Table 4

Parameter estimates for the final population PK model for fusidic acid

Population meanBetween-subject variabilityBetween-occasion variability
Apparent maximum clearance without autoinhibitionCL/F70kgliters/h1.28b33.4%
Distribution clearance between the central and peripheral compartmentsCLd/F70kgliters/h0.714b56.0%
Vol of central compartmentV1/F70kgliters12.3b14.7%
Vol of peripheral compartmentV2/F70kgliters6.96b46.6%
Vol of distribution at steady stateVss/F70kgliters19.2b,c
Concn causing half-maximal autoinhibition of clearanceIC50mg/liter46.336.5%
Maximum extent of autoinhibitionImax0.710c0.530–0.821d
Imax on transformed scaleTr_Imax0.8970.338e
Hill coefficientγ4.6115% (fixed)f
Mean turnover time of inhibition compartmenttoutgh0.94095.1%
Maximum rate of drug release from stomach to intestine at time zero divided by dosehVmax(0)/doseh1/h0.554e
Fraction of fusidic acid dose associated with 50% of Vmax(0)Km/doseh0.037659.2%18.4%
Fastest half-life of gastric release, if the fraction of dose in stomach is ≪Km/doseLn(2) · Km/Vmax(0)min2.82i6.8%88.2%
Mean absorption time from the intestine to the central compartmenttabsgmin33.365.0%
Time past last dose at which Vmax(t) changed by 50%TSD50h0.509c20.5%47%
Maximum fold change in Vmax over timeEmax1.51c−0.978–8.93d
Emax on transformed scaleTr_Emax−1.091.99e1.87e
Relative extent of bioavailability with a high-fat, high-calorie breakfastFfed0.81811.4%
Ratio of Vmax(0) in fed vs fasted statecVmaxfed1.392.7%
Ratio of Km in fed vs fasted statecKmfed0.1244.3%
Ratio of TC50 in fed vs fasted statecTSD50,fed1.894.4%
Emax in fed state on untransformed scaleEmaxfed9.00c8.97–9.00d
Difference of Emax in fed vs fasted state on transformed scaledEmaxfed12.20.156e
Ratio of Vmax(0) in evening vs morningcVmaxEve0.324j
Ratio of Km in evening vs morningcKmEve1.27j
Ratio of TC50 in evening vs morningcTSD50,Eve3.02j
Emax in evening on untransformed scaleEmaxEve0.733
Difference of Emax in evening vs morning on transformed scaledEmaxEve−0.471j
SD of proportional residual errorCVCP0.143
SD of additive residual errorSDCPmg/liter0.319
  • a Relative standard errors for all variability terms could not be computed due to the complexity of the model.

  • b Estimates apply to a healthy volunteer with a total body weight of 70 kg using an allometric size model.

  • c Not an estimated parameter. Value was calculated from the other parameter estimates.

  • d Range of individual estimates.

  • e Estimate represents the standard deviation on logistically transformed scale.

  • f The between-subject variability of the Hill coefficient was fixed to a small value (15% CV) to allow estimation of the population mean using the MC-PEM algorithm.

  • g tout equals 1/kout; tabs equals 1/kabs.

  • h Dose is measured in mg of fusidic acid.

  • i We estimated the ratio of Vmax(0)/Km which represents the apparent first-order release rate constant if the fraction of drug remaining in stomach is ≪Km/dose. The half-life of this process is reported in the table since this value is easier to interpret.

  • j These differences in the absorption parameters between the morning and evening doses were estimated within the between-occasion variability model. The mean of the random deviates for the evening dose was allowed to be different from 1 for Vmax(0), Km, and TSD50 and different from 0 for Tr_Emax.