New Drug Development and approval process Flashcards
Food, Drug and Comestic Act (1938)
Mandated testing of all drugs for harmful effects and that drug labels must be accurate and simple
Wheeler-Lea Act (1938)
Defined criteria for non-fraudulent advertising
Durkham-Humphney Amendment (1952)
Distinguish between drugs that can be sold with/without a prescription and those that cannot be refilled
Comprehensive Drug Abuse Prevention and Control Act (1970)
Categorized controlled substances based on their relative potential for abuse
Drug Regulation Reform Act (1978)
Shortened the drug investigation process to release drugs sooner to the public
Drug Names can be categorized into
- Chemical: Precise description of the drug’s chemical composition and molecular structure
- Generic: Name assigned to a new drug by the manufacturer who first develops the drug and is not copyrighted
- Official: Officially assigned to a new drug and listed in official compendium
- Trade/brand: Assigned to a new drug by its manufacturer that sells drug, copyright
What consist of a preclinical study?
- Chemical characterization
- Animal testing and screening
- > application for IND (Investigational New Drug) status
What consist of a clinical study?
Phase 1 - healthy human volunteers
Phase 2 - human patient volunteers
Phase 3 - expansion of human patients
Application for NDA (New Drug Application)
After approval, Phase 4 - post marketing trials
What consist of the Drugs Design Process?
- Find lead compounds from potential drug candidates
- Have some activity against a disease
- May have side effects
- Provide a starting point for structural refinements - Isolate molecular bases for the disease
Know the drug binding on proteins or nucleotides sites to tailor made a drug to bind that specific site
Techniques used:
- Molecular interactions
- Rational drug design techniques (De Nova techniques)
- X-ray crystallography
- Distance geometry ( NMR-NOE) - Drug activity refinements: Examine the molecular structure of the drug to achieve high drug activity and few side effects
Techniques used:
- Synthesis
- Computational
What consist of a Drug Development Process?
- Pharmacology
- Metabolism
- Toxicology
- Preformulation
- Formulation
- Analytical
- Pharmacokinetics
What is pharmacology?
Study of drugs - what they are, how they work, what they do
What is metabolism?
Biotransformation: a series of animal studies of a proposed drug’s ADME to determine:
- extent and rate of drug absorption from various routes of administration
- rate of drug distribution in the body, and the site(s) and duration of drug’s residence
- rate, sites and mechanism of the drug’s metabolism and the chemistry of the metabolites
- proportion of the administered dose eliminated from the body and its rate and route of elimination
What is toxicology?
Study of adverse/undesired effects of drugs
Determine:
- substances potential for toxicity (acute/chronic)
- substances potential for specific organ toxicity
- mode, site and degree of toxicity
- dose-response relationship for low, high and intermediate dose
- gender, reproductive or teratogenic toxicities
- substance’s carcinogenic and genotoxic potential
What is preformulation?
Application of pharmaceutical principles to the physicochemical parameters of a drug for designing an optimum drug delivery system
What consists of preformulation studies?
Drug solubility pKa determination Partition coefficient Chemical stability Crystal properties and polymorphism Particle size, shape and surface area
What is partition coefficient?
Measure of a drug’s lipophilicity and an indication of its ability to cross cell membranes
Factors affecting chemical stability
- Temperature
- pH
- Enzymes
- Excipients
What is polymorphism?
Drugs existing in more than 1 crystalline form with different space lattice arrangements. Polymorphs generally have different physical properties but identical chemical properties
Advantages of polymorphism
- When the absorption of a drug is dissolution rate limited, a more soluble and faster-dissolving polymorph may be used to increase rate and extent of bioavailability
- Chemically more stable polymorph -> less likely to degrade
- Different polymorphs -> different morphology, tensile strength and density of powder bed -> compression characteristics of materials
What is therapeutic index
TI = lethal dose (LD)/ effective dose (ED)
Describe phase I clinical trials
Takes around 2 years, 70% are sent to the next phase. Done on a small no. of healthy subjects (20-100) who take the drug to determine its safety and pharmocokinetics.
Data to be reported to FDA before proceeding
Describe phase II clinical trials
Takes ~2 years, 45% are sent to the next phase.
Done on a small no, of diseased subjects (several 100s) who take the drug in gradually increasing dosages noting effectiveness and side effects
Data to be reported to FDA before proceeding
Describe phase III clinical trials
5-10% pass this phase.
Extended clinical evaluation on a large no. of diseased subjects who take the drug according to protocols to determine clinical effectiveness, drug safety, and establishment of tolerated dosage
Desribe phase IV
- Identify rare adverse reactions not detected during pe-licensure studies
- Monitor increase in known reactions
- Identify risk factors/ pre-existing conditions that may promote reactions
- identify particular lots with unusually high rate/types of events
What types of controls are there?
