4 convert hyperlinks to lower case (#5)

* Fixes #4 Convert hyperlinks to lower case

* typo in README.md

* wordlist.txt

* wordlist.txt

* fix crossref

* fix crossref

Co-authored-by: Yuri05 <Yuri05@github.com>

.github/workflows/MarkdownLinksCheck.yml

@@ -0,0 +1,12 @@
+name: Check Markdown links
+
+on: 
+  push:
+    branches:
+      - review
+
+jobs:
+  markdown-link-check:
+    uses: Open-Systems-Pharmacology/Workflows/.github/workflows/MarkdownLinksCheck.yml@main
+    with:
+      folder-path: 'Evaluation/report'

.github/workflows/SpellChecker.yml

@@ -0,0 +1,8 @@
+name: Spellcheck
+
+on: 
+  [push, pull_request]
+
+jobs:
+  Spellcheck:
+    uses: Open-Systems-Pharmacology/Workflows/.github/workflows/SpellChecker.yml@main

.github/workflows/XRefCheck.yml

@@ -0,0 +1,12 @@
+name: XRefCheck
+
+on: 
+  push:
+    branches:
+      - review
+
+jobs:
+  crossref-check-without-anchors:
+    uses: Open-Systems-Pharmacology/Workflows/.github/workflows/XRefCheck.yml@main
+    with:
+      ignored-folders: 'Evaluation/Input'

.github/workflows/wordlist.txt

@@ -0,0 +1,4 @@
+agarwala
+ias
+iasconfpath
+reyataz

Evaluation/Input/Content/Concentration_time_profiles.md

@@ -1,2 +1,2 @@
-Simulated versus observed concentration-time profiles of all data listed in [Section 2.2.2](#222-Clinical-data) are presented below.
+Simulated versus observed concentration-time profiles of all data listed in [Section 2.2.2](#222-clinical-data) are presented below.
 

Evaluation/Input/Content/GOF_diagnostics.md

@@ -1,4 +1,4 @@
-Below you find the goodness-of-fit visual diagnostic plots for the PBPK model performance of all data used presented in [Section 2.2.2](#222-Clinical-data).
+Below you find the goodness-of-fit visual diagnostic plots for the PBPK model performance of all data used presented in [Section 2.2.2](#222-clinical-data).
 
 The first plot shows observed versus simulated plasma concentration, the second weighted residuals versus time. 
 

Evaluation/Input/Content/Section1_Introduction.md

@@ -2,5 +2,5 @@ The presented model building and evaluation report evaluates the performance of
 
 Atazanavir, sold under the trade name Reyataz among others, is an azapeptide protease inhibitor and used as antiretroviral medication to treat and prevent HIV/AIDS. It is taken orally once a day at a dose of 300 mg, if co-administered with ritonavir 100 mg orally once a day, and 400 mg, if administered without ritonavir. 
 
-After oral administration, atazanavir is rapidly absorbed. A positive food effect has been observed, atazanavir is recommended to be taken with food. Protein binding is relatively high (86%) and independent of the concentration of serum proteins ([US Food and Drug Administration 2002](#5-References)). Atazanavir undergoes extensive metabolism by CYP3A isoenzymes with a dose fraction excreted unchanged in urine of approximately 7% ([US Food and Drug Administration 2002](#5-References), [Le Tiec 2005](#5-References)). Previous in vitro studies suggest that atazanavir is a mechanism-based inhibitor of CYP3A ([US Food and Drug Administration 2002](#5-References), [Perloff 2005](#5-References)) as well as a competitive inhibitor of CYP1A2, CYP2C9 and UGT1A1 ([US Food and Drug Administration 2002](#5-References), [Zhang 2005](#5-References)).
+After oral administration, atazanavir is rapidly absorbed. A positive food effect has been observed, atazanavir is recommended to be taken with food. Protein binding is relatively high (86%) and independent of the concentration of serum proteins ([US Food and Drug Administration 2002](#5-references)). Atazanavir undergoes extensive metabolism by CYP3A isoenzymes with a dose fraction excreted unchanged in urine of approximately 7% ([US Food and Drug Administration 2002](#5-references), [Le Tiec 2005](#5-references)). Previous in vitro studies suggest that atazanavir is a mechanism-based inhibitor of CYP3A ([US Food and Drug Administration 2002](#5-references), [Perloff 2005](#5-references)) as well as a competitive inhibitor of CYP1A2, CYP2C9 and UGT1A1 ([US Food and Drug Administration 2002](#5-references), [Zhang 2005](#5-references)).
 

