Mechanism-Based Pharmacokinetic-Pharmacodynamic Models of In Vitro Fungistatic and Fungicidal Effects against Candida albicans

DOI: 10.1128/AAC.01030-07

Article Figures & Data

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FIG. 1.
Weighted residuals versus time for the fungistatic (A) and fungicidal (B) models. Included are horizontal lines at 0.
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FIG. 2.
Goodness-of-fit plots of individual observed CFU·ml⁻¹ versus model-predicted CFU·ml⁻¹ for the fungistatic (A) and fungicidal (B) models. Included are lines of identity. Arrows indicate beginning inoculum values.
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FIG. 3.
Plots showing CFU·ml⁻¹ of fungi over time for the fungistatic (A) and fungicidal (B) models. Each graph represents one experiment. Symbols for fungistatic experiments shown in panel A: control, □; C₀ = 100 μg·ml⁻¹, ▴; C₀ = 10 μg·ml⁻¹, ▪; C₀ = 1 μg·ml⁻¹, •; C₀ = 0.1 μg·ml⁻¹, ⧫; C₀ = 0.01 μg·ml⁻¹, *. Symbols for fungicidal experiments shown in panel B: control, □; C₀ = 10 μg·ml⁻¹, ▴; C₀ = 1 μg·ml⁻¹, •; C₀ = 0.1 μg·ml⁻¹, ▪; C₀ = 0.01 μg·ml⁻¹, ⧫; C₀ = 0.001 μg·ml⁻¹, *. Lines represent individual predictions based on the developed PK-PD models.

TABLE 2.

Parameter estimates of PK-PD models with typical values

Parameter^a	Typical value	SE^b
Candida specific
K_g (h⁻¹)	8.64 × 10⁻¹	3.21 × 10⁻²
K_d (h⁻¹)	4.14 × 10⁻²	2.45 × 10⁻²
N_max (CFU·ml⁻¹)	1.48 × 10⁶	5.54 × 10⁵
Fluconazole PK-PD
IC₅₀ (μg·ml⁻¹)	9.29 × 10⁻²	5.67 × 10⁻²
I_max	6.75 × 10⁻¹	3.42 × 10⁻²
Caspofungin PK-PD
EC₅₀ (μg·ml⁻¹)	2.51 × 10⁻⁴	4.62 × 10⁻⁵
E_max (h⁻¹)	8.04 × 10⁻¹	5.11 × 10⁻²
Interindividual variability (% CV)
η (N_max)	225	218
η (E_max)	65	56
Residual variability (% CV)
ε₁ Fluconazole	197	199
ε₁ Caspofungin	96	63