Drug Development Process Overview
• Phase I: evaluate pharmacokinetics with assessment of any side effects
• Phase II studies (small # of patients) are aimed at defining the most likely safe and efficacious dosage regimens
• Phase III clinical trials (thousands) – main efficacy trials
- Those compounds that have sufficient efficacy and safety for a particular clinical indication are then approved by drug regulatory authorities
• Phase 4: postmarketing surveillance to further refine its pharmacotherapeutic profile
Pharmacokinetics
- Kinetics of drug absorption, distribution, metabolism, and excretion
- What the body does to the drug
Pharmacodynamics
- Relationship between the drug concentration at the site of action (receptor) and the pharmacologic response
- What the drug does to the body
BIOAVAILABILITY
Statutory Definition
- “The rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action.
- Cont: For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient becomes available at the site of action.”
BIOEQUIVALENT DRUG PRODUCTS
• Purpose: predict the clinical outcome of a new product, when the actual clinical trials (used for collecting efficacy and safety data) were obtained with another product
• Basic assumption: if…
1. same active ingredient
2. same dosage form and route of administration
3. similar pharmacokinetics (rate and extent of abs.)
…then the therapeutic outcome will be the same (therapeutic equivalence, same clinical effect and safety)
• Full clinical efficacy trial not necessary
Standard Bioequivalence Study
- Cross-over (may be parallel if necessary- ie long half-life / tolerance effect)
- Small number of healthy normal adults (usually 24-36)
- Single doses of test and reference products (multiple dose conditions may be acceptable)
- Measures of AUC and Cmax examined by statistical procedures
Statistical Criteria
- Two one-sided tests procedure
• Test (T) is not significantly less than reference
• Reference (R) is not significantly less than test
• Significant difference predefined as 20% - T/R = 80/100 = 80%
- R/T = 80% (all data expressed as T/R so the reciprocal becomes 100/80 or 125%)
- Used to calculate the 90% CI for the ratio of the generic (T) to the innovator (R)
- Limits of acceptability are 0.8 to 1.25 for AUC and Cmax for the 90% CI
- The question is not whether or not they are different, but rather whether or not they are sufficiently similar.
Bioequivalent / Pharmaceutical / Therapeutic Equivalence
• Pharmaceutical equivalence
- Same active ingredient, same dosage form, same route of administration and identical strength /concentration
• Bioequivalence
- The 90% CI for Cmax and AUC for comparison of test product to reference product is within 80-125%
• Therapeutic equivalence
- Pharmaceutical equivalence AND having same safety and efficacy
- (Tmax matters for acute conditions only)!!
Bioavailability More Variable with Low Values
Drugs that have low bioavailability will have much more variability and need more test subjects
BCS
- The BCS is a scientific framework for classifying drugs based on their aqueous solubility and intestinal permeability.
Class I
HIGH solubility and HIGH permeability
Class II
LOW solubility and HIGH permeability
Class III
HIGH solubility and LOW permeability
Class IV
LOW solubility and LOW permeability
Solubility
Highly soluble when the highest dose strength is soluble in ≤ 250 mL water over pH range of 1 to 6.8 at 37 ± 1°C
- SLIDES SAY only pH range 1-7.5
Permeability
Highly permeable when extent of absorption in humans is determined to be ≥ 85% of dose (based on mass balance or compared to IV reference dose)
- SLIDES SAY > 90%
Dissolution
Rapidly dissolving when ≥ 85% dissolves within 30 minutes in 0.1 HCl, pH 4.5, and pH 6.8 buffers using Rotating Basket at 100 rpm or Paddle at 50 rpm.
Biowaivers
- Pharmaceutical companies may request waivers of in vivo bioequivalence testing for drug substances that are immediate-release solid oral dosage forms intended to be swallowed and meet the following:
- Rapid and similar dissolution
- High solubility
- High permeability
- Wide therapeutic window
- Excipients previously approved in IR solid oral dosage forms
