1_Review of Drug Discovery and Development Process

Grading system:

50% exams (2)

35% activities/cases

15% quizzes

NO FINALS

Drug Discovery and Development Activities

  1. basic research

  • lead identification

  • synthesis scale-up

  • in vitro pcol

    1. Preclinical Development

  • mutagenicity

  • in vitro toxicity

  • metabolic stability

  • Pkin: ADME

  • Genomic Biomarker Analysis → different responses from different subjects

  • CYP Screen

  • Assay Metabolites

  • In Vivo toxicity

  1. Clinical Trials: ethics review, regulatory reviews, IND/Investigational New Drug, Phase I, Long-term

  2. FDA filing & Approval: Regulatory Review NDA/New Drug Application

  3. Pharmacovigilance and Post-Marketing Surveillance

GLP (from start of basic reserach to preclinical development)

GMP (during basic research until the very end of production, until post-marketing)

GCP (from clinical trials, only involved when there are humans involved)

Terminologies in Drug Discovery

  1. Active - compounds showing an effect in a biological screen (assay) e.g.

  2. Hit Compound - a molecule that shows the desired type of activity in a screening assay

  3. Lead Compound

    • selected from a collection of hits by refining the screening criteria

    • prototype moiety with desired pharmacologic activity

  4. High Throughout Screening (HTS)

    • Uses technologies of automation to collect a large amount of experimental data in a relatively short time

    • automated = robots, detectors, and softwares

Basic Research

  • Early Discovery

    • in between: Lead series

  • Lead optimization

    • in between: super qualifiers: next level screened products

  • Late discovery

    • in between: development compound

  • Early development: product in crystalline form

  • Full development: product in kilograms

> Early discovery

  • to identify compounds with properties that are acceptable for a drug

  • large number of compounds are ranked from a physicochemical point of view

    • Factors that affect the product: acid/base properties, solubility, lipophilicity

  • compounds are grouped into: good, acceptable, bad, or unacceptable

> Lead optimization

  • improvement of target specificity, selectivity, pharmacokinetics, and safety profiles

  • done by medicinal chemists using advanced organic synthesis methods or by biotechnological methods

  • if the structure of the drug target is known, computational in silico methods is used

  • Terms

    • Lead compound has

    • Pharmacophore: part of the structure that will exhibit the activity, cannot be modified

    • Auxophore: part of the structure of the product that will be used for varying physicochemical properties

  • To optimize the series as regards to physicochemical properties:

    • pKa

    • logP/logD

    • aqueous solubility

    • stability

> Late discovery

  • few promising compounds are selected, known as super qualifiers

  • characterize them and judge

  • to check also the solid states of the drug

  • solid state charcterization

    • Effect of crystal form on dissolution

    • Characterization of polymorphs

    • X-ray diffraction

> Early Development

  • whether the prodrug formation should be considered to find the best form of the compound for development into a drug

  • compatibility studies: compatibility of API with inactive ingredient

  • look for best salt for the development has to be identified

    • polymorphism

    • intrinsic dissolution rate

    • thermal properties (TGA, DSC)

    • solid state stability (if stable to light, heat & humidity?); stability is tested under stressed conditions to be able to rank the compounds in a short time

      • check appropriate dosage form and product

    • hygroscopicity

> Full development

  • eval during scale up

Pre-clinical development

  • bioassays: measurement of biological activity of a substance based on response of a biological test system to the test substance

    • in vitro: lower organisms, enzymes, cells

    • in vivo: animals (mice, rat)

    • ex vivo: tissues, organs

Clinical Trials: Phases

Phase 0: relationship of mechanism of action and treatment of disease, pkin, including biodistribution

  • microdoses

  • no therapeutic event

  • di pa dito makikita yung tamang pharmacologic event, just pkin ng drug

  • 7-14 days (short-term)

Phase 1: prioritizes safety, Pharmacokinetics, Ideal Dosage Range, Non-blind or open studies

  • no need ng bias basta makita na safe

Phase 2: prioritizes efficacy

  • IIA: best and effective dose

  • IIB: drug response to the dose

  • Single-blind design: di dapat alam ng subject mo kung ano ang meron sa product, aka. placebo

    • established active drug in addition to the investigational agent

Phase 3: prioritizes safety & efficacy

  • IIIA: done prior to marketing

  • IIIB: supplemental/label expansion

  • certain toxic effects may first become apparent

  • double-bind and crossover techniques

    • blind both patient and researcher (to remove bias of researcher)

    • crossover techniques: at least 2 participants from placebo and the drug itself

Regulatory Application and Review

  • if phase 3 results meet expectations, application is made for permission to market the new agent

  • full reports of all pre-clinical and clinical data = Registration Dossier

    • US: NDA

    • EU: Marketing Authorization Application

Post Marketing Surveillance (Phase IV)

  • Additional pharmacological & toxicological data

  • ADR reporting

  • Product defect reporting