- Standard
- Placebo
- Comparator
- Active drug
What is the purpose of New Drug Application (NDA)?
Gain permission to market the drug product
Factors affecting drug dosage
- Characteristics of the drug
- Drug dosage form
- Route of administration
- Patient factors: Age, weight, general health status, pathologic conditions, concomitant drug therapy
What does it mean by usual adult dose?
Amount of drug that will produce the desired effect in most adult patients (~70kg)
What is maintenance dose?
A dose sufficient to maintain at the desired level the influence of a drug achieved by earlier administration of larger amounts
What is therapeutic dose?
A quantity several times larger than the maintenance dose, used in vitamin therapy when a marked deficiency exists
What is median effective dose?
Amount that will produce the desired intensity of effect in 50% of the individuals
What is drug’s half life?
The amount of time for half the drug to be eliminated from the system
What is bioavailability?
Ability of the drug to be released from dosage form, dissolved, absorbed and transported to the site of action
Factors to consider in Drug’s dosage response
- Age
- Weight
- Body surface area
- Gender: different compositions and hormone levels, water composition, pregnancy
- Existing pathology
- Tolerance: ability to endure the influence of a drug esp during continuous use
- Concomitant drug therapy: drug-drug interactions: physical & chemical interactions between drugs ; interactions after ADME
- Time and conditions of administration: before/after food (drug-food interactions)
- Dosage form and route of administration (oral/injection)
Factors affecting drug-dose response
- Plasma levels of a drug
- Biologic half-life: the time interval needed for the drug’s elimination processes to reduce the plasma conc. of the drug in the body by 1/2
- Therapeutic Index
Treatment IND
Permits the use of an investigational drug in the treatment of patients not enrolled in the clinical study but who have serious/immediately life threatening disease for which there is no satisfactory alterative therapy
- e.g. advanced AIDS, Herpes simplex encephalitis, advanced cancer, Alzheimer’s disease, Parkinson disease
Drug must show sufficient evidence of safety and efficacy to supports its use as treatment IND
What is prodrugs? What does it provide?
A compound that is converted within the body into its active form that has medical effects.
May provide improved physicochemical properties, enhanced delivery characteristics and/or therapeutic value of the drug.
Definition of drug
An agent intended for use in the diagnosis, mitigation, treatment, cure, or prevention of disease in man/other animals
Sources of drugs
- Plants, natural products e.g. Taxol, morphine, heronin (opium)
- Humans and animals e.g. Insulin (pork, human), estrogen (horse urine)
- Minerals e.g. Sodium bicarbonate, iron, iodine
- Synthetic e.g. diazepam, human insulin
- Semisynthetic e.g. Mexican yams rich in steroid structures
- Microorganisms e.g. penicillum notatum mold (penicillin)
- Natural vs artificial (natural - atrophine form Nightshade, quinine from cinchona bark vs artificial - savarsan, ibuprophen, acetaminophen)
What consists of a drug selection process?
- Health needs
- Research objectives
- Company policies
What is drug solubility?
- Drugs administered by any route must have some aqueous solubility for systemic absorption and therapeutic effect
- Affects bioavailability, rate of drug release and its therapeutic efficiency
What is pharmacokinetics?
Aim to quantify drug absorption, distribution, metabolism (biotransformation), and excretion (ADME)
Animal studies are performed to ascertain:
- Toxicities of the potential new drug - acute, subacute,, subchronic and chronic toxicity
- Therapeutic index (TI) of the potential new drug - TI = LD/ED
- Pharmacokinetics (ADME) of the potential new drug
- Animal testing and screening: drug tested for its biological activity on living cells and animals: in vitro screening - isolated cells, tissues and organs, in vivo screening - only with intact animals
What is usual dose raange?
The quantitative range/amounts of the drug that may be prescribed safely within the framework of usual medical practice
What is dosage regiment
Schedule of the dosage and depends on the drug’s duration of action, dosage form and the pharmacokinetics
What is initial/loading/priming dose?
A quantity several times larger than the maintenance dose, used at the initiation of therapy to rapidly establish the desired blood and tissue levels of the drug
Minimum effective concentration/minimum therapeutic concentration (MEC)
concentration of drug in the blood/plasma needed for a therapeutic effect
Maximum therapeutic concentration/minimum toxic concentration (MTC)
largest amount of drug that is helpful w/o having dangerous/intolerable side effects
Therapeutic range?
concentrations between MEC and MTC
When are prodrugs useful?
When the active drug is too toxic to administer systematically or absorbed poorly by the digestive tract.
