Published on September 25, 2013
Presented by: Vinitha Nair M.Sc Bio-analytical Sciences Part 2
Contents • Bioequivalence • Bioequivalence: Background • Goals of BE • Pharmaceutical Equivalents • Pharmaceutical Equivalence • Pharmaceutical Alternatives • Therapeutic Equivalence • Interchangeable Pharmaceutical Products • Parameters • Concept of “Half Life” • References
Bioequivalence Two medicinal products are bioequivalents if they are pharmaceutical equivalents or alternatives and if their bioavailabilities (rate and extent) after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essential the same.
Bioequivalence: Background 1 • Using bioequivalence as the basis was established by the “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the Waxman-Hatch Act. 2 • This Act permits FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials. 3 • At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed. 4 • Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation.
Goals of BE Bioequivalence studies focus on changes to the dosage form process after pivotal studies commence to ensure product on the market is comparable to that upon which the efficacy is based. Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product. Important for linking the commercial drug product to clinical trial material at time of NDA. Important for post-approval changes in the marketed drug formulation.
7 Pharmaceutical Equivalents • Contain the same amount of the same active substance in the same dosage form. • Meet the same or comparable standards. • Intended to be administered by the same route. Pharmaceutical equivalence by itself does not necessarily imply therapeutic equivalence
Pharmaceutical Equivalence Reference Test Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution specifications)
Pharmaceutical Alternatives identical therapeutic moiety, or its precursor not necessarily the same: • salt or ester of the therapeutic moiety • amount • dosage form
Therapeutic Equivalence • Pharmaceutically equivalent • Their effects, with respect to both efficacy and safety, will be essentially the same as derived from appropriate studies Clinical studies & In vitro studies Pharmaco dynamic studies Bio equivalnce studies
Interchangeable Pharmaceutical Products If a product is demonstrated to be therapeutically equivalent to a reference product, then the products are considered interchangeable.
Concept of interchangeability includes the equivalence of the dosage form as well as for the indications and instructions for use. Therapeutic equivalence of a multiscource product can be assured when the multiscource product is both pharmaceutically equivalent/alternative and bioequivalent. TE = PE + BE
Parameters These are following parameters:
• AUC: area under the concentration-time curve measure of the extent of bioavailability • Cmax: the observed maximum concentration of drug measure of both the rate of absorption and the extent of bioavailability (µg/mL or ng/mL) • Tmax: the time after administration of drug at which Cmax is observed measure of the rate of absorption (minutes or hours) Note that bioequivalence standards are applied to the pharmacokinetic parameters AUC and Cmax but not to Tmax.
• Pharmacokinetic Studies Key Measurements • AUC – Area under the concentration- time curve • Cmax – Maximum concentration – A difference of greater than 20% in Cmax or the AUC represents a significant difference between the test and reference compounds • Tmax – Time to maximum concentration Test Compound Reference Compound Time(Hr) Plasma Concentration(µgml) Cmax Tmax AUC 9/25/2013 15
To establish BE: The calculated 90% CI for Cmax & AUC, should fall within range: 80-125% (Range of Bioequivalence) Non-parametric data 90% CI for Tmax should lie within clinical acceptable range
Concept of “Half Life” ½ life = how much time it takes for blood levels of drug to decrease to half of what it was at equilibrium There are really two kinds of ½ life… “distribution” ½ life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in body’s tissue reservoirs “elimination” ½ life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated It is usually the elimination ½ life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug
References www.authorstream.com/.../sanketrekhawar111-466277-bioequivalence www.thaifda.com/editor/data/files/.../BABE_concept www.icmcc.org/ppt/roy.ppt www.powershow.com www.fda.gov/ohrms/dockets/ac/04/slides/4034S2_12_Lionberger.ppt www.fda.gov/ohrms/dockets/ac/04/slides/4034S2_07_Haidar.ppt
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