Bioequivalency

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

For dmgs approved originally between 1938 and 1962, the FDA has utilized the Abbreviated New Dmg AppHcation (ANDA) for review of generic products that are pharmaceutical equivalents of the initially approved products. In this way, costiy dupHcation of animal and human experimentation is avoided. The new manufacturer has to show only that its manufacturing methodology, specifications, quaUty control, and labeling are acceptable. In some cases, the FDA does require proof of bioequivalence. 

Fig. 1. Blood—drug concentration curve used to determine bioavailabiLitv and bioequivalence. C is the maximum dmg concentration in the blood and corresponds to some The AUC (shaded) represents the total amount of orally adininistered dmg the time from points A to B represents dmg onset, from points B to D, the duration MEC = minimum effective concentration MTC = minimum toxic concentration and TI = therapeutic index.

Fig. 1), these are adjudged to be bioequivalent. The FDA sets the degree of similarity needed to be so termed. This concept is of obvious importance for the acceptance of generic dmg products for marketing. 

Generic applications for chiral medicinal products should be supported by bioequivalence studies using enantiospecific bioanalytical methods unless both products contain the same, stable, single enantiomer or both products contain a racemate where both enantiomers show linear pharmacokinetics. 

Bioavailahility studies are used to compare different formulations of the drug product, or different batches of the same formulation and, as discussed in Chapter 8, generic copies of a reference drug. Their comparative value is based on the premise that, if similar amounts of identical active substance are delivered to the site of action at similar rates, then a similar biological response can be expected, which leads to the conclusion that the two preparations are bioequivalent. 

The procedure for introducing changes to an approved drug in the US is dictated by type of data that must be submitted to support the alteration. Changes that require review of new investigations to approve the modification, other than bioavailability or bioequivalence studies, must be submitted as supplementary ND As/NAD As, as they... 

Pancreatic enzyme replacement is the mainstay of gastrointestinal therapy. Most enzyme products are formulated as capsules containing enteric-coated microspheres or microtablets to avoid inactivation of enzymes in the acidic stomach instead, they dissolve in the more alkaline environment of the duodenum. Capsules may be opened and the microbeads swallowed with food, as long as they are not chewed. A powder form is available for patients unable to swallow the capsules or microbeads, but bioavailability is poor. While products may contain similar enzyme ratios, they are not bioequivalent and cannot be substituted. Generic enzyme products generally display poor dissolution and should not be used.5 Table 13-3 lists commonly used enzyme replacement products. 

Discuss the issues regarding levothyroxine product bioequivalence and the advantages of maintaining patients on the same product. 

More important than bioequivalence is the therapeutic equivalence of LT4 products. Will patients have the same outcomes if bioequivalent products are used The study by Dong... 

Evidence does exist that small differences in the LT4 dose can result in large changes in TSH. The impact on TSH of small changes in LT4 dose was assessed in 21 adult hypothyroid patients.21 When the daily dose was reduced by 25 meg, 78% had an elevated TSH level. When the daily dose was increased by 25 meg, 55% had a low TSH level. Clearly, differences in the LT4 dose or bioavailability within the FDA-allowed variance for bioequivalent products can cause significant changes in TSH. 

WA Ritschel, DD Denson. Influence of disease on bioavailability. In PG Welling, FLS Tse, SV Dighe, eds. Pharmaceutical Bioequivalence. New York Marcel Dekker, 1991, pp. 67-115. 

A discussion of the statistical methods used in analyzing the data from bioequivalence studies is beyond the scope of this chapter. For a discussion of these considerations, the reader is referred to a description by Westlake [6]. 

Occluded applications Composition relatively invariant in use System size (area) predetermined Specific site prescribed for application Application technique highly reproducible Delivery is sustained Generally operate at unit drug activity, at least operate at steady activity Delivery is zero-order Serum levels related to product efficacy Bioequivalency based on pharmacokinetic (blood level) endpoint Unavoidable local tissue levels consequential only to system toxicity Individual dose interruptable Whole system removed when spent... 

Experience profound compositional shifts in use May experience phases changes in use Site in the disease s location Operate at variable drug activity Highly nonstationary state kinetics Application technique and amount are highly individualized Applications short-acting Local tissue levels tied to efficacy Used on diseased, damaged skin No easy bioequivalency endpoint Systemic absorption absolutely undesirable, but some unavoidable... 

Hard gelatin capsules are uniquely suitable for blinded clinical tests and are widely used in preliminary drug studies. Bioequivalence studies of tablet formulations may be conveniently blinded by inserting tablets into opaque capsules, often along with an inert filler powder. Even capsule products may be disguised by inserting them into larger capsules. 

It is interesting that the in vitro dissolution test (USP) was more sensitive to the piroxicam formulation variables than the biodata. The fast, moderate, and slow products were found bioequivalent to each other and to the lot of innovator product studied [100]. It is possible that either the formulation variables studied did not affect in vivo dissolution and/or the differences were not discernible because of the long biological half-life of piroxicam [146]. 

DA Piscitelli, S Bigora, C Propst, S Goskonda, P Schwartz, L Lesko, L Augsburger, D Young. The impact of formulation and process changes on in vitro dissolution and bioequivalence of piroxicam capsules. Pharm Devel Tech 3(4) 443-452, 1998. 

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