Journal: Drug Metabolism and Disposition

Article Title: Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

doi: 10.1124/dmd.120.000318

Figure Lengend Snippet: Final PBPK model parameters for solithromycin, ketoconazole, and midazolam

Article Snippet: 3 where [S] is solithromycin concentration ( http://www.graphpad.com/guides/prism/7/statistics/index.htm ).

Techniques: Molecular Weight, Solubility, Permeability

Journal: Drug Metabolism and Disposition

Article Title: Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

doi: 10.1124/dmd.120.000318

Figure Lengend Snippet: Population simulations depicting solithromycin concentration (mg/L) versus time in hours (hr) after first dose after solithromycin intravenous administration in healthy adults. Population simulations were performed for 100 virtual subjects using a Black American population with demographics from study CE01-102 for healthy subjects: 27% female with a mean (range) age of 32.9 (20–55) years and a weight of 74.5 (61.4–90.3) kg. (A) 400 mg intravenously daily × 7 days administered over a 60-minute infusion; (B) 800 mg intravenous single dose administered over a 40-minute infusion. The solid gray region is the 90% prediction interval, the solid black line is the simulated geometric mean, and black dots are observed data from subject. The AFE was calculated as 10(1n)*Σlog(predictedobserved), where the predicted values were the simulated geometric mean values and n was the sample size. The AFE was 1.0 and 0.7 for the 400 mg intravenous and 800 mg intravenous plots, respectively.

Article Snippet: 3 where [S] is solithromycin concentration ( http://www.graphpad.com/guides/prism/7/statistics/index.htm ).

Techniques: Concentration Assay

Journal: Drug Metabolism and Disposition

Article Title: Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

doi: 10.1124/dmd.120.000318

Figure Lengend Snippet: Comparison of C max and AUC 0- τ in adults for solithromycin between observed data and PBPK model simulations. Data are presented as the mean ± S.D. Overall, 50%, 60%, and 85% of simulated C max or AUC values were within 1.33-, 1.5-, and 2.0-fold of the observed values reported in adults.

Article Snippet: 3 where [S] is solithromycin concentration ( http://www.graphpad.com/guides/prism/7/statistics/index.htm ).

Techniques:

Journal: Drug Metabolism and Disposition

Article Title: Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

doi: 10.1124/dmd.120.000318

Figure Lengend Snippet: Comparison of adult DDI simulations and observed data for solithromycin plus midazolam or ketoconazole.

Article Snippet: 3 where [S] is solithromycin concentration ( http://www.graphpad.com/guides/prism/7/statistics/index.htm ).

Techniques:

Journal: Drug Metabolism and Disposition

Article Title: Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

doi: 10.1124/dmd.120.000318

Figure Lengend Snippet: Population simulations for solithromycin depicting concentration versus time in hours (hr) after the first dose of solithromycin intravenous administration in pediatric patients. Pediatric population simulations for 100 virtual White American subjects from 4 days to 17.9 years of age receiving 1 mg/kg intravenous solithromycin. The solid gray region is the 90% prediction interval, the solid black line is the simulated arithmetic mean line, and the black dots are observed data from pediatric subjects. Solithromycin plasma concentration data were normalized by dose and time relative to the last drug administration since dose and administration differed slightly for each individual.

Article Snippet: 3 where [S] is solithromycin concentration ( http://www.graphpad.com/guides/prism/7/statistics/index.htm ).

Techniques: Concentration Assay

Journal: Drug Metabolism and Disposition

Article Title: Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

doi: 10.1124/dmd.120.000318

Figure Lengend Snippet: Population simulations depicting concentration versus time in hours (hr) after the first dose of solithromycin oral administration (capsules or suspension) in pediatric patients. (A) Population simulations for 100 White American virtual infants and children from 4 days to 12 years of age receiving 1 mg/kg oral solithromycin as a suspension. (B) Population simulations for 100 White American virtual children and adolescents from 6 to 17 years of age receiving 1 mg/kg oral solithromycin as a capsule. The solid gray region is the 90% prediction interval, the solid black line is the simulated arithmetic mean, and the black dots are observed data from pediatric subjects. Solithromycin plasma concentration data were normalized by dose and time relative to the last drug administration since dose and administration differed for each individual.

