Overcoming Severe Systemic Side Effects Pharmacokinetic Advantage

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The severe systemic side-effects experienced by patients during lung cancer chemotherapy have the dual disadvantage of limiting the effectiveness of therapeutic regimens while significantly decreasing the patient's quality of life (16,17). During therapy, the delicate balance between patient tolerability and effectiveness of intravenously infused chemotherapy must be rigorously maintained, and any deviations can result in sub-optimal treatment. As a means of overcoming this obstacle, it would be highly desirable to deliver significant increases in local concentrations while minimizing, if not circumventing entirely, exposure to the systemic circulation.

Direct aerosol administration possesses the capabilities necessary to achieve this goal and is corroborated by clinical studies that have been recently performed. The rationale for such an approach to lung cancer treatment is succinctly described by a variable termed pharmacokinetic advantage, or Rd. This variable has previously been described to elucidate the principle of regional therapy (18,19). For example, in inhaled drug delivery Rd can be defined (for drugs with linear pharmacokinetics) by the following equation:

inhalation where the numerator and denominators in this equation represent the ratios of the areas under the curves (AUCs) in lung and plasma with inhalational and IV administrations, respectively. Using this model, Sharma et al. estimated Rd for a drug with a relatively low LogP (0.46), revealing an advantage of approximately 24 for the inhalational delivery of this compound (20). Essentially this indicates a 24-fold improvement in regional targeting, unambiguously demonstrating the potential for controlled release of chemotherapy in the lung, and indicating the likelihood of achieving Rd values greater than 24.

The pharmacokinetic advantage of inhaled chemotherapy is assisted not only by the direct deposition of drug in the tumor region, but also through the avoidance of hepatic metabolism, a critical drug delivery advantage that is especially important for drugs with high hepatic metabolism and/or toxic effects on the liver. Moreover, because of the specific targeting to the lung, the potential for increased exposure times and dosing frequency will, as discussed below, become mechanistically and therapeutically important.

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