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Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment.

Desai A, Schmitt-Hoffmann AH, Mujais S, Townsend R - Antimicrob. Agents Chemother. (2016)

Bottom Line: The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 liters/h (5th and 95th percentiles: 1.3 and 1.8 liters/h) and 1.32 liters/h (5th and 95th percentiles: 1.05 and 1.35), respectively.Peripheral volume of distribution increased with body mass index.After administration of the single dose, safety data for subjects with mild and moderate hepatic impairment were generally comparable to those for healthy subjects in both studies.

View Article: PubMed Central - PubMed

Affiliation: Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA amit.desai@astellas.com.

No MeSH data available.


Related in: MedlinePlus

Goodness-of-fit plots for the best covariate model. (A) Log of predicted concentrations versus log of observed concentrations. (B) Log of individual predicted concentrations versus log of observed concentrations. (C) Plot of conditional weighted residual versus time. (D) Plot of conditional weighted residual versus log of predicted concentrations.
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Figure 1: Goodness-of-fit plots for the best covariate model. (A) Log of predicted concentrations versus log of observed concentrations. (B) Log of individual predicted concentrations versus log of observed concentrations. (C) Plot of conditional weighted residual versus time. (D) Plot of conditional weighted residual versus log of predicted concentrations.

Mentions: Following the development of the base model, covariates of interest were then added in stepwise manner using the forward-addition/backward-elimination procedure. The only covariate statistically significant for CL was the liver function index. The liver function index was also significant for Q. BMI was significant on Vp. The best model with covariates wasCL=θ1,8,9 ×exp(njCL)Q=θ3,10,11 ×exp(njQ)V3=θ4 ×[1+θ12 ×(BMI−27.00)]where θ1,8,9 are the typical values of CL for healthy subjects and those with mild and moderate hepatic impairment, respectively; θ3,10,11 are the typical Q values for healthy subjects and those with mild and moderate hepatic impairment, respectively; and nj denotes difference between the true parameter value of individual j and the typical value of CL and Q predicted for the individual. The goodness-of-fit plots, as shown in Fig. 1, showed that the model was consistent with the observed data, with no systematic and no observable covariate trends remained with the full model. Plots of the NPDE demonstrated that the normality assumption was not rejected (Fig. 2A), and plots of NPDE versus time (independent variable) and predicted concentrations did not show any trend (Fig. 2B and C). Parameter estimates are shown in Table 4.


Population Pharmacokinetics of Isavuconazole in Subjects with Mild or Moderate Hepatic Impairment.

Desai A, Schmitt-Hoffmann AH, Mujais S, Townsend R - Antimicrob. Agents Chemother. (2016)

Goodness-of-fit plots for the best covariate model. (A) Log of predicted concentrations versus log of observed concentrations. (B) Log of individual predicted concentrations versus log of observed concentrations. (C) Plot of conditional weighted residual versus time. (D) Plot of conditional weighted residual versus log of predicted concentrations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4862513&req=5

Figure 1: Goodness-of-fit plots for the best covariate model. (A) Log of predicted concentrations versus log of observed concentrations. (B) Log of individual predicted concentrations versus log of observed concentrations. (C) Plot of conditional weighted residual versus time. (D) Plot of conditional weighted residual versus log of predicted concentrations.
Mentions: Following the development of the base model, covariates of interest were then added in stepwise manner using the forward-addition/backward-elimination procedure. The only covariate statistically significant for CL was the liver function index. The liver function index was also significant for Q. BMI was significant on Vp. The best model with covariates wasCL=θ1,8,9 ×exp(njCL)Q=θ3,10,11 ×exp(njQ)V3=θ4 ×[1+θ12 ×(BMI−27.00)]where θ1,8,9 are the typical values of CL for healthy subjects and those with mild and moderate hepatic impairment, respectively; θ3,10,11 are the typical Q values for healthy subjects and those with mild and moderate hepatic impairment, respectively; and nj denotes difference between the true parameter value of individual j and the typical value of CL and Q predicted for the individual. The goodness-of-fit plots, as shown in Fig. 1, showed that the model was consistent with the observed data, with no systematic and no observable covariate trends remained with the full model. Plots of the NPDE demonstrated that the normality assumption was not rejected (Fig. 2A), and plots of NPDE versus time (independent variable) and predicted concentrations did not show any trend (Fig. 2B and C). Parameter estimates are shown in Table 4.

Bottom Line: The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 liters/h (5th and 95th percentiles: 1.3 and 1.8 liters/h) and 1.32 liters/h (5th and 95th percentiles: 1.05 and 1.35), respectively.Peripheral volume of distribution increased with body mass index.After administration of the single dose, safety data for subjects with mild and moderate hepatic impairment were generally comparable to those for healthy subjects in both studies.

View Article: PubMed Central - PubMed

Affiliation: Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA amit.desai@astellas.com.

No MeSH data available.


Related in: MedlinePlus