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Update Qualification Report for DDI_Qualification_CYP3A4#245

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Update Qualification Report for DDI_Qualification_CYP3A4#245
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test-13.0.8-Qualification-DDI-CYP3A4

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@osp-reports-creator osp-reports-creator commented Jul 14, 2026 •
edited by coderabbitai Bot
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Tools

Tool Version Url
R 4.5.2 NA
ospsuite-R v13 NA
Reporting Engine 2.4.7 NA
RUtils 1.11.1 NA
TLF 1.6.2 NA
rClr NA NA
rSharp V13 NA
Qualification Runner 13.0.3 https://github.com/Yuri05/Test20/releases/download/Test13_01/QualificationRunner-13.0.3.zip
Qualification Framework 3.7 NA
PK-Sim 13.0.8 https://github.com/Yuri05/Test20/releases/download/Test13_01/PKSimPortable_13.0.8.zip

Qualification plans

Execute Repository name Released version Workflow name Folder name
true Qualification-DDI-CYP1A2 2.0 DDI_Qualification_CYP1A2
true Qualification-DDI-CYP2C19 2.0 DDI_Qualification_CYP2C19
true Qualification-DDI-CYP3A4 2.2 DDI_Qualification_CYP3A4
true Qualification-DDI-P-gp 1.2 DDI_Qualification_P-gp
true Qualification-DDI-UGT 2.0 DDI_Qualification_UGT
true Pediatric_Qualification_Package_CYP2C8_Ontogeny 2.0 Pediatric_Qualification_Package_CYP2C8_Ontogeny
true Pediatric_Qualification_Package_CYP3A4_Ontogeny 2.0 Pediatric_Qualification_Package_CYP3A4_Ontogeny
true Pediatric_Qualification_Package_GFR_Ontogeny 2.0 Pediatric_Qualification_Package_GFR_Ontogeny
true Qualification-CKD 1.1 Qualification-CKD
true Pediatric_Qualification_Package_P-gp_Ontogeny 1.0 Pediatric_P-gp

Summary by CodeRabbit

  • Documentation
    • Updated the CYP3A4 DDI qualification report metadata.
    • Revised qualification results, including predicted-to-observed ratios, acceptance statistics, and study-level findings across the report’s summary and breakdown tables.

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DDI_Qualification_CYP3A4/images/037_section_qualification-cyp3a4-ddi/DDIRatio_1_victim_Alfentanil_ddi_ratio_plot_CMAX_residualsVsObserved.png 0.9995
DDI_Qualification_CYP3A4/images/038_section_ct-profiles/066_section_rifampicin-alfentanil-ddi/comparison_time_profile_Kharasch_2011b__iv_during_simultaneous_administration_of_iv_unlabeled_alfentanil_and_oral_deuterated_alfentanil__74.png 0.9996
DDI_Qualification_CYP3A4/images/038_section_ct-profiles/066_section_rifampicin-alfentanil-ddi/comparison_time_profile_Kharasch_2011b__iv_during_sequential_administration_of_iv_unlabeled_alfentanil_and_oral_deuterated_alfentanil__73.png 0.9996
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DDI_Qualification_CYP3A4/images/037_section_qualification-cyp3a4-ddi/DDIRatio_1_perpetrator_Cimetidine_ddi_ratio_plot_CMAX_residualsVsObserved.png 0.9999
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DDI_Qualification_CYP3A4/images/038_section_ct-profiles/061_section_fluvoxamine-alprazolam-ddi/comparison_time_profile_Fleishaker_1994__Day_10__45.png 1.0000
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DDI_Qualification_CYP3A4/images/037_section_qualification-cyp3a4-ddi/DDIRatio_1_perpetrator_Fluconazole_ddi_ratio_plot_CMAX_predictedVsObserved.png 1.0000
DDI_Qualification_CYP3A4/images/037_section_qualification-cyp3a4-ddi/DDIRatio_1_victim_Verapamil_ddi_ratio_plot_AUC_residualsVsObserved.png 1.0000
DDI_Qualification_CYP3A4/images/037_section_qualification-cyp3a4-ddi/DDIRatio_1_victim_Verapamil_ddi_ratio_plot_CMAX_predictedVsObserved.png 1.0000
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DDI_Qualification_CYP3A4/images/037_section_qualification-cyp3a4-ddi/DDIRatio_1_perpetrator_Fluconazole_ddi_ratio_plot_AUC_residualsVsObserved.png 1.0000
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PDF Text Comparison

