Selection of Dose

Current recommendations for dose selection for safety testing are based on those demonstrated in efficacy models to provide gene transfer sufficient for pharmacologic effect, as well as inclusion of doses with a likelihood of demonstrating toxicity. Dose selection should be based on preliminary activity data from studies both in vitro and in vivo. For the determination of safety, a no-observable adverse effect level dose (NOAEL), an overtly toxic dose, and several intermediate doses should be evaluated, to determine not only the dose relationship of the toxicities to the amount of vector administered and/or transgene expression, but also to evaluate the shape and steepness of the dose-response curve. Preclinical safety studies should include one dose equivalent to, and at least one dose escalation level exceeding, those proposed for the clinical trial. The multiples of the human dose required to determine adequate safety margins may vary with each class of vector employed and the relevance of the animal model to humans.

Allometric scaling of doses based on either body weight or total body surface area as appropriate facilitates comparisons across species and allows determination (retrospectively) of whether an animal model was predictive of toxicities observed in the clinic. For example, adenoviral vectors used in cystic fibrosis demonstrated very similar toxicities after direct instillation into the lungs of Cotton rats, mice, hamsters, Rhesus monkeys, and baboons (Table V). These toxicities included dose-related, perivascular, and peribronchiolar inflammation, mononuclear inflammatory cell infiltrates, pulmonary edema, and interstitial pneumonia. When the NOAEL doses were calculated for each species after scaling by total body surface area, with the exception of Rhesus monkeys, it was discovered that these values were remarkably similar between the different species. Additionally, when scaled by total body surface area, the NOAEL doses in mice, Cotton rats, hamsters, and baboons for direct instillation of adenovirus into the lungs were approximately equivalent to the human dose of 2 x 109 IU, or 1.2 x 109 IU/m2, which was the first dose in humans at which toxicity was observed, when scaled by body surface areas.

Table V

Allometric Scaling of Adenovirus Dose in Animals and Man

Species Apparent NOAEL NOAEL (pfu/m2 surface area)

Table V

Allometric Scaling of Adenovirus Dose in Animals and Man

Species Apparent NOAEL NOAEL (pfu/m2 surface area)

C57B1/6 mouse

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