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Modeling of Toxicities Due to Antibiotics 455FIGURE 4 Two-compartment model used to fit linezolid oral and i.v. data. Abbreviations: Vc,volume of distribution of the central compartment; Ka, absorption rate constant; T lag , lag timebefore onset of absorption; CLd, distributional clearance; K m , Michaelis–Menten constant; CLi,intrinsic clearance; F, oral bioavailability; CL ratio*Clcr, renal clearance as a function of creatinineclearance.indexed to AUC 0–24 . To emphasize this point, we present Figure 5 the data andpredicted concentration–time curves from two patients in this database.Clearly, both efficacy and toxicity would be expected to be different forpatients with such differences in concentration–time profiles.A25B25Linezolid concentration (mg/liter)2015105Linezolid concentration (mg/liter)20151050 00 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7Days of treatmentDays of treatmentFIGURE 5 Fitted functions in two study patients. Solid circles represent the observed concentrationsand the solid line represents the fitted function for two illustrative patients in the population.The dashed lines represent the average concentration during the first seven days of treatment. (A)Patient PK parameters typical of those found in this study (CL i ¼ 36.6 L/hr/65 kg; K m ¼ 1.8 mg/L;CL ratio 0.38; Cl cr ¼ 82 mL/min; IBW ¼ 75.3 kg). (B) Patient PK parameters similar to those found inhealthy volunteers (CL i ¼ 21.3 L/hr/65 kg; K m ¼ 1.2 mg/L; CL ratio ¼ 0.33; Cl cr ¼ 62 mL/min; IBW ¼70.0 kg). Abbreviations: CLi, intrinsic clearance; K m , Michaelis–Menten constant; IBW, ideal bodyweight.