DDI_Qualification_CYP3A4/report.pdf

Text Differences (click to expand) 
--- a/DDI_Qualification_CYP3A4/report.pdf
+++ b/DDI_Qualification_CYP3A4/report.pdf
@@ -1,7 +1,7 @@
 CYP3A4 DDI Qualification

-Version 2.2-OSP12.3

+Version 2.2-OSP13.0

 Qualification Plan Release https://github.com/Open-Systems-Pharmacology/Qualification-DDI-CYP3A4/releases/tag/v2.2

-OSP Version 12.3

+OSP Version 13.0

 Qualification Framework Version 3.7

 This qualification report is filed at:

 https://github.com/Open-Systems-Pharmacology/OSP-Qualification-Reports

@@ -1341,19 +1341,19 @@
 Figure 2-4: CYP3A4 DDI. Predicted/Observed vs. Observed CMAX Ratio. (δ = 1 in Guest et al. formula)

 Table 2-1: GMFE for CYP3A4 DDI Ratio

 PK parameter GMFE

-AUC 1.36

-CMAX 1.32

+AUC 1.37

+CMAX 1.33

 Table 2-2: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

 32/277

 AUC Number Ratio [%]

 Points total 172 -

-Points within Guest et al. 120 69.77

+Points within Guest et al. 121 70.35

 Points within 2 fold 154 89.53

 Table 2-3: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

 CMAX Number Ratio [%]

 Points total 116 -

-Points within Guest et al. 66 56.90

-Points within 2 fold 106 91.38

+Points within Guest et al. 65 56.03

+Points within 2 fold 107 92.24

 Table 2-4: Summary table for CYP3A4 DDI

 33/277

 Predicted Observed Pred/Obs Predicted Observed Pred/Obs

@@ -1363,13 +1363,13 @@
 50 100 mg, PO, Midazolam, PO 3.48 5.75 0.61 1.96 2.56 0.77 Ahonen 1995

 MD OD (4 days)

 Rifampicin, 600

-54 mg, PO, MD OD Midazolam, PO 0.04 0.04 0.94 0.10 0.06 1.59 Backman 1996

+54 mg, PO, MD OD Midazolam, PO 0.04 0.04 0.94 0.10 0.06 1.60 Backman 1996

 (5 days)

 Rifampicin, 600

-56 mg, PO, MD OD Midazolam, PO 0.04 0.02 1.67 0.10 0.05 1.82 Backman 1998

+56 mg, PO, MD OD Midazolam, PO 0.04 0.02 1.68 0.10 0.05 1.83 Backman 1998

 (5 days)

 Rifampicin, 600

-57 mg, PO, MD OD Midazolam, PO 0.12 0.13 0.95 0.23 0.20 1.15 Backman 1998

+57 mg, PO, MD OD Midazolam, PO 0.13 0.13 0.95 0.23 0.20 1.15 Backman 1998

 (5 days)

 Itraconazole,

 58 200 mg, PO, Midazolam, PO 4.88 7.97 0.61 2.23 3.12 0.71 Backman 1998

@@ -1384,10 +1384,10 @@
 132 mg, PO, MD OD Midazolam, PO 0.03 0.05 0.65 0.09 0.11 0.77 Eap 2004

 (5 days)

 Clarithromycin,

-173 500 mg, PO, Midazolam, PO 9.22 7.14 1.29 3.08 - - Gorski 1998

+173 500 mg, PO, Midazolam, PO 9.13 7.14 1.28 3.07 - - Gorski 1998

 MD BID (7 days)

 Clarithromycin,

-175 500 mg, PO, Midazolam, IV 3.07 2.67 1.15 1.24 - - Gorski 1998

+175 500 mg, PO, Midazolam, IV 3.05 2.67 1.14 1.24 - - Gorski 1998

 MD BID (7 days)