Evaluation/Input/Content/Section2.1_Modeling_Strategy.md

@@ -1,26 +1,26 @@
-The general workflow for building an adult PBPK model has been described by Kuepfer et al. ([Kuepfer 2016](#5-References)). Relevant information on the anthropometry (height, weight) was gathered from the respective clinical study, if reported. Information on physiological parameters (e.g. blood flows, organ volumes, hematocrit) in adults was gathered from the literature and has been incorporated in PK-Sim® as described previously ([Willmann 2007](#5-References)). The  applied activity and variability of plasma proteins and active processes that are integrated into PK-Sim® are described in the publicly available ‘PK-Sim® Ontogeny Database Version 7.3' ([PK-Sim Ontogeny Database Version 7.3](#5-References)).
+The general workflow for building an adult PBPK model has been described by Kuepfer et al. ([Kuepfer 2016](#5-references)). Relevant information on the anthropometry (height, weight) was gathered from the respective clinical study, if reported. Information on physiological parameters (e.g. blood flows, organ volumes, hematocrit) in adults was gathered from the literature and has been incorporated in PK-Sim® as described previously ([Willmann 2007](#5-references)). The  applied activity and variability of plasma proteins and active processes that are integrated into PK-Sim® are described in the publicly available ‘PK-Sim® Ontogeny Database Version 7.3' ([PK-Sim Ontogeny Database Version 7.3](#5-references)).
 
 The PBPK model was developed based on clinical data of healthy adult subjects obtained from the literature, covering available dosing ranges for oral administration. Plasma concentration-time profiles following multiple-dose application and mass balance information on the urinary excretion of unchanged atazanavir were included in model development. 
 
-First, a base mean model was built using plasma concentration-time profiles and the dose fraction excreted unchanged in urine following single dose administration of 400 mg po. The mean PK model was developed using a typical White American individual. Structural model selection was mainly guided by visual inspection of the resulting description of data and biological plausibility. The following parameters were identified using the Parameter Identification module provided in PK-Sim® and MoBi® ([Open Systems Pharmacology Documentation](#5-References)):
+First, a base mean model was built using plasma concentration-time profiles and the dose fraction excreted unchanged in urine following single dose administration of 400 mg po. The mean PK model was developed using a typical White American individual. Structural model selection was mainly guided by visual inspection of the resulting description of data and biological plausibility. The following parameters were identified using the Parameter Identification module provided in PK-Sim® and MoBi® ([Open Systems Pharmacology Documentation](#5-references)):
 
 - `Dissolution shape`
 - `Dissolution time (50% dissolved)`
 - `Specific intestinal permeability (transcellular)`
 - `GFR fraction`
 - `CLspec/[Enzyme]`
 
