Cefaclor Lilly

Fewer cephalosporins have been of clinical interest for oral administration. Studies of cefatrizine (BLS-640 SKF 60771) (7) have continued to determine in vitro characteristics,65-67 human pharmacokinetics,66 68,69 and clinical effectiveness.69-71 Extensive clinical trial data documented the effectiveness of cefadroxil (BLS-578 -OH cephalexin).72 Cefaclor (Lilly 99638) ( ) has been shown in in vitro studies to have better activity than cephalexin against gram-negative bacteria, especially H. influenzae. 56 60 73 7 The excellent oral absorption in mice, rats, and dogs paralleled that of cephalexin.75 Metabolism was observed in dogs76 but not in rodents. Human pharmacology studies indicated that cefaclor gave acceptable blood and urine levels.77... 

Trade names Alfatil Apo-Cefaclor CEC 500 Ceclor (Lilly) Cefabiocin Distaclor Kefolor Panoral Sigacefal Indications Various infections caused by susceptible organisms Category Cephalosporin, 2nd generation Half-life 0.6-0.9 hours... 

Since the introduction of the first cephalosporin antibiotic in 1962, every year several new /1-lactam antibiotics of the cephalosporin-type have reached the market. Continual improvement in the activity spectrum is necessary to overcome resistance phenomena caused by the widespread application of antibiotics. Referring to the hit1 -list of the commercially most successful therapeutics, three /1-lactam antibiotics range among the top twenty. These are cefaclor by E. Lilly, ceftriaxone by Roche, and clavulanic acid as a most efficient /1-lacta-mase inhibitor marketed by Smith Kline-Beecham in combination with the semi-synthetic penicillin derivative amoxicillin under the trade name of Aug-... 

This situation changed when an efficient chemical method was developed at Eli Lilly in Indianapolis, which would remove the side-chain of cephalosporin C to produce a bare cephalosporin nucleus, the so-called 7-aminocephalosporanic acid, from which a whole range of semi-synthetic cephalosporins could be produced. Of these, cephaloridine and cephalothin were the most widely used. Of even greater significance was the invention of some very clever chemistry, also by the Lilly group, which involved the conversion of the penicillin nucleus into the cephalosporin nucleus in a short sequence of chemical transformations (Fig. 2.2). This meant that the very cheap penicillin G could be converted into what became the best-selling cephalopsorin cephalexin (Keflex). This had excellent oral bioavailability, was very stable to metabolism, and resisted the actions of penicillinases. The other semi-synthetic cephalosporin that came to be widely used was cefaclor... 

When Lilly s Ceclor (cefaclor) comes off patent in the U.S. in 1992, unit sales of the antibiotic, which account for roughly 15 percent of the company s total sales, could be eroded by 70-80 percent by generic competition in the first 18 months, according to Kidder, Peabody analyst James Flynn. 

Ceclor AF is unlikely to be introduced in the United States much before the cefaclor product patent expires, Mr. Flynn says. A preferred dosing regimen is the only benefit he is aware Ceclor AF would have over generic competition. The analyst notes that Lilly s Keftabs formulation of Keflex (cefalexin) gained less than 15 percent... 

Lilly s dominant position in the oral antibiotic market will survive the expiration of the U.S. patent on Ceclor in December 1992, the company maintained at a meeting with financial analysts in New York on Feb. 28. Based on a process protection for cefaclor and a pending NDA application for the follow-up compound loracarbef, Lilly is forcefully declaring its intention to hold its place in the oral antibiotic field... 

Asked to comment on the impact of the upcoming patent expiration on Ceclor sales, Lilly Pharmaceutical President Gene Step said the relevant questions should be what will be Lilly s overall position in the oral antibiotic market and what is the likelihood of generic versions of cefaclor reaching the market. 

While 3-methylenecephams themselves are completely devoid of antimicrobial activity, the exomethylene function is a distinctive feature of these compounds that many workers recognized could be a key intermediate in a chemical route to novel classes of cephalosporins with direct heteroatom substitution at C-3. Whereas 3-methylenecephams were first employed to produce deacetoxycephalosporins, exploration of their chemistry has led to the preparation of 3-chloro-3-cephems and 3-methoxyl-3-cephems that possess marked antimicrobial activity. These compounds represent a new and different generation of cephalosporin antibiotics. Two members of this class of p-lactams have achieved clinical importance. One bears the D-phenylglycyl side chain Lilly compound 99638, with the generic name cefaclor (Ceclor, Lilly). The other bears the D-cyclohexadienylglycyl side chain Ciba-Geigy Compound 9000. Both compounds are potent broad-spectrum p-lactam antibiotics with oral therapeutic efficacy. 

Cefaclor is the generic name for [67 -[6a,7p(/ )]]-7-[(aminophenyl-acetyl)amino] -3-chloro-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-car-boxylic acid, monohydrate (Ceclor, Lilly). 

Laboratory studies conducted at Lilly Research Laboratories (Preston, 1979) and at other institutions (Bill and Washington, 1977 Shadomy et ai, 1977) have shown that cefaclor is active in vitro against all classes of bacteria generally susceptible to cephalothin and cephalexin. These organisms are listed in Table VII. 

While Lilly scientists were working on the discoveries leading to cefaclor, scientists in Basel were searching for orally active cephalosporins. At that time it was well known that biological properties of cephalosporins were strongly influenced by the substituent at the 3-position of the cephem molecule, since this substituent is electronically linked via the 3,4-double bond with the p-lactam bond of the azetidinone ring (Murphy and Webber, 1973 Sweet and Dahl, 1970 Gorman and Ryan, 1973). 

Cefaclor Eli Lilly Cephalosporin (antibacterial) 1974 2nd generation cephalosporin... 

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