 Rifampicin, 600

 177 mg, PO, MD OD Midazolam, PO 0.05 0.10 0.46 0.12 0.10 1.17 Gorski 2003

@@ -1415,16 +1415,16 @@
 215 mg, PO, MD Midazolam, PO 0.04 0.06 0.77 0.11 0.12 0.90 Gurley 2006

 BID (7 days)

 Clarithromycin,

-217 500 mg, PO, Midazolam, PO 7.69 8.39 0.92 2.74 3.80 0.72 Gurley 2006

+217 500 mg, PO, Midazolam, PO 7.64 8.39 0.91 2.73 3.80 0.72 Gurley 2006

 MD BID (7 days)

 Rifampicin, 300

 221 mg, PO, MD Midazolam, PO 0.04 0.06 0.73 0.11 0.11 1.01 Gurley 2008a

 BID (7 days)

 Clarithromycin,

-223 500 mg, PO, Midazolam, PO 7.69 5.48 1.40 2.74 2.17 1.26 Gurley 2008a

+223 500 mg, PO, Midazolam, PO 7.64 5.48 1.39 2.73 2.17 1.26 Gurley 2008a

 MD BID (7 days)

 Rifampicin, 600

-276 mg, PO, MD OD Midazolam, IV 0.47 0.38 1.25 0.90 - - Kharasch 1997

+276 mg, PO, MD OD Midazolam, IV 0.47 0.38 1.25 0.91 - - Kharasch 1997

 (5 days)

 Rifampicin, 600

 278 mg, PO, MD OD Alfentanil, IV 0.36 0.36 0.99 0.90 - - Kharasch 1997

@@ -1436,7 +1436,7 @@
 283 mg, PO, MD OD Alfentanil, IV 0.49 0.38 1.30 1.20 1.00 1.20 Kharasch 2004

 (6 days)

 Rifampicin, 600

-286 mg, PO, MD OD Midazolam, PO 0.04 0.05 0.69 0.08 0.11 0.69 Kharasch 2004

+286 mg, PO, MD OD Midazolam, PO 0.04 0.05 0.69 0.08 0.11 0.70 Kharasch 2004

 (6 days)

 Rifampicin, 600

 288 mg, PO, MD OD Alfentanil, PO 0.04 0.05 0.87 0.09 0.11 0.79 Kharasch 2004

@@ -1458,7 +1458,7 @@
 DataID Perpetrator Victim AUC AUC AUC CMAX CMAX CMAX Reference

 Ratio Ratio Ratio Ratio Ratio Ratio

 Rifampicin, 5

-299 mg, PO, MD OD Alfentanil, IV 0.98 0.83 1.19 1.31 1.04 1.26 Kharasch 2011

+299 mg, PO, MD OD Alfentanil, IV 0.98 0.83 1.18 1.31 1.04 1.26 Kharasch 2011

 (6 days)

 Rifampicin, 10

 300 mg, PO, MD OD Alfentanil, IV 0.85 0.75 1.13 1.29 1.05 1.23 Kharasch 2011

@@ -1479,7 +1479,7 @@
 306 mg, PO, MD OD Midazolam, PO 0.16 0.40 0.41 0.27 0.51 0.54 Kharasch 2011

 (6 days)

 Rifampicin, 75

-307 mg, PO, MD OD Midazolam, PO 0.08 0.25 0.33 0.15 0.34 0.46 Kharasch 2011

+307 mg, PO, MD OD Midazolam, PO 0.08 0.25 0.32 0.15 0.34 0.46 Kharasch 2011

 (6 days)

 Rifampicin, 5

 309 mg, PO, MD OD Alfentanil, PO 0.46 0.74 0.62 0.60 0.86 0.69 Kharasch 2011

@@ -1497,10 +1497,10 @@
 342 mg, PO, MD OD Midazolam, IV 0.47 0.66 0.72 0.90 1.11 0.82 Link 2008

 (6 days)

 Rifampicin, 600

-344 mg, PO, MD OD Midazolam, PO 0.03 0.02 1.97 0.08 0.03 2.23 Link 2008

+344 mg, PO, MD OD Midazolam, PO 0.03 0.02 1.98 0.08 0.03 2.25 Link 2008

 (6 days)

