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Executive Summary

ANTIVIRAL DRUG TESTING: GONADAL TOXICITY MULTIGENERATIONAL STUDIES were suggested at FDA's Anti-Infective Drugs Advisory Cmte.'s Jan. 17 workshop. Richard Sherins, MD, Natl. Institutes of Health told the cmte. that the effects of antivirals in humans "is, in part, age dependent." Sherins said some drug combinations have an effect in the adult at one level, and a considerably greater effect at the same dosage in the adolescent through puberty. He added that in "the prepubertal, for which there is little information," there may be a resistance to drug effects. Therefore, Sherins concluded, "the age effects are quite crucial in understanding risk." The cmte. and a panel of invited scientific experts specifically looked at the gonadal toxic effects of acyclovir, the first orally administered antiviral drug for long-term use approved by FDA. Four other antivirals have since been approved: trifluridine, amantadine HCl, ribavirin, and vidarabine. Burroughs Wellcome Senior Toxicologic Pathologist George Szczech, PhD, told the cmte. that acyclovir research with cynomologus monkeys might resolve practical difficulties associated with primate studies. Whereas earlier studies with rhesus monkeys were unsuccessful, Szczech noted, because the rhesus monkeys do not absorb acyclovir, the cynomologus macaque monkey may metabolize acyclovir in a manner similar to humans. At its meeting last October, the cmte. concluded that additional primate studies were necessary to assess the gonadal toxicity of acyclovir. Summarizing the data on acyclovir, Szczech reported that "testicular toxicity was not seen with low oral doses given for one year to dogs and two years to rodents. High parenteral doses produced severe effects. In rats, severe effects caused by short term administration of high parenteral doses were reversible." Recent human studies show that the likelihood of effects on spermatogenesis in man with oral dosing "would seem to be low," he added. Participants at the workshop reiterated that there is a need for more animal studies, noting that the lifespan and reproductive development of primates make them an important animal model to use in studying at least the most serious adverse reproductive effects of antiviral drugs. James Overstreet, MD/PhD, University of California at Davis, stated, "it's important to remember that primates . . . have cervical function which is similar to women. We believe that the interaction of the spermatazoa with the cervix and its complementary mucus could be important in this function." FDA Anti-Infective Drugs Div. Director Edward Tabor, MD, said that postmarketing surveillance of individuals receiving antivirals "is essential," and controlled investigations comparing drug-treated versus drug-free patients are needed. Cmte. member Stanley Lemon, MD, University of North Carolina, recommended that where biological correlates are relevant, human experience with older drugs would be a helpful resource for understanding gonadal toxicity of the new class of antivirals. John McLachlan, PhD, Natl. Institute of Environmental Health Sciences, told the cmte. that it is "prudent to be especially cautious and suspicious with compounds that have structural similarities to estrogen." He explained that many compounds can have a functionally "estrogenic effect, even if they are not themselves estrogenic." He said compounds may be similar to estrogen in the way they remain in the body, trigger hormones, and are metabolized, and thus have a similar effect on the development of the genital tract. Donald Mattison, MD, University of Arkansas, commented that reproductive toxicity of antivirals includes impairment of fertility, birth defects, and impairment of contraception. Mattison suggested "coding" antivirals for gonadal toxicity and infertility in the same way drugs are weighted for their teratogenic risks, to indicate which drugs whould be used only as a last resort in serious illness when no other drug is available.

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