Phase I studies

Phase I studies are human toxicology studies. Their endpoint is safety and they usually include 15-30 patients. They are designed to define a feasible dose for further studies. These studies begin at a dose that is expected to be safe in man. This dose is projected from toxicology studies in animals, most frequently rodent studies (although other species are used).

If there is no difference in the sensitivity between species, the starting dose of the study in humans is frequently 10% of the LD10 (the dose that is lethal to 10% of the animals exposed to it) in mice. Once this dose is found safe, it is escalated. Dose escalation is usually between cohorts and infrequently in individual patients. It can be:

♦ According to the Fibonnaci method (dose is escalated in decreasing percentages of the previous dose i.e. 100%, 66%, 50%, 33%, 25%).

♦ According to pharmacokinetics (Pharmacokinetically Guided Dose Escalation or PGDE), using a method that combines statistics with the experience and expectations regarding side-effects (continuous reassessment method).

♦ Variation on these methods.

The aim of the Phase I study is to describe the side-effects that limit further dose escalation (dose limiting toxicities or DLTs) and to recommend a dose for further studies with the drug or the new administration method (maximal tolerated dose or MTD). Most often the MTD is the dose level just below that that induces DLTs.

This approach assumes that there is a linear relationship between drug dose and therapeutic effect. For studies with biological agents the MTD may be different from the optimal dose due to a bell-shaped efficacy curve.

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