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Human Pharmacodynamics of Anti-infectives 425TABLE 1 Precision (%) of Kinetic Parameters of Theophylline as Determined from DifferentOptimal Sampling Strategies Relative to Those Determined from the Full Sampling Strategy a– V c V SS V area S cl T 1/2*Correct7 2.20 1.26 1.30 2.97 2.99Wrong7 1.66 1.01 1.04 3.56 3.98Patient's7 2.28 1.34 1.30 2.98 3.66Patient's4 2.60 2.20 2.28 2.99 3.77a Correct7 represents the seven sample times derived from the “correct” prior population. Wrong7 represents theseven sample times derived from the “wrong” prior population. Patient's7 and Patient's4 represent the seven andfour sample times derived from the patient's own prior parameter values.levofloxacin dose would be required for robust activity with the new target valueand with the changed MIC distribution. This has been demonstrated in clinicaltrials of levofloxacin in community-acquired pneumonia (22,28,29).It is also possible to examine schedule with this technique. Drusano et al.(30) examined the combination of abacavir plus amprenavir for HIV. The interactionof the two agents was quantitated in the presence of human binding proteinsin vitro using the Greco interaction equation (31). Population pharmacokineticmodels were then derived from clinical trial data for both drugs. Monte Carlosimulations were derived of the effect-time curves for 500 subjects. In the simulations,doses of 300 mg of abacavir every 12 hours (q12h) plus 800 mg of amprenavirevery eight hours (q8h) were simulated, as well as doses of abacavir 300 mgevery 12 hours plus 1200 mg of amprenavir every 12 hours. In Figure 9A and B,the mean concentration-time profiles are shown for the various simulations for 500subjects. Figure 9C and D show one subject selected from the population. Figure 9Eand F show the effect versus time curves derived from that specific patient at steadystate for the different schedules of administration.The effect-time curves can be integrated over a 24-hour steady-state intervaland divided by the interval length (24 hours). An average percent of maximaleffect results from the calculation. These are plotted in Figure 10 for the twoschedules of administration for all 500 simulated subjects.It is obvious from inspection that the schedule of administration that is morefractionated for the protease inhibitor (amprenavir q8h) is providing greatereffects. This can clearly be seen in the frequency histograms presented in Figure 11.Irrespective of how one tests the differences between regimes (frequency > 90%maximal effect, frequency > 70% maximal effect, difference between mean percentmaximal effects), the more fractionated regimen is always statistically significantlysuperior.TABLE 2 Levofloxacin 10,000-Subject Monte Carlo Simulation: Target Attainment Over a 4296Isolate Database of Streptococcus pneumoniaeTarget 1 Log drop (34.5 AUC/MIC ratio) Stasis (27 AUC/MIC ratio)Attainment 94.7 97.8Target Attainment for a fAUC/MIC ¼ 30500 mg Levofloxacin 750 mg Levofloxacin86.7% 95.6%Abbreviations: AUC, area under the plasma concentration–time curve; MIC, minimal inhibitory concentration.Source: PK parameters, from Ref. 26; Isolate MICs from the 1998–1999 TRUST study; target-attainment datafrom Craig WA. Personal communication; Ambrose target from Ref. 27.