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298 Drusanolinear function. Finally (Fig. 4), the amount of intracellular drug is related to thedecrement of p24 output, as indexed through an inhibitory sigmoid-E max model. Itis clear through this series of experiments that only the free-drug concentration caninduce a decrease in viral production.These data make it clear that it is important to interpret drug concentrationsin the hollow fiber system as representing the external free-drug concentrationsnecessary to induce the desired antiviral effect.The most obvious place to initiate evaluation of anti-HIV agents is with thenucleoside analogs and with the HIV-1 protease inhibitors. The first published hollowfiber evaluation of an antiviral was the nucleoside analog stavudine (d4T). Bilelloet al. (7) examined issues of dose finding and schedule dependency for this drug.It is important to examine the development of stavudine in order to place itsevaluation in the hollow fiber system in the proper perspective. The initial clinicalevaluation of stavudine was initiated at a total daily dose of 2 mg/kg/day. Theinitial schedule chosen was every eight hours. Whereas the initial dose had aneffect, dose escalation to 12 mg/kg/day produced no change in effect but muchhigher rates of drug-related neuropathy (8).After this, the dose was deescalated to 4 mg/kg/day and the schedule waslengthened to every 12 hours. Further dose de-escalation was taken from thispoint on a 12-hour schedule, and nine dosing cohorts were eventually examined.This process took approximately two years.The hollow fiber evaluation took approximately three months. The identifieddose was ultimately the dose chosen by the phase I/II trial and has stood the testof time and usage. It is, at least to our knowledge, the first prospective identificationof a drug dose and schedule from an in vitro test system with clinicalvalidation. The outcome of the experiments is illustrated in Figure 5. This evaluationmakes clear that for nucleoside analogs, the pharmacodynamically linkedvariable is area under the plasma concentration–time curve (AUC)/EC-90. Withmatching AUCs (Fig. 5), there was no difference in outcome between the exposurebeing given in a continuous infusion mode and half the exposure every 12 hours(data not shown). The reason is likely the phosphorylation of the parent compoundinto the virologically active form of the molecule (the triphosphate for15001200r 2 = 1.001.5 mg/ml AGPp24 pg per ml9006003001 mg/ml0.5 mg/mlNo AGP0 0 250 500 750 1000Intracellular A-80987 (CPM)1250 1500FIGURE 4 Relationship (inhibitory sigmoid E max ) between intracellular A-80987 and HIV viraloutput from infected peripheral blood mononuclear cells (PBMCs).