Potency profile

Indeed, for a number of years, it was widely believed that branded biopharmaceuticals were unhkely ever to be threatened by lower-priced, post-patent expiry versions of the products because they are too sensitive and sophisticated to copy safely (see also Part Vll, Chapter 4). The intellectual property is complicated, and could be protected by an extensive array of composition and process-related patents that would extend patent lifetimes practically indefinitely. Moreover, it was widely understood that biopharmaceutical product safety and potency profiles are often exquisitely sensitive to the parameters of the production and purification processes used, and small fluctuations in process specs can result in substantially different biologic activity and immunogenicity. To produce a close copy of such a product, near-exact replication of the innovator company s process may be required. However, biopharmaceutical companies have often chosen to exclude the details in patent filings, preferring to maintain exact process specifications as closely guarded... 

The rate of removal of the local anesthetic from the site of injection also affects its profile. AH local anesthetic agents possess some vasodilatory activity at clinically useful concentrations. Agents which are more potent in this regard tend to be absorbed more rapidly by the vasculature. They are less potent anesthetics and have shorter durations than those having lower vasodilatory activity. A comparison of potency, onset, and duration as a function of physiochemical properties is presented in Table 4. 

The disaccharide stmcture of (12) (trade name SPLENDA) is emphasized by the manufacturer as responsible for a taste quaUty and time—intensity profile closer to that of sucrose than any other high potency sweetener. The sweetness potency at the 10% sucrose solution sweetness equivalence is between 450 and 500X, or about two and one-half times that of aspartame. When compared to a 2% sugar solution, the potency of sucralose can be as high as 750X. A moderate degree of synergy between sucralose and other nonnutritive (91) or nutritive (92) sweeteners has been reported. 

Alitame (trade name Adame) is a water-soluble, crystalline powder of high sweetness potency (2000X, 10% sucrose solution sweetness equivalence). The sweet taste is clean, and the time—intensity profile is similar to that of aspartame. Because it is a stericaHy hindered amide rather than an ester, ahtame is expected to be more stable than aspartame. At pH 2 to 4, the half-life of aUtame in solution is reported to be twice that of aspartame. The main decomposition pathways (Fig. 6) include conversion to the unsweet P-aspartic isomer (17) and hydrolysis to aspartic acid and alanine amide (96). No cyclization to diketopiperazine or hydrolysis of the alanine amide bond has been reported. AUtame-sweetened beverages, particularly colas, that have a pH below 4.0 can develop an off-flavor which can be avoided or minimized by the addition of edetic acid (EDTA) [60-00-4] (97). 

A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed. 

Quetiapine is another of the D2/5-HT2 blocking agents, with a multireceptor profile similar to clozapine but of generally lower overall potency (Sailer and Salama, 1993). It... 

The metabolic and pharmacokinetic profile of sucralose (this is a novel intense sweetener with a potency about 600 times that of sucrose) in human volunteers was studied by Roberts and coworkers [82]. Part of this study was realized using PLC in the following chromatographic system in which the stationary phase was silica gel and the mobile phase was ethyl acetate-methanol-water-concentrated ammonia (60 20 10 2, v/v). Separated substances were scraped off separately, suspended in methanol, and analyzed by filtration, scintillation counting, or enzymatic assay. It was shown that the characteristics of sucralose include poor absorption, rapid elimination, limited conjugative metabolism of the fraction absorbed, and lack of bio-accumulative potential. 

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