for receptor specicity rapidly and at low expense. Table 2.1 presents a summary (Keiser et al., 2015). Until the mid-1980s, animal model -and patient exposure were quanti- tated in terms of administered dose by whateverTaylor route utilized. The relationship between administered dose and achieved systemic exposure was generally taken to be linear. With the advent of the common measurement and evaluation of pharmacokinetic data, we came to understand that these relationships could be subproportional or supraproportional, or something more complex. With our improved abilities to identify andand quantitate levels of molecules in biological matrices, especially plasma, which was and is readily available for in vivo sampling, PK/TK measurements became the standard for such measurements, moving us much closer to determiningFrancis actual exposure of any patient or animal model. But from the beginning, it has been clear that the relationship between PK/TK and the biological effects we wanted and those we wanted to avoid is neither linear, propor- tional, or occurring in the same time dimension. In classical pharmacology, bioassays or the measurement of effects as seen in very specic animal models or isolated tissue preparations were used as tools to understand these relationships. While some of these survive in the USP or various guidances, such as the hERG assay, for the most part they have been largely abandoned.

* Nature being conservative, evolution has come to use the same receptor for a closely related set of tasks in multiple parts of the body. The adverse side effects seen in some individuals treated for psoriasis or rheumatoid arthritis are prime examples of this problem. Pharmacotherapy, Toxicodynamics, and Regulatory Science 11

TABLE 2.1 Receptor Panel Assay System Receptor Adenosine A1 Human recombinant α1-Andrenergic (non-selective) Rat brain Copyrightedα2-Andrenergic (non-selective) Rat cerebral cortex β-Andrenergic (non-selective) Rat brain Androgen AR Rat prostate Ca channel Type L, Phenylalkylamine Rat cerebral cortex Cannabinoid CB1 Human recombinant Dopamine D1 Human recombinant Dopamine transporter Human recombinant Estrogen Rat uterus Endothelin ETA Human recombinant GABA GABA A (agonist site) Rat cerebellum GABA GABAMaterials A (BZ central) Rat brain GABA GABA B Rat cerebellum Glucocorticoid Human recombinant Glutamate non-selective Rat cerebral cortex Glutamate AMPA Rat cerebral cortex Glutamate kainate Rat brain Glutamate NMDA (agonist site) Rat cerebral cortex Glutamate NMDA (glycine site) - Rat cerebral cortex Glycine strychnine sensitive TaylorRat spinal cord Histamine H1 Human recombinant Histamine H2 Human recombinant Histamine H3 Human recombinant K channel KATP Rat brain Leukotriene CysLT2 Human recombinantand Leukotriene BLT1 Human recombinant Melatonin MT1 Human recombinant Muscarinic non-selective Rat cerebral cortex Francis Muscarinic M1 Human recombinant Muscarinic M2 Human recombinant Na channel Rat brain Norepinephrine transporter Human recombinant Human receptor Nicotinic Ni (non-recombinant) Opiate non-selective Rat cerebral cortex Opiate ORL1 Human recombinant PAF Rabbit platelet Prostanoid CRTH2 Human recombinant Prostanoid DP Human recombinant Prostanoid EP2 Human recombinant (Continued) 12 Nonclinical Drug Administration

TABLE 2.1 (Continued) Receptor Panel Assay System Receptor Prostanoid EP3 Human recombinant Prostanoid EP4 Human recombinant CopyrightedSerotonin 5HT1 (non-selective) Rat striatum Serotonin 5HT1A Human recombinant Serotonin 5HT1B Human recombinant Serotonin 5HT2A Human recombinant Serotonin transporter Human recombinant Sigma non-selective Guinea pig brain Thromboxane A2 TBD Vasopressin V1 Rat liver

But PK/TK are rarelyMaterials related to PD/TD in an obvious manner. For these we either need to measure levels at the receptor sites in the tissues of “dosed” patients or animal models and relate or correlate this data to patient/animal model “effects” or measure administered dose versus effects in vivo or at a molecular level of interest across a wide range of “dose” levels and with sufcient numbers (statistical power) to understand the variability of this relationship. The rst of these is more likely to provide a useful broad understanding, that is, the use of a valid model.- Another complication is that drugs are Taylorintended to treat diseases, poten- tially leading to our “normal, healthy, young” animal models being an addi- tional step away from where we want to be in the extrapolation/modeling chain. The use of relevant disease models has, of course, been the standard for understanding PD and has come back to active discussion for understanding TD (Morgan et al., 2013; Gad, 2015). Disease models are nowand commonly used to understand and “calibrate” therapeutic effects, and are increasingly used to avoid “discovering” adverse effects and the limits thereof only in patients. Francis

References Albert A. (1965) Selective Toxicity, 3rd Ed. New York, NY: John Wiley and Sons. Blass BE. (2015) Basic Principles of Drug Discovery and Development. San Diego, CA: Academic Press, pp. 307–309. Boroujerdi M. (2015) Pharmacokinetics and Toxicokinetics. Boca Raton, FL: CRC Press, pp. 1–3, 295–297. Brouwer KR, Hsiao P, Rosania GR, Kim LR. (2015) Intracellular drug concentrations: A critical consideration for in vitro assays. AAPS, 18(4):16–19. Copeland RA. (2016) The drug–target residence time model: A 10-year retrospective. Nat Rev Drug Discovery, 15:87–95. Pharmacotherapy, Toxicodynamics, and Regulatory Science 13

Ehlert FJ. (2015) Affinity and Efficacy: The Components of Drug Receptor Interactions. London: World Scientic. Gad SC. (2015) Animal Models in Toxicology, 3rd Ed. Boca Raton, FL: CRC Press. Hammarlund-Udenaes M, deLange ECM, Thorne RG. (Eds.). (2014) Drug Delivery to the Brain. New York, NY: Springer. Hill RG, Rang HP. (2013) Drug Discovery and Development, 2nd Ed. New York, CopyrightedNY: Churchill Livingstone, pp. 291–301. Jameson JL, Collins FS. (Eds.). (1998) Principles of Molecular Medicine. Totowa, NJ: Humana Press. Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, Jensen NH, Kuijer MB, Matos RC, Tran TB, Whaley R, Glennon RA, Hert J, Thomas KLH, Edwards DD, Shoichet BK, Roth BL. (2015) Predicting new molecular targets for known drugs. Nature, 462:175–182. Morgan SJ, Elangbam CS, Berens S, Janovitz E, Vitsky A, Zabka T, Conour L. (2013) Use of animal models of human disease for nonclinical safety assessment of novel pharmaceuticals. Toxicol Pathol, 41(3):508–518. Ng R. (2015) Drugs: FromMaterials Discovery to Approval , 3rd Ed. Hoboken, NJ: Wiley, pp. 154–156.

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