Based on the 17 studies uniquely identified in this investigation

Based on the 17 studies uniquely identified in this investigation, 23 data points were derived for the analysis of

the relative bioavailability between CR and IR formulations, 8 of which were directly given in the reports whilst the rest were calculated from the information given in the reports. The detailed information in terms of AUC ratios, 90% confidence intervals and their references are shown in Table S2 of the Supplementary Material. The simulated parameters and their ranges are summarized in Table 2. Solubility varied from 10−5 to 104 mg/mL as derived from Eq. (2). The range of solubility values was truncated to a minimum of 0.001 mg/mL and a maximum of 100 mg/mL in order to improve the computational

performance of the simulations. Human Peff ranged from 0.04 to 10 × 10−4 cm/s. Calculated Papp,Caco-2 values (Eq. (3)) varied find more from 0.01 to 80 × 10−6 cm/s, covering the range from low to highly permeable compounds ( Lennernas, 2007). The Vmax,CYP3A4 and Km,CYP3A4 range varied from 1 to 10,000 pmol/min/mg microsomal protein and 1–10,000 μM, respectively. Jmax,P-gp and Km,P-gp ranges were 1–1500 pmol/min and 1–2,000 μM, respectively. The values that defined the limits for high and low solubility were 10 mg/mL (Dn = 1.2) and 1.0 mg/mL (Dn = 0.12), respectively. Likewise, the value for high permeability was 5 × 10−6 cm/s (fa ≈ 0.89) DAPT chemical structure whereas for low permeability, the value was 0.5 × 10−6 cm/s (fa ≈ 0.34). For both solubility and permeability, the selected cut-off values coincided with the 25th and 50th percentile of their selected range (values 2 and 3 in Fig. 1). In general, a reduction in release rate, i.e., changing from an IR formulation to a CR formulation, was associated with a decrease in AUC for a majority of the CYP3A4 substrates (Figs. 3A and S1A–S3A). However, in certain cases, the AUC either remained constant as compared to the IR formulation or increased when the CR formulations were Libraries employed; dependent on both BCS class and CLint,CYP3A4. When Vmax,CYP3A4 was kept fixed (scenarios Ia and IIa in Table 1), Cediranib (AZD2171) the increase in exposure was only observed

for BCS class 1 CYP3A4 substrates with CLint,CYP3A4 values equal to or greater than 250 μL/min/mg ( Figs. 3A and S1A). A similar situation was observed when Km,CYP3A4 was fixed to the ‘medium’ value (scenario Ib in Table 1) though the CLint,CYP3A4 necessary to observe a similar change in exposure was reduced to 50 μL/min/mg (Fig. S2). The use of a low Km,CYP3A4 in scenario IIb, i.e., high affinity for CYP3A4, resulted in a similar outcome. However, the AUC also remained constant for CR formulations of highly cleared (CLint,CYP3A4 ⩾ 2500 μL/min/mg) BCS classes 2 and 3 drugs ( Fig. S3A). For scenarios Ia-IIb the BCS classification had an effect on fa, where fa decreased when moving from BCS class 1 to class 4. CLint,CYP3A4 had no impact on fa.

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