Article Figures & Data
Figures
- Fig. 1.
Chemical structures of ASV (BMS-650032), DCV (BMS-790052), BCV (BMS-791325), and BCV-M1 (major metabolite of BCV).
- Fig. 2.
Curve fitting of CYP3A4 mRNA induction data from two individual donor hepatocytes treated with BCV using the simple Emax model (A: donor 1; C: donor 2) and the four parameter logic model. (B: donor 1; D: donor 2)
- Fig. 3.
Strategies to evaluate P450 DDI risk for single and multiple perpetrators using static models.
Tables
- TABLE 1
CYP3A4 mRNA change relative to dimethylsulfoxide (DMSO) (0.1%) treatment in hepatocytes from three human donors following incubation with ASV, DCV, BCV, or BCV-M1
Drug Treatment CYP3A4 mRNAa Donor 1 Donor 2 Donor 3 ASV Donor HC3-15 HC1-18 HC5-10 DMSO (0.1%) 1 1 1 0.049 µg/ml 3.73b ND 0.802 0.15 µg/ml 1.53 1.86 1.13 0.49 µg/ml 4.72 3.58 1.77 1 µg/ml 7.79 5.5 2.92 2 µg/ml 8.6 ND 3.66 4.9 µg/ml 12.1 6.7 4.3 10 µg/ml 8.7c 4.73c 3.7 20 µg/ml 4.95c 2.39c 1.74c Rifampin (10 µM) 26 18.1 8.15 DCV Donor HC3-15 HC1-18 HC5-10 DMSO (0.1%) 1 1 1 0.16 µg/ml 1.38 1.45 1.21 0.32 µg/ml 1.44 1.66 1.34 0.75 µg/ml 2.5 2.27 1.47 1.6 µg/ml 5.59 5.7 4.91 2.5 µg/ml 7.48 9.22 3.7 4 µg/ml 12.8 12.1 6.35 6 µg/ml 20.3 13.2 6.68 9.6 µg/ml 27.3 13 8.76 Rifampin (10 µM) 26 18.1 8.15 BCV Donor HC3-15 HC3-17 HC5-10 DMSO (0.1%) 1.00 1.00 1.00 0.15 µg/ml 1.96 1.45 1.90 0.35 µg/ml 3.27 1.99 1.67 0.8 µg/ml 5.64 2.59 2.67 1.5 µg/ml 6.36 2.61 2.43 3.5 µg/ml 5.77 2.18 2.64 8 µg/ml 3.88c 2.09 2.45 15 µg/ml 2.70c 1.38c 1.43c 30 µg/ml 0.29c 0.08c 0.26c Rifampin (10 µM) 29.80 3.70 7.93 BCV-M1 Donor HC3-15 HC3-17 HC5-10 DMSO (0.1%) 1.00 1.00 1.00 0.028 µg/ml 1.04 1.15 0.97 0.08 µg/ml 1.63 1.26 1.05 0.28 µg/ml 3.57 1.99 1.61 0.8 µg/ml 7.17 2.49 2.22 2.8 µg/ml 8.23 2.26 2.41 8 µg/ml 5.24c 2.14 1.89c 15 µg/ml 3.78c 1.87c 3.08 30 µg/ml 0.32c 0.15c 0.14c Rifampin (10 µM) 29.80 3.70 7.93 ND, not determined due to sample analysis error.
↵a Values are relative to vehicle control, normalized to glyceraldehyde 3-phosphate dehydrogenase and are the average of triplicate determinations.
↵b Anomalous data, possibly due to sample analysis error. Data were excluded from the curve fitting.
↵c Data were excluded from the curve fitting because fold increase was <80% of the observed Emaxvalue.
- TABLE 2
Induction kinetic parameters (Emax and EC50) of ASV, DCV, BCV, and BCV-M1 following incubation with hepatocytes from three individual donors
Drug Parameter Fold Induction Fold Increase HC3-15 HC1-18/HC3-17a HC5-10 HC3-15 HC1-18/HC3-17a HC5-10 ASV Emax 14.21 6.74 3.94 14.10 6.68 3.00 EC50 (µg/ml) 1.00 0.61 0.58 1.38 0.68 0.78 DCV Emax 28.24 13.05 8.27 45.30 11.90 12.80 EC50 (µg/ml) 4.32 1.83 2.38 7.64 1.96 6.54 BCV Emax 6.54 2.36 2.44 6.17 2.23 1.64 EC50 (µg/ml) 0.20 0.03 0.02 0.46 0.45 0.19 BCV-M1 Emax 9.68 2.30 2.74 9.13 1.55 1.62 EC50 (µg/ml) 0.39 0.02 0.21 0.58 0.19 0.47 ↵a Induction of ASV and DCV was evaluated using lot HC1-18 hepatocytes; induction of BCV and BCV-M1 was evaluated using lot HC3-17 hepatocytes.
