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Executive Summary

Changes in dosing and route of administration for already approved aminoglycosides based on pharmacokinetic (PK) and pharmacodynamic (PD) parameters in lieu of clinical efficacy trials may be possible, FDA's Anti-Infective Drugs Advisory Committee agreed at its Sept. 24 meeting. The committee's decision came after its review of PK/PD animal and human data for beta-lactams, fluoroquinolones and aminoglycosides as part of a "Scientific Exchange" of available data for the three classes of anti-infective drugs sponsored by FDA. Seven of nine committee members agreed that in general there were enough PK/PD data available to approve changes in dosing and administration of already approved anti-infective drugs in lieu of clinical efficacy trials. On the question of whether there are adequate PK/PD data for particular classes of anti-infectives, the committee agreed that there were for aminoglycosides but not for beta-lactams and fluoroquinolones. Commenting on the data presented, Committee Chairman Thomas Beam, MD, Buffalo V-A Medical Center, said: "I feel comfortable with the information that is available for a class of drugs like the aminoglycosides. I feel less comfortable but still reasonably so with beta-lactams and quinolones. And, with all the other drugs, I don't know if they have been put through an analysis with the same, I would like to see more data on some of the older drugs [such as metronidazole] before the kinetic principles might be used to modify the dosing or route of administration." Committee consultant William Craig, MD, Middleton Memorial V-A Hospital, Madison, Wisc., presented PK/PD data from 14 comparative studies conducted over the last nine years involving 200 patients. Five of the studies are of aminoglycosides alone and nine used aminoglycosides with beta-lactam concentrations. The studies used 40 different drug-organism combinations with five different aminoglycosides: gentamicin, tobramycin, isepamicin, netromycin and amikacin. Craig pointed out that for concentration-dependent aminoglycosides, area under the curve (AUC) is the "best PK parameter." He warned that "a problem with higher AUC for aminoglycosides is that they have significant toxicity as far as the kidney and the ear and one would raise many safety issues." To avoid higher toxicities associated with aminoglycosides, Craig suggested going to a single daily dose. "Once daily dosing of aminoglycosides is a way of enhancing reduce the emergence of resistant organisms and reduce nephro- and oto- toxicity." "Another reason to go to 24-hour dosing is the first exposure effect of aminoglycosides [which leads to] down-regulation of subsequent uptake which lasts for several hours and exposure to another dose of the drug results in decreased killing," said Craig. "By spreading this time out [in dosing], you make the aminoglycoside more efficient, so that with each dose, one would get maximum [organism] kill." Additionally, in a comparison of once-a-day dosing and intermittent dosing studies, Craig stated that "once-a-day patients would have to be on therapy for a longer period of time to show nephrotoxicity than patients receiving intermittent therapy." Currently, FDA has approved eight-hour dosing regimens for gentamicin and tobramycin. Craig commented: "This area needs change. Our European colleagues have already approved once-a-day dosing." For the committee's discussion of fluoroquinolones, consultant Jerome Schentag, MD, State University of New York at Buffalo, presented data from a ciprofloxacin simulation study that included 74 patients receiving 400 mg of the fluoroquinolone every 12 hours and 200 mg every eight hours. For beta-lactams, the committee heard from consultant George Drusano, MD, Albany Medical College, who presented PK data from a University of Maryland study. For fluoroquinolones, Schentag said, PK surrogates like time above the Minimum Inhibitor Concentration (MIC) for concentration- independent molecules "is more important" than other surrogates. The PK data "are supportive of animal studies and of in vitro findings," he noted. Schentag acknowledged, however, that the weakness of the ciprofloxacin study was that it was conducted on "a small number of compromised patients and only a few drugs were studied." The study presented by Drusano measured time above the MIC for cephalosporins, carboxy penicillins and carbopenams against the nosocomial organisms E. coli, Klebsiella and Pseudomonas aeruginosa. The data showed that beta-lactams average six hours above the MIC. Drusano pointed out that "it falls apart when you look at Pseudomonas aeruginosa. Time above the MIC for that organism is a half an hour." Returning to a discussion of aminoglycoside dosing regimens -- specifically of the possibility of moving to once-daily dosing for aminoglycosides -- committee member Barth Rellar, MD, Duke University Medical Center, said: "It seems a shame that something that is as efficacious, or possibly more efficacious, and probably in some patients less toxic, and [is] less expensive, that we can't use it under the guidance of the package insert. We need something to allow us to get out of this dilemma and do the right thing for patients in this country." Committee member Franklyn Judson, MD, University of Colorado at Denver, suggested that the committee "can lead the way to help some of this irrationality." Craig said: "I think [labeling] needs to be changed with aminoglycosides and there is enough data that it could be done with what we have right now." Schentag agreed with Craig except to "qualify [labeling changes by] staying with extracellular pathogens until we get more data on the intracellulars." Drusano concurred: "It needs to be changed with aminoglycosides, only to extracellular pathogens and we have clearly shown concordance between in vitro animal models and human data all along the way." Drusano added, "We have a theoretical framework that makes predictions and those predictions have been proven out in animal and human data." Committee member George Counts, MD, National Institute of Allergy & Infectious Diseases, said: "it is very dear that changes need to be made with aminoglycosides. I am a little less dear with beta-lactams;" and with fluoroquinolones, "I'm uneasy." Rellar replied, "I would concur with that. PD data should be a supplement to clinical studies...I would like to see the package insert be a more telling document for aminoglycosides than it already is. In summary, the PD should be used in a supplemental way; and I hope that we could use the aminoglycosides as a test case." Committee member Robert Allen, MD, University of Virginia Medical Center, commented: "I am very swayed by the [aminoglycosidel pharmacodynamic data. But there is, in my opinion, no substitute for a pivotal study. I would hope we are not talking about abandoning trials in toto." Drusano concluded that "I don't think anybody would want to do away with traditional clinical studies. We just have to design them better. We have to move forward in collaboration with industry to use this information to change our study designs early so we develop these drugs in an optimal manner. So that they are developed quickly, safely and we can get to regimens that have optimal safety and minimal toxicity. We have to apply these principles to the design of pivotal clinical trials early on in drug development and never get away from doing the pivotal clinical trials."

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