 Clarithromycin,

-354 500 mg, PO, Midazolam, PO 6.07 5.56 1.09 2.62 - - Markert 2013

+354 500 mg, PO, Midazolam, PO 5.94 5.56 1.07 2.60 - - Markert 2013

 MD BID (4 days)

 36/277

 Predicted Observed Pred/Obs Predicted Observed Pred/Obs

@@ -1522,13 +1522,13 @@
 MD QID (7

 days)

 Erythromycin,

-366 500 mg, PO, Midazolam, PO 3.86 4.07 0.95 1.89 2.70 0.70 Olkkola 1993

+366 500 mg, PO, Midazolam, PO 3.56 4.07 0.87 1.83 2.70 0.68 Olkkola 1993

 MD TID (7 days)

 Erythromycin,

-368 500 mg, PO, Midazolam, IV 2.05 1.96 1.04 1.02 - - Olkkola 1993

+368 500 mg, PO, Midazolam, IV 1.91 1.96 0.98 1.02 - - Olkkola 1993

 MD TID (7 days)

 Itraconazole,

-370 200 mg, PO, Midazolam, PO 5.28 10.80 0.49 2.24 3.40 0.66 Olkkola 1994

+370 200 mg, PO, Midazolam, PO 5.29 10.80 0.49 2.24 3.40 0.66 Olkkola 1994

 MD OD (4 days)

 Itraconazole,

 377 Midazolam, PO 4.49 3.40 1.32 2.20 1.80 1.22 Olkkola 1996

@@ -1544,7 +1544,7 @@
 400 mg, PO, SD

 Fluconazole,

 400/200 mg,

-381 Midazolam, IV 2.13 2.04 1.05 0.32 - - Olkkola 1996

+381 Midazolam, IV 2.14 2.04 1.05 0.32 - - Olkkola 1996

 PO, MD OD (4

 days)

 Fluconazole,

@@ -1567,7 +1567,7 @@
 DataID Perpetrator Victim AUC AUC AUC CMAX CMAX CMAX Reference

 Ratio Ratio Ratio Ratio Ratio Ratio

 Rifampicin, 600

-392 mg, PO, MD OD Midazolam, PO 0.21 0.12 1.67 0.27 0.16 1.66 Reitman 2011

+392 mg, PO, MD OD Midazolam, PO 0.21 0.12 1.72 0.28 0.16 1.70 Reitman 2011

 (28 days)

 Rifampicin, 600

 393 mg, PO, MD OD Midazolam, PO 0.37 0.38 0.98 0.51 0.40 1.27 Reitman 2011

@@ -1584,13 +1584,13 @@
 422 mg, PO, MD OD Midazolam, IV 0.49 0.58 0.85 0.75 - - Szalat 2007

 (7 days)

 Itraconazole, 50 Templeton

-424 Midazolam, PO 3.26 2.00 1.63 2.20 - -

+424 Midazolam, PO 3.19 2.00 1.60 2.17 - -

 mg, PO, SD 2010

 Itraconazole, Templeton

-425 Midazolam, PO 7.60 4.70 1.62 3.44 - -

+425 Midazolam, PO 7.45 4.70 1.59 3.41 - -

 200 mg, PO, SD 2010

 Itraconazole, Templeton

-426 Midazolam, PO 9.74 5.40 1.80 3.73 - -

+426 Midazolam, PO 12.20 5.40 2.26 3.92 - -

 400 mg, PO, SD 2010

 Erythromycin,

 Carbamazepine,

@@ -1598,7 +1598,7 @@
 PO

 MD

 Clarithromycin,

-469 250 mg, PO, Midazolam, PO 2.38 3.57 0.67 1.59 2.44 0.65 Yeates 1996

+469 250 mg, PO, Midazolam, PO 2.37 3.57 0.66 1.59 2.44 0.65 Yeates 1996

 MD BID (5 days)

 Erythromycin,

 Zimmermann

@@ -1606,7 +1606,7 @@
 1996

 MD TID (3 days)

 Erythromycin,

-757 333 mg, PO, Triazolam, PO 3.87 2.06 1.88 2.11 1.46 1.44 Phillips 1986

+757 333 mg, PO, Triazolam, PO 3.50 2.06 1.70 2.03 1.46 1.39 Phillips 1986

 MD TID (3 days)

 Rifampicin, 600

 Kharasch

@@ -1642,25 +1642,25 @@
 500 mg, PO, SD 1989

 Erythromycin,

 Bartkowski

-780 500 mg, PO, Alfentanil, IV 1.69 1.46 1.16 1.03 - -

+780 500 mg, PO, Alfentanil, IV 1.55 1.46 1.06 1.02 - -

 1989

 MD BID (6 days)

 Erythromycin,

 Greenblatt

-781 500 mg, PO, Triazolam, PO 3.12 3.65 0.86 1.90 1.77 1.07

+781 500 mg, PO, Triazolam, PO 2.92 3.65 0.80 1.86 1.77 1.05

 1998a

 MD OD (2 days)

 Efavirenz, 600

-801 mg, PO, MD OD Alfentanil, PO 0.23 0.22 1.07 0.36 0.43 0.83 Kharasch 2012

+801 mg, PO, MD OD Alfentanil, PO 0.17 0.22 0.76 0.27 0.43 0.64 Kharasch 2012

 (19 days)

 Efavirenz, 600

-803 mg, PO, MD OD Alfentanil, IV 0.56 0.54 1.04 0.92 1.10 0.84 Kharasch 2012

+803 mg, PO, MD OD Alfentanil, IV 0.51 0.54 0.94 0.90 1.10 0.82 Kharasch 2012

 (19 days)

 Erythromycin,

 828 Midazolam, PO 3.51 1.72 2.04 3.21 - - Carls 2014

 250 mg, PO, SD

 Erythromycin,

-829 1000 mg, PO, Midazolam, PO 4.07 4.99 0.81 3.63 - - Carls 2014

+829 1000 mg, PO, Midazolam, PO 4.06 4.99 0.81 3.63 - - Carls 2014

 SD

 Cimetidine, 300 Carbamazepine,

 900 1.07 1.25 0.85 1.01 - - Dalton 1985a

@@ -1669,16 +1669,16 @@
 943 Midazolam, PO 0.25 0.28 0.89 0.39 0.44 0.89 Kanefendt 2023

 , PO,

 Carbamazepine,

-959 200/400 mg, Efavirenz, PO 0.94 0.64 1.47 0.96 0.79 1.21 Ji 2008

+959 200/400 mg, Efavirenz, PO 0.94 0.64 1.47 0.95 0.79 1.21 Ji 2008

 PO, MD

 Efavirenz, 600 Carbamazepine,

-961 0.49 0.73 0.66 0.58 0.80 0.73 Ji 2008

+961 0.44 0.73 0.60 0.54 0.80 0.67 Ji 2008

 mg, PO, MD PO

 Rifampicin, 450

 1001 mg, PO, MD OD Alprazolam, PO 0.20 0.12 1.70 0.69 0.64 1.08 Schmider 1999

 (4 days)

 Rifampicin, 600

-1004 mg, PO, MD OD Triazolam, PO 0.03 0.05 0.65 0.11 0.12 0.93 Villikka 1997

+1004 mg, PO, MD OD Triazolam, PO 0.03 0.05 0.65 0.12 0.12 0.93 Villikka 1997

 (5 days)

 Itraconazole,

 1026 200 mg, PO, Alprazolam, PO 2.29 2.66 0.86 1.10 1.29 0.85 Yasui 1998

@@ -1694,13 +1694,13 @@
 1078 Triazolam, PO 4.22 3.11 1.36 1.98 1.41 1.40 Neuvonen 1996

 200 mg, PO, SD

 Itraconazole,

-1079 Triazolam, PO 5.59 4.79 1.17 2.42 1.76 1.38 Neuvonen 1996

+1079 Triazolam, PO 6.62 4.79 1.38 2.61 1.76 1.48 Neuvonen 1996

 200 mg, PO, SD

 Itraconazole,

-1080 Triazolam, PO 2.25 4.63 0.49 1.67 1.76 0.95 Neuvonen 1996

+1080 Triazolam, PO 3.10 4.63 0.67 1.92 1.76 1.09 Neuvonen 1996

 200 mg, PO, SD

 Itraconazole,

-1081 Triazolam, PO 2.10 3.82 0.55 1.39 1.71 0.81 Neuvonen 1996

+1081 Triazolam, PO 2.53 3.82 0.66 1.53 1.71 0.89 Neuvonen 1996

 200 mg, PO, SD

 Fluvoxamine,

 50/100 mg, PO,

@@ -1712,27 +1712,27 @@
 administered for

 6 days

 Rifampicin, 600

-1092 mg, PO, MD OD Midazolam, IV 1.18 1.15 1.03 2.26 - - Shin 2013

+1092 mg, PO, MD OD Midazolam, IV 1.19 1.15 1.03 2.26 - - Shin 2013

 (10 days)

 Rifampicin, 600

-1095 mg, PO, MD OD Midazolam, IV 1.18 1.23 0.97 2.26 1.77 1.27 Shin 2016

+1095 mg, PO, MD OD Midazolam, IV 1.19 1.23 0.97 2.26 1.77 1.27 Shin 2016

 (10 days)

 Itraconazole,

 Prueksaritanont

-1097 200 mg, PO, Midazolam, PO 19.36 7.04 2.75 4.67 3.71 1.26

+1097 200 mg, PO, Midazolam, PO 19.80 7.04 2.81 4.82 3.71 1.30

 2017

 MD OD (5 days)

 Rifampicin, 600 Prueksaritanont

-1098 Midazolam, PO 2.24 0.94 2.39 1.88 1.30 1.45

+1098 Midazolam, PO 2.25 0.94 2.40 1.89 1.30 1.45

 mg, PO, SD 2017

 Clarithromycin,

 Prueksaritanont

-1099 500 mg, PO, Midazolam, PO 7.83 4.84 1.62 3.18 2.69 1.18

+1099 500 mg, PO, Midazolam, PO 7.68 4.84 1.59 3.16 2.69 1.17

 2017

 MD BID (5 days)

 Clarithromycin,

 Greenblatt

-1102 500 mg, PO, Triazolam, PO 3.58 5.06 0.71 2.01 1.97 1.02

+1102 500 mg, PO, Triazolam, PO 3.52 5.06 0.70 2.00 1.97 1.01

 1998a

 MD OD (2 days)

 Fluvoxamine,

@@ -1750,7 +1750,7 @@
 DataID Perpetrator Victim AUC AUC AUC CMAX CMAX CMAX Reference

 Ratio Ratio Ratio Ratio Ratio Ratio

 Verapamil, 240

-1111 mg, PO, MD OD Midazolam, IV 1.94 1.45 1.33 1.15 - - Wang 2005

+1111 mg, PO, MD OD Midazolam, IV 1.93 1.45 1.33 1.15 - - Wang 2005

 (7 days)

 Fluvoxamine,

 50/100 mg, PO,

@@ -1760,7 +1760,7 @@
 day 1-3, then

 100 mg

 Verapamil, 240

-1116 mg, PO, MD OD Midazolam, PO 4.17 3.51 1.19 2.10 - - Wang 2005

+1116 mg, PO, MD OD Midazolam, PO 4.16 3.51 1.19 2.10 - - Wang 2005

 (7 days)

 Carbamazepine,

 1133 Midazolam, PO 0.26 0.32 0.81 0.40 0.46 0.89 Kanefendt 2023

@@ -1815,14 +1815,14 @@
 1332 mg, PO, MD Alprazolam, PO 1.05 1.58 0.67 1.02 1.03 0.98 Abernethy 1983

 QID (1 day)

 Cimetidine, 300

-1334 mg, PO, MD Triazolam, PO 1.80 1.54 1.17 1.52 1.20 1.26 Abernethy 1983

+1334 mg, PO, MD Triazolam, PO 1.81 1.54 1.17 1.52 1.20 1.26 Abernethy 1983

 QID (1 day)

 Cimetidine, 300

 1336 mg, PO, MD Triazolam, PO 1.82 1.32 1.38 1.52 1.39 1.10 Friedman 1988

 QID (2 days)

 Cimetidine, 300

 Triazolam,

-1338 mg, PO, MD 1.61 1.55 1.04 1.41 1.35 1.04 Cox 1986

+1338 mg, PO, MD 1.61 1.55 1.04 1.40 1.35 1.04 Cox 1986

 intraduodenal

 QID (1 day)

 Cimetidine,

@@ -1966,52 +1966,52 @@
 2010 mg, PO, MD OD Alprazolam, PO 0.97 0.92 1.06 1.00 - - Gashaw 2003

 (5 days)

 Clarithromycin,

-2027 500 mg, PO, Midazolam, IV 3.03 3.20 0.95 1.24 1.17 1.06 Quinney 2008

+2027 500 mg, PO, Midazolam, IV 3.01 3.20 0.94 1.24 1.17 1.06 Quinney 2008

 MD BID (7 days)

 Clarithromycin,

-2030 500 mg, PO, Midazolam, PO 9.33 8.00 1.17 3.14 2.75 1.14 Quinney 2008

+2030 500 mg, PO, Midazolam, PO 9.26 8.00 1.16 3.13 2.75 1.14 Quinney 2008

 MD BID (7 days)

 Rifampicin, 600

-2036 mg, PO, MD OD Midazolam, IV 1.18 1.15 1.03 2.26 - - Kim 2018

+2036 mg, PO, MD OD Midazolam, IV 1.19 1.15 1.03 2.26 - - Kim 2018

 (10 days)

 Efavirenz, 400

 Katzenmaier

-2041 mg, PO, MD OD Midazolam, PO 0.11 0.10 1.11 0.24 0.18 1.32

+2041 mg, PO, MD OD Midazolam, PO 0.09 0.10 0.89 0.20 0.18 1.10

 2010

 (14 days)

 Efavirenz, 400

-2044 Midazolam, PO 0.53 0.59 0.89 0.65 - - Mikus 2017

+2044 Midazolam, PO 0.48 0.59 0.82 0.61 - - Mikus 2017

 mg, PO, SD

 Efavirenz, 400

-2045 Midazolam, IV 0.83 0.79 1.06 0.93 - - Mikus 2017

+2045 Midazolam, IV 0.79 0.79 1.01 0.92 - - Mikus 2017

 mg, PO, SD

 Efavirenz, 400

-2047 Midazolam, PO 0.54 0.61 0.89 0.66 - - Mikus 2017

+2047 Midazolam, PO 0.46 0.61 0.74 0.58 - - Mikus 2017

 mg, PO, SD

 44/277

 Predicted Observed Pred/Obs Predicted Observed Pred/Obs

 DataID Perpetrator Victim AUC AUC AUC CMAX CMAX CMAX Reference

 Ratio Ratio Ratio Ratio Ratio Ratio

 Efavirenz, 400

-2048 Midazolam, IV 0.79 0.78 1.01 0.91 - - Mikus 2017

+2048 Midazolam, IV 0.74 0.78 0.96 0.89 - - Mikus 2017

 mg, PO, SD

 Efavirenz, 400

-2049 Midazolam, PO 0.70 0.77 0.92 0.78 - - Mikus 2017

+2049 Midazolam, PO 0.64 0.77 0.84 0.74 - - Mikus 2017

 mg, PO, SD

 Efavirenz, 400

-2050 Midazolam, IV 0.86 0.94 0.92 0.94 - - Mikus 2017

+2050 Midazolam, IV 0.83 0.94 0.88 0.93 - - Mikus 2017

 mg, PO, SD

 Efavirenz, 400

-2051 Midazolam, PO 0.82 0.75 1.09 0.87 - - Mikus 2017

+2051 Midazolam, PO 0.78 0.75 1.05 0.85 - - Mikus 2017

 mg, PO, SD

 Efavirenz, 400

-2052 Midazolam, IV 0.91 0.85 1.07 0.97 - - Mikus 2017

+2052 Midazolam, IV 0.90 0.85 1.05 0.96 - - Mikus 2017

 mg, PO, SD

 Efavirenz, 400

-2053 Midazolam, PO 0.90 0.84 1.07 0.93 - - Mikus 2017

+2053 Midazolam, PO 0.88 0.84 1.05 0.91 - - Mikus 2017

 mg, PO, SD

 Efavirenz, 400

-2054 Midazolam, IV 0.95 0.92 1.03 0.98 - - Mikus 2017

+2054 Midazolam, IV 0.94 0.92 1.02 0.98 - - Mikus 2017

 mg, PO, SD

 Rifampicin, 600

 Barbarash

@@ -2020,7 +2020,7 @@
 (15 days)

 Rifampicin, 600

 Barbarash

-2058 mg, PO, MD OD Verapamil, PO 0.08 0.07 1.20 0.12 0.04 3.21

+2058 mg, PO, MD OD Verapamil, PO 0.08 0.07 1.20 0.12 0.04 3.22

 1988

 (15 days)

 Cimetidine, 300

@@ -2030,7 +2030,7 @@
 QID

 Cimetidine, 300

 Abernethy et al.

-16150 mg, PO, MD Verapamil, PO 1.15 0.86 1.34 1.21 1.03 1.18

+16150 mg, PO, MD Verapamil, PO 1.15 0.86 1.33 1.21 1.03 1.18

 1985

 QID

 Cimetidine, 400

@@ -2071,8 +2071,8 @@
 formula)

 Table 2-5: GMFE for CYP3A4 DDI Ratio

 PK parameter GMFE

-AUC 1.41

-CMAX 1.42

+AUC 1.42

+CMAX 1.43

 Table 2-6: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

 AUC Number Ratio [%]

 Points total 86 -

@@ -2083,7 +2083,7 @@
 CMAX Number Ratio [%]

 Points total 57 -

 Points within Guest et al. 26 45.61

-Points within 2 fold 48 84.21

+Points within 2 fold 49 85.96

 2.1.2 Mechanism-based Inactivation

 Figure 2-9: CYP3A4 DDI. Mechanism: Mechanism-based Inactivation. Predicted vs. Observed AUC Ratio. (δ = 1 in

 Guest et al. formula)

@@ -2099,7 +2099,7 @@
 Table 2-8: GMFE for CYP3A4 DDI Ratio

 PK parameter GMFE

 AUC 1.24

-CMAX 1.22

+CMAX 1.21

 Table 2-9: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

 AUC Number Ratio [%]

 Points total 32 -

@@ -2125,18 +2125,18 @@
 Guest et al. formula)

 Table 2-11: GMFE for CYP3A4 DDI Ratio

 PK parameter GMFE

-AUC 1.37

+AUC 1.36

 CMAX 1.25

 Table 2-12: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

 AUC Number Ratio [%]

 Points total 54 -

-Points within Guest et al. 31 57.41

+Points within Guest et al. 32 59.26

 Points within 2 fold 49 90.74

 57/277

 Table 2-13: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

 CMAX Number Ratio [%]

 Points total 39 -

-Points within Guest et al. 26 66.67

+Points within Guest et al. 25 64.10

 Points within 2 fold 38 97.44

 2.2 Perpetrator

 2.2.1 Carbamazepine

@@ -2164,7 +2164,7 @@
 Table 2-16: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

 CMAX Number Ratio [%]

 Points total 7 -

-Points within Guest et al. 5 71.43

+Points within Guest et al. 6 85.71

 Points within 2 fold 7 100.00

 2.2.2 Cimetidine

 Figure 2-21: CYP3A4 DDI. Perpetrator: Cimetidine. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al. formula)

@@ -2231,8 +2231,8 @@
 al. formula)

 Table 2-23: GMFE for CYP3A4 DDI Ratio

 PK parameter GMFE

-AUC 1.10

-CMAX 1.27

+AUC 1.15

+CMAX 1.33

 Table 2-24: Summary table for CYP3A4 DDI - AUC Ratio. (δ = 1 in Guest et al. formula)

 AUC Number Ratio [%]

 Points total 14 -

@@ -2242,7 +2242,7 @@
 Table 2-25: Summary table for CYP3A4 DDI - CMAX Ratio. (δ = 1 in Guest et al. formula)

 CMAX Number Ratio [%]

 Points total 4 -

-Points within Guest et al. 2 50

+Points within Guest et al. 1 25

 Points within 2 fold 4 100

 2.2.5 Erythromycin

 Figure 2-33: CYP3A4 DDI. Perpetrator: Erythromycin. Predicted vs. Observed AUC Ratio. (δ = 1 in Guest et al.

@@ -2339,18 +2339,18 @@
... (truncated 121 lines)

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