Clinical Pharmacology

CLINICAL PHARMACOLOGY (Pharmacotherapeutics)

CLINICAL PHARMACOLOGY • Also known as pharmacotherapeutics, it is a branch of medical sciences which is most concerned with rational development of drugs, effective and safe use of drugs (RDU or RUD). • Proper evaluation of drugs and other chemical entities in humans for the diagnosis, prevention, alleviation, and cure of disease and disease

CLINICAL PHARMACOLOGY • Simple blind trials – Physician and associates – but not the patient – know the substance being used. • Double blind trials – Neither the individual administering the compound nor the patient knows the identity of the substance. All the materials are coded including the test substance and a placebo and, if possible, an already known active substance therapeutically similar to the one being tested (standard reference of positive

DEVELOPMENT OF NEW DRUG Animal study  human study.

• • Human dose – Initial single human dose would be a fraction of a minimum effective dose in animal study. Example: Minimum effective dose is 10 mg. – If rat is the test animal – human dose is 1/200 of 10 mg. – If dog is the test animal – human dose in 1/10 of 10 mg. – Monkeys or orangutans and baboons – human dose is ½ of MED.

• Dose is gradually increased until a response appears or until a maximum tolerated dose is established (dose which does not elicit undesirable effects). • No individual should be exposed to more than a single dose in a short period of time – preventing cumulative effect. • Minimum effective dose based on doseresponse relationship

NEW DRUG DEV’T. AND APPROVAL PROCESS New chemical entity: Sources, drug synthesis, molecular modification, isolation from plants Pre-clinical Studies: Chemistry, physical properties, biological pharmacology, toxicology, pre-formulation

Clinical Trials: Phases I, II, III

Investigational New Drug Application (IND): Submission, FDA Review Pre-clinical Studies continued + long-term animal toxicity, product formulation, manufacturing and controls, package New Drug Application (NDA):and label design Submission, FDA Review, Preapproval plant inspection, FDA Action

Post-marketing: Phase IV clinical studies, clinical pharmacology/toxicology, additional indications/ADR reporting, product defect

CLINICAL TRIALS IN DEVELOPING A NEW DRUG IN HUMANS • 2-3 years Phase I Measurement of pharmacologic action, potency, side effects (pharmacodynamics), pharmacokinetics usually in normal, healthy volunteers done by clinical pharmacologists in research setting. • 1-2 years Phase II – Early: Selection of few patients with disease syndrome. Determination of drug efficacy and dosage ranges. Special toxicity studies if indicated. – Late: Large number of clinical patients. Longer periods of therapy.

CLINICAL TRIALS IN DEVELOPING A NEW DRUG IN HUMANS • 1-2 years Phase III Large scale comparative trials in patients. Designed to establish efficacy. Compare the new drug with other available treatments. Establish optimal dosage. Determine incidence of ADR before drug is licensed for marketing. Set up blind or double-blind study with randomized selection of patients and controls. Dosage forms and routes of administration clearly defined. • 1-3 years Phase IV Approval of NDA by FDA for marketing. Surveillance of the safety and efficacy of the drug by the manufacturer who reports periodically to the FDA. Drug may be withdrawn if unexpected undue toxicity becomes evident. Drug may be released only for a limited use in selected patients under