Article Snippet: 3 where [S] is solithromycin concentration ( http://www.graphpad.com/guides/prism/7/statistics/index.htm ).

Techniques: Concentration Assay

Journal: Drug Metabolism and Disposition

Article Title: Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

doi: 10.1124/dmd.120.000318

Figure Lengend Snippet: Simulated solithromycin and ketoconazole daily steady-state area under the concentration versus time curve from 0 to 24 hours (AUC0-24,ss) stratified by age group. Dosing was simulated in 500 virtual individuals between the ages of 1 and <6 months, 0.5 to <2 years, 2 to <6 years, 6 to <12 years, 12 to <18 years, and 18 to 65 years. The boxplots display the median (interquartile range), the upper whiskers are the 75th percentile to 1.5 times the interquartile range, the lower whisker is the 25th percentile subtract 1.5 times the interquartile range, and observations outside the whiskers are represented as black dots. (A) The simulated solithromycin daily AUC0-24,ss based on the age- and weight-based intravenous solithromycin dosing for 5 days as presented in Table 5. The red dot is the arithmetic mean for each age group. The black horizontal line refers to the mean daily AUC0-24,ss value observed in healthy adults whom received 400 mg intravenously for 7 days, in which the reported mean ± S.D. was 13 ± 4.38 mg*h/L (sponsor data on file). (B) The simulated ketoconazole daily AUC0-24,ss based on the age- and weight-based oral ketoconazole dosing for 5 days as presented in Table 5.

Article Snippet: 3 where [S] is solithromycin concentration ( http://www.graphpad.com/guides/prism/7/statistics/index.htm ).

Techniques: Concentration Assay, Whisker Assay

Journal: Drug Metabolism and Disposition

Article Title: Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

doi: 10.1124/dmd.120.000318

Figure Lengend Snippet: Forest plots of the geometric mean fold ratios for the simulated AUC of midazolam with and without solithromycin and of solithromycin with and without ketoconazole, stratified by age groups. Dosing was simulated in 500 virtual individuals in each age category (1 to <6 months, 0.5 to <2 years, 2 to <6 years, 6 to <12 years, 12 to <18 years, and 18 to 65 years) according to the age- and weight-based dosing presented in Table 5. The vertical blue line corresponds to a ratio of 1.00 and the dotted vertical lines refer to the equivalence range of 0.80 to 1.25. (A) Virtual individuals received a single intravenous dose of midazolam alone and on the last date after 5 days of daily solithromycin intravenous dosing. The geometric mean ratio and 90% confidence interval of the AUC0-∞ was calculated for a group of virtual individuals receiving midazolam plus solithromycin relative to a group of virtual individuals receiving midazolam alone. (B) Virtual individuals received 5 days of solithromycin intravenous dosing alone as well as in combination with 5 days of oral ketoconazole dosing. The geometric mean ratio and 90% confidence interval of the AUC0-24,ss was calculated for the group of patients receiving solithromycin plus ketoconazole relative to a group receiving of virtual individuals solithromycin alone.

Article Snippet: 3 where [S] is solithromycin concentration ( http://www.graphpad.com/guides/prism/7/statistics/index.htm ).

Techniques:

Journal: Drug Metabolism and Disposition

Article Title: Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population

doi: 10.1124/dmd.120.000318

Figure Lengend Snippet: Simulated dosing and DDI potential stratified by age group for solithromycin in combination with midazolam and ketoconazole.

Article Snippet: 3 where [S] is solithromycin concentration ( http://www.graphpad.com/guides/prism/7/statistics/index.htm ).

Techniques: