Merge pull request #7 from TWendl/master

Efavirenz-Model.json and sections 2.2 and 2.3 updated
Open-Systems-Pharmacology · Jun 10, 2020 · caf3bf7 · caf3bf7
2 parents 56959a7 + 243650d
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diff --git a/Efavirenz-Model.json b/Efavirenz-Model.json
@@ -3674,7 +3674,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Mouly 2002, 200mg MD",
           "OriginText": "Efavirenz\nMouly 2002, 200mg MD\n2020-03-19 13:36"
         }
       ],
@@ -3909,7 +3909,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Mouly 2002, 400mg MD",
           "OriginText": "Efavirenz\nMouly 2002, 400mg MD\n2020-03-19 13:37"
         }
       ],
@@ -4089,7 +4089,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Xu 2013, 600mg SD EM",
           "OriginText": "Efavirenz\nXu 2013, 600mg SD EM\n2020-03-19 11:55"
         }
       ],
@@ -4269,7 +4269,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Xu 2013, 600mg SD IM",
           "OriginText": "Efavirenz\nXu 2013, 600mg SD IM\n2020-03-19 11:55"
         }
       ],
@@ -4449,7 +4449,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Xu 2013, 600mg SD PM",
           "OriginText": "Efavirenz\nXu 2013, 600mg SD PM\n2020-03-19 11:56"
         }
       ],
@@ -4629,7 +4629,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Ogburn 2010, 600mg SD",
           "OriginText": "Efavirenz\nOgburn 2010, 600mg SD\n2020-03-19 11:53"
         }
       ],
@@ -4911,7 +4911,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Dooley 2012, 600mg MD EM",
           "OriginText": "Efavirenz\nDooley 2012, 600mg MD EM\n2020-03-19 12:14"
         },
         {
@@ -4963,7 +4963,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis 1",
+          "Name": "Dooley 2012, 600mg MD EM",
           "OriginText": "Efavirenz\nDooley 2012, 600mg MD EM\n2020-03-19 12:14"
         }
       ],
@@ -5245,7 +5245,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Dooley 2012, 600mg MD IM",
           "Settings": {
             "SideMarginsEnabled": true,
             "LegendPosition": "BottomInside",
@@ -5533,7 +5533,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Dooley 2012, 600mg MD PM",
           "OriginText": "Efavirenz\nDooley 2012, 600mg MD PM\n2020-03-19 13:21"
         }
       ],
@@ -5795,7 +5795,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Garg 2013, 600mg MD",
           "OriginText": "Efavirenz\nGarg 2013, 600mg MD\n2020-03-19 13:23"
         }
       ],
@@ -6062,7 +6062,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Huang 2012, 600mg MD",
           "OriginText": "Efavirenz\nHuang 2012, 600mg MD\n2020-03-19 13:35"
         }
       ],
@@ -6391,7 +6391,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Liu 2008, 400 mg PO OD",
           "OriginText": "Efavirenz\nLiu 2008, 400 mg PO OD\n2020-03-19 12:08"
         }
       ],
@@ -6653,7 +6653,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Malvestutto 2014, 600mg PO OD",
           "OriginText": "Efavirenz\nMalvestutto 2014, 600mg PO OD\n2020-03-19 11:54"
         }
       ],
@@ -6855,7 +6855,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Damle 2008, 600 mg PO OD",
           "OriginText": "Efavirenz\nDamle 2008, 600 mg PO OD\n2020-03-19 12:09"
         }
       ],
@@ -7390,7 +7390,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Katzenmaier 2010, Midazolam +  Efavirenz 400mg MD",
           "OriginText": "Efavirenz\nKatzenmaier 2010, Midazolam +  Efavirenz 400mg MD\n2020-03-19 13:48"
         }
       ],
@@ -7783,7 +7783,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Katzenmaier 2010, Midazolam alone",
           "OriginText": "Efavirenz\nKatzenmaier 2010, Midazolam alone\n2020-03-19 13:49"
         }
       ]
@@ -8348,7 +8348,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Mikus 2017, Midazolam + Efavirenz 400mg SD",
           "FontAndSize": {
             "ChartWidth": 800,
             "ChartHeight": 500,
@@ -8831,7 +8831,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Mikus 2017, Midazolam alone",
           "OriginText": "Efavirenz\nMikus 2017, Midazolam alone\n2020-03-19 13:50"
         }
       ]
@@ -9167,7 +9167,7 @@
               }
             }
           ],
-          "Name": "Time Profile Analysis",
+          "Name": "Soon 2010, 600mg MD over 28 days",
           "OriginText": "Efavirenz\nSoon 2010, 600mg MD over 28 days\n2020-03-19 13:41"
         }
       ],

diff --git a/Evaluation/Input/Content/Section2.2_Data.md b/Evaluation/Input/Content/Section2.2_Data.md
@@ -1,28 +1,26 @@
-### 2.2.1	In vitro / physicochemical Data
+### 2.2.1 In vitro / physico-chemical Data
 
-A literature search was performed to collect available information on physicochemical properties of efavirenz. The obtained information from literature is summarized in the table below. 
+A literature search was performed to collect available information on physiochemical properties of efavirenz. The obtained information from literature is summarized in the table below. 
 
 | **Parameter**   | **Unit** | **Value**       | Source                                                       | **Description**                                 |
 | :-------------- | -------- | --------------- | ------------------------------------------------------------ | ----------------------------------------------- |
-| MW              | g/mol    | 315.675         | [DrugBank DB00625](#5-References) | Molecular weight                                |
+| MW              | g/mol    | 315.675         | https://www.drugbank.ca/                                     | Molecular weight                                |
 | pK<sub>a</sub>  | 10.1     | (base)          | [Rabel 1996](#5-References)                                | Acid dissociation constant                      |
 | Solubility (pH) | mg/L     | 11.5 (6.4) | [Cristofoletti 2013](#5-References)        | Water solubility                               |
-| logP            |          | 2.07       | [Almond 2005](#5-References)     | Partition coefficient between octanol and water |
-| logP | | 4.6 | [DrugBank DB00625](#5-References) | Partition coefficient between octanol and water |
-| logD            |          | 5.1       | [Janneh 2009](#5-References) | Partition coefficient between octanol and buffer solution at pH 7.4 |
-| fu              |         | 0.006 [0.004 - 0.015]<sup>a</sup> | [Almond 2005](#5-References) | Fraction unbound in plasma                      |
-| Emax (CYP3A4) |          | 7.27, 3.15 (average: 5.21) | [Shou 2008](#5-References) | Maximum induction effect |
-| EC50 (CYP3A4) | µmol/l | 12.5, 2.18 (average: 7.34) | [Shou 2008](#5-References) | Concentration at half maximum induction |
+| logP            |          | 2.07, 4.6       | [Almond 2005](#5-References), https://www.drugbank.ca/     | Partition coefficient between octanol and water |
+| logD            |          | 5.1       | [Janneh 2009](#5-References) | Partition coefficient between octanol and buffer solution |
+| fu              |         | 0.006 [0.004 - 0.015] | [Almond 2005](#5-References) | Fraction unbound in plasma                      |
+| Emax (CYP3A4) |          | 7.27, 3.15 (average 5.21) | [Shou 2008](#5-References) | Maximum induction effect |
+| EC50 (CYP3A4) | µmol/l | 12.5, 2.18 (average 7.34) | [Shou 2008](#5-References) | Concentration at half maximum induction |
 | Emax (CYP2B6) |          | 5.1       | [Ke 2016](#5-References) | Maximum induction effect |
 | EC50 (CYP2B6) | µmol/l | 5.1       | [Ke 2016](#5-References) | Concentration at half maximum induction |
-<sup>a</sup> denotes median [range]
 
 
-### 2.2.2	Clinical Data
+### 2.2.2 Clinical Data
 
 A literature search was performed to collect available clinical data on efavirenz in healthy adults.
 
-#### 2.2.2.1	Model Building
+#### 2.2.2.1 Model Building
 
 The following studies were used for model building:
 
@@ -31,17 +29,17 @@ The following studies were used for model building:
 | [Mouly 2002](#5-References)  | Healthy subjects receiving a single oral dose of 200 and 400 mg |
 | [Ogburn 2013](#5-References) | Healthy subjects receiving a single oral dose of 600 mg      |
 | [Xu 2013](#5-References)     | Healthy subjects with different CYP2B6 genotypes receiving a single oral dose of 600 mg |
-| [Dooley 2012](#5-References) | Healthy subjects with different CYP2B6 genotypes receiving multiple oral doses of 600 mg |
-| [Garg 2013](#5-References)   | Healthy subjects receiving multiple oral doses of 600 mg     |
-| [Huang 2012](#5-References)  | Healthy subjects receiving multiple oral doses of 600 mg     |
+| [Dooley 2012](#5-References) | Healthy subjects with different CYP2B6 genotypes receiving multiple doses of 600 mg |
+| [Garg 2013](#5-References)   | Healthy subjects receiving multiple doses of 600 mg          |
+| [Huang 2012](#5-References)  | Healthy subjects receiving multiple doses of 600 mg          |
 
 
 
-#### 2.2.2.2	Midazolam interaction studies used to parameterize CYP3A4 interaction
+#### 2.2.2.2 Midazolam interaction studies used to parameterize CYP3A4 interaction
 
 The following studies were used for parameterization of CYP3A4 interaction:
 
 | Publication                       | Arm / Treatment / Information used for model building        |
 | :-------------------------------- | :----------------------------------------------------------- |
 | [Mikus 2017](#5-References)       | Healthy subjects receiving a single oral dose of  400 mg Efavirenz at t=0h, 4 mg midazolam at t=12h and a single intravenous dose of 2 mg midazolam at t=18h. |
-| [Katzenmaier 2010](#5-References) | Healthy subjects receiving multiple oral doses of 400 mg efavirenz QD. On day 14, subjects received a single oral midazolam dose of 3 mg. |
+| [Katzenmaier 2010](#5-References) | Healthy subjects receiving multiple oral doses of 400 mg efavirenz QD. On day 14, subjects receive a single oral midazolam dose of 3 mg. |
diff --git a/Evaluation/Input/Content/Section2.3_Model_Parameters_and_Assumptions.md b/Evaluation/Input/Content/Section2.3_Model_Parameters_and_Assumptions.md
@@ -1,36 +1,36 @@
-### 2.3.1	Absorption
+### 2.3.1 Absorption
 
 Absorption observed in clinical studies can be fully explained by passive absorption.
 
-### 2.3.2	Distribution
+### 2.3.2 Distribution
 
-After testing the available organ-plasma partition coefficient and cell permeability calculation methods built in PK-Sim®, observed clinical data was best described by choosing the partition coefficient calculation by `Schmitt` and cellular permeability calculation by `PK-Sim Standard`. 
+After testing the available organ-plasma partition coefficient and cell permeability calculation methods built in PK-Sim, observed clinical data was best described by choosing the partition coefficient calculation by `Schmitt` and cellular permeability calculation by `PK-Sim Standard`. 
 
-### 2.3.3	Metabolism, Elimination and Induction
+### 2.3.3 Metabolism, Elimination and Induction
 
 Efavirenz is metabolized by CYP2B6, CYP3A4, CYP3A5, CYP1A2 and CYP2A6. 
 
-Induction of CYP3A4 ([Shou 2008](#5-References)) and CYP2B6 ([Ke 2016](#5-References)) was taken into account.
+Induction of CYP3A4  ([Shou 2008](#5-References)) and CYP2B6 ([Ke 2016](#5-References)) was taken into account.
 
-### 2.3.4	Automated Parameter Identification
+### 2.3.4 Automated Parameter Identification
 
-The parameter identification tool in PK-Sim® has been used to estimate selected model parameters. For some of the parameters, factors were optimized to maintain their absolute value, e.g. a global factor for the k<sub>cat</sub> values of CYP2B6, CYP3A4, CYP3A5, CYP1A2 and CYP2A6 was optimized (rather than the absolute k<sub>cat</sub> values) to keep the ratio between the different k<sub>cat</sub> values constant.
+The parameter identification tool in PK-Sim has been used to estimate selected model parameters by adjusting to PK data of the clinical studies that were used in the model building process. For some of the parameters, factors were optimized to maintain their ratio, e.g. a factor for the kcat clearances values for CYP2B6, CYP3A4, CYP3A5, CYP1A2 and CYP2A6 was optimized to keep the ratio constant.
 
-The result of the final parameter identification is shown in the table below:
+The is result of the final parameter identification is shown in the table below:
 
 | Model Parameter            | Optimized Value | Unit |
 | -------------------------- | --------------- | ---- |
-| `Lipophilicity` | 3.437       |        |
-| `Specific intestinal permeability` | 2.972E-5    | cm/min |
-| `Solubility at Ref-pH` | 39.922   | mg/l |
-| `Fraction Unbound` | 5.955E-3 |  |
-| `kcat` (CYP2B6) | 1.601 (factor: 0.31833 of literature reference) | 1/min |
-| `kcat` (CYP3A4) | 0.051 (factor: 0.31833 of literature reference) | 1/min |
-| `kcat` (CYP3A5) | 0.191 (factor: 0.31833 of literature reference) | 1/min |
-| `kcat` (CYP1A2) | 0.191 (factor: 0.31833 of literature reference) | 1/min |
-| `kcat` (CYP2A6) | 0.318 (factor: 0.31833 of literature reference) | 1/min |
-| `EC50` (CYP3A4) | 0.071 (factor: 0.009711of literature reference) | µmol/l |
-| `EC50` (CYP2B6) | 0.012 (factor: 0.009711of literature reference) | µmol/l |
-| `Dissolution time (50% dissolved)` | 60 | min  |
-| `Dissolution shape` | 0.272 |   |
+| Lipophilicity             | 3.437       |        |
+| Specific intestinal permeability | 2.972E-5    | cm/min |
+| Solubility at reference pH | 39.922   | mg/l |
+| fraction unbound | 5.955E-3 |  |
+| kcat CYP2B6 | 1.601 (factor: 0.31833 of literature reference) | 1/min |
+| kcat CYP3A4 | 0.051 (factor: 0.31833 of literature reference) | 1/min |
+| kcat CYP3A5 | 0.191 (factor: 0.31833 of literature reference) | 1/min |
+| kcat CYP1A2 | 0.191 (factor: 0.31833 of literature reference) | 1/min |
+| kcat CYP2A6 | 0.318 (factor: 0.31833 of literature reference) | 1/min |
+| EC50 CYP3A4 | 0.071 (factor: 0.009711of literature reference) | µmol/l |
+| EC50 CYP2B6 | 0.012 (factor: 0.009711of literature reference) | µmol/l |
+| Dissolution time (50% dissolved) | 60 | min  |
+| Dissolution shape | 0.272 |   |
 
diff --git a/Evaluation/Workflow.m b/Evaluation/Workflow.m
@@ -11,8 +11,9 @@
 
 % --------------------------------------------------------------
 % replace qualificationRunnerFolder and markdownJoinerFolder with your paths
-qualificationRunnerFolder = 'C:\Open Systems Pharmacology\QualificationRunner 8.0.51';
-markdownJoinerFolder = 'C:\Open Systems Pharmacology\markdown-joiner';
+qualificationRunnerFolder = 'C:\Open Systems Pharmacology\QualificationRunner 9.0.82';
+markdownJoinerFolder = 'C:\Open Systems Pharmacology\markdown-joiner 1.2.0.8';
+PKSimPortableFolder = 'C:\OSP\PK-Sim9.0.163';
 
 % --------------------------------------------------------------
 % replace basisDir and qualificationPlanName with your paths
@@ -46,7 +47,7 @@
 
 % --------------------------------------------------------------
 % STEP #1: start qualification runner to generate inputs for the reporting engine
-startQualificationRunner(qualificationRunnerFolder, qualificationPlan, REInput_path);
+startQualificationRunner(qualificationRunnerFolder, qualificationPlan, REInput_path, ['-p ' PKSimPortableFolder ' --logLevel Debug']);
 
 % --------------------------------------------------------------
 % STEP #2: start reporting engine