- TABLE 3
In vitro kinetic parameters of ASV, DCV, BCV, and BCV-M1 interaction with human CYP3A4
Drug Reverse inhibition, Ki,u TDI Induction Kinact KI,u Emax EC50 µg/ml 1/min µg/ml µg/ml ASV 2.72 0.032 1.035 7.93 0.95 DCV 1.91 ND ND 23.33 5.38 BCV 2.62 ND ND 3.35 0.37 BCV-M1 1.95 ND ND 4.10 0.41 ND, not determined
Perpetrator Drug Midazolam Oral Dose Reference Drug Oral Dose Cmax fu ka Fa mg µg/ml min−1 mg ASV (twice a day) 200 0.351 0.002 0.0063a 1b 5 Eley et al. (2011) ASV (twice a day) 600 0.632 0.002 0.0053a 1b 5 Unpublished datac DCV (every day) 60 1.288 0.006 0.013a 0.71 5 Bifano et al. (2013) BCV (twice a day) 150 1.835d/0.434e 0.012d,e 0.0067a,d 0.72d 5 AbuTarif et al. (2014) BCV (twice a day) 300 3.875d/0.944e 0.012d,e 0.0067a,d 0.72d 5 AbuTarif et al. (2014) Triple I ASV (twice a day) 200 0.492 0.002 0.0063f 1 5 Tao et al. (2016)g DCV (twice a day) 30 0.975 0.006 0.013f 0.71 BCV (twice a day) 75 1.675d/0.350e 0.012d,e 0.0067d,f 0.72d Triple II ASV (twice a day) 200 0.473 0.002 0.0063f 1 5 Tao et al. (2016)g DCV (twice a day) 30 0.974 0.006 0.013f 0.71 BCV (twice a day) 150 3.141d/0.664e 0.012d,e 0.0067d,f 0.72d ↵a Determined based on plasma concentration profile from the same study.
↵b The Fh value of ASV is calculated to be 7%, which is lower than the oral bioavailability of ASV (9.3%), suggesting ASV oral absorption is high in humans. Thus, the Fa value of ASV is set as 1.
↵c Data from an open-label, single-sequence study (AI447007), in which 18 healthy subjects (17 male and one female) received: 1) a single oral dose of 5 mg midazolam on day 1; 2) an oral dose of 600 mg ASV twice daily from day 2 to day 8; and 3) a single dose of 5 mg midazolam on day 8 (morning). The study protocol was approved by the Institutional Review Board at the investigational site (MDS Pharma Services (US) Inc., Lincoln, NE). All subjects were closely monitored for adverse events throughout the study.
↵d Values for BCV.
↵e Values for BCV-M1.
↵f Determined based on plasma concentration profile from the single agent studies.
↵g Data from an open-label, single-sequence study (AI443021), in which 20 healthy subjects (19 male and one female) received the following: 1) a cocktail of P450 and transporter probe substrates (including 5 mg midazolam) administered orally as a single dose on day 1; 2) a combination of 200 mg ASV, 20 mg DCV, and 75 mg BCV administered orally twice daily from day 6 to 20 and a cocktail of P450 and P-glycoprotein substrates (including 5 mg midazolam) administered orally as a single dose on day 16; and 3) a combination of 200 mg ASV, 20 mg DCV, and 150 mg BCV administered orally twice daily from day 21 to 35 and a cocktail of P450 and transporter probe substrates (including 5 mg midazolam) administered orally as a single dose on day 31. The study protocol was approved by the Institutional Review Board at the investigational site (IntegReview, LTD, Austin, TX). All subjects were closely monitored for adverse events throughout the study.
Perpetrator Drug Observed AUCR (90% CI) Predicted AUCR R3 Averagea (Individualb) AUCR Averagea (Individualb) AUCR′c Averagea (Individualb) ASV (200 mg twice a day) 0.71 (0.67–0.75) 0.32 (0.26; 0.31; 0.52) 2.36 (2.29; 2.37; 2.46) 0.50 (0.35; 0.54; 0.83) ASV (600 mg twice a day) 0.56 (0.50–0.64) 0.24 (0.18; 0.24; 0.43) 3.02 (2.94; 3.01; 3.16) 0.70 (0.51; 0.75; 1.09) DCV (60 mg every day) 0.87 (0.83–0.92) 0.18 (0.13; 0.17; 0.32) 0.43 (0.33; 0.44; 0.68) —g BCV (150 mg twice a day) 0.50 (0.45–0.57) 0.17 (0.10; 0.26; 0.31) 0.53 (0.34; 0.70; 0.72) —g BCV (300 mg twice a day) 0.44 (0.40–0.48) 0.14 (0.08; 0.23; 0.27) 0.55 (0.34; 0.75; 0.77) —g Triple Combination Id 0.53 (0.47–0.60) 0.084 (0.06; 0.17) 1.94 (1.70; 2.12) 0.33 (0.21; 0.59) Triple Combination IIe 0.42 (0.37–0.48) 0.078 (0.05; 0.16) 1.73 (1.45; 1.94) 0.32 (0.19; 0.58) CI, confidence interval.
↵a Model prediction using the average values of EC50 and Emax from Table 3.
↵b Model prediction using the EC50 and Emax of individual donors from Table 2.
↵c Mechanistic static model approach not including the TDI effect of ASV.
↵d ASV (200 mg twice a day); DCV (30 mg twice a day); and BCV (75 mg twice a day).
↵e ASV (200 mg twice a day); DCV (30 mg twice a day); and BCV (150 mg twice a day).
↵g Study did not involve ASV, thus AUCR' value is not applicable.
Data Supplement
Files in this Data Supplement:
- Supplemental Data -
Methods
Supplement Figure 1 - Inhibition of CYP3A4 catalyzed midazolam 1'-hydroxylation by HCV compounds
Supplement Figure 2 - Time dependent inhibition of CYP3A4 catalyzed midazolam 1'-hydroxylation by ASV (each point represents mean of triplicate, error bar represents standard deviation)
Supplement Table 1 - Kinetic parameters of CYP3A4 inhibition and TDI by ASV, DCV, BCV and BCV-M1 in human liver microsomes
Supplement Table 2 - Fitting outcomes for the CYP3A4 induction data
- Supplemental Data -
In this issue
Predicting DDI Risk for Hepatitis C Virus Drug Combination
