A THEORETICAL-ANALYSIS OF INTERVAL DRUG DOSING FOR CELL-CYCLE-PHASE-SPECIFIC DRUGS

A formal method is provided for predicting the effect on treatment efficacy of cell-cycle-phase-specific drugs, such as the AIDS drug zidovudine (AZT) or the cancer drug cytosine arabinoside (ara-C). Our analysis shows that the elimination of somatic cells or viruses depends not only on the drug's pharmacokinetic and pharmacodynamic properties, but also on the duration of the dosing interval per se and on the life-cycle parameters, that is, the duration of the drug-susceptible life phase, the duration of the whole life cycle, and the proliferation rate. The results support those of simplified models in showing that drug toxicity to the host may be minimized when the dosing interval is an integer multiple of the average cycle time of the host susceptible cells. This prediction has been verified in mice treated with AZT or ara-C.