-Structural model selection was mainly guided by visual inspection of the resulting description of PK data and biological plausibility. On the basis of in vitro findings, atazanavir has been suggested to be a mechanism-based inhibitor of CYP3A ([Perloff 2005](#5-References)); however, no kinetic parameters have been reported for this interaction. Hence, to avoid non-identifiability issues, mechanism-based inhibition of CYP3A was not considered during parameter identification of the mean base model for single dose administration. All models implemented in PK-Sim for estimating the intracellular-to-plasma partition coefficient and those for estimating the permeability between interstitial and intracellular space were tested in this step. Once an appropriate structural model was identified, a second parameter identification was conducted fixing all previously optimized parameter values (except the `GFR fraction`) and including additional PK data following multiple dose administration of 200 mg, 300 mg, 400 mg, and 800 mg po. Optimized parameters were:
+Structural model selection was mainly guided by visual inspection of the resulting description of PK data and biological plausibility. On the basis of in vitro findings, atazanavir has been suggested to be a mechanism-based inhibitor of CYP3A ([Perloff 2005](#5-references)); however, no kinetic parameters have been reported for this interaction. Hence, to avoid non-identifiability issues, mechanism-based inhibition of CYP3A was not considered during parameter identification of the mean base model for single dose administration. All models implemented in PK-Sim for estimating the intracellular-to-plasma partition coefficient and those for estimating the permeability between interstitial and intracellular space were tested in this step. Once an appropriate structural model was identified, a second parameter identification was conducted fixing all previously optimized parameter values (except the `GFR fraction`) and including additional PK data following multiple dose administration of 200 mg, 300 mg, 400 mg, and 800 mg po. Optimized parameters were:
 
 - `GFR fraction`
 - `k_inact`
 - `k_kinact_half`
 
 Of note, since neither *in vitro* data on the kinetics of the mechanism-based inhibition of CYP3A nor *in vivo* pharmacokinetic data on drug-drug-interactions (DDI) with a CYP3A index substrate and atazanavir as CYP3A-perpetrator were available, the model should **not** be used to predict CYP3A DDI studies unless it has been verified for this purpose.
 
-Details about input data (physicochemical, *in vitro* and clinical) can be found in [Section 2.2](#22-Data).
+Details about input data (physicochemical, *in vitro* and clinical) can be found in [Section 2.2](#22-data).
 
-Details about the structural model and its parameters can be found in [Section 2.3](#23-Model-Parameters-and-Assumptions).
+Details about the structural model and its parameters can be found in [Section 2.3](#23-model-parameters-and-assumptions).
 
 
 

Evaluation/Input/Content/Section2.2_Data.md

@@ -4,20 +4,20 @@ A literature search was carried out to collect available information on physicoc
 
 | **Parameter**          | **Unit** | **Value**                                   | **Description**                                       |
 | :--------------------- | -------- | ------------------------------------------------------------ | ----------------------------------------------------- |
-| Molecular weight       | g/mol    | 704.9 ([drugbank.ca](#5-References))                         | Molecular weight                                      |
-| pK<sub>a</sub> (basic) |          | 4.7 ([Berlin 2015](#5-References))                           | Acid dissociation constant                            |
-| logP                   |          | 2.12 ([Hyland 2008](#5-References))                          | Partition coefficient between octanol and water       |
-| f<sub>u</sub>          |          | 0.14 ([US Food and Drug Administration 2002](#5-References)) | Fraction unbound in human plasma                      |
-| Solubililty in FaSSIF  | µg/mL    | 2.74 ([Berlin 2015](#5-References))                          | Solubility in Fasted State Simulated Intestinal Fluid |
-| Solubililty in FeSSIF  | µg/mL    | 4.13 ([Berlin 2015](#5-References))                          | Solubility in Fed State Simulated Intestinal Fluid    |
+| Molecular weight       | g/mol    | 704.9 ([drugbank.ca](#5-references))                         | Molecular weight                                      |
+| pK<sub>a</sub> (basic) |          | 4.7 ([Berlin 2015](#5-references))                           | Acid dissociation constant                            |
+| logP                   |          | 2.12 ([Hyland 2008](#5-references))                          | Partition coefficient between octanol and water       |
+| f<sub>u</sub>          |          | 0.14 ([US Food and Drug Administration 2002](#5-references)) | Fraction unbound in human plasma                      |
+| Solubililty in FaSSIF  | µg/mL    | 2.74 ([Berlin 2015](#5-references))                          | Solubility in Fasted State Simulated Intestinal Fluid |
+| Solubililty in FeSSIF  | µg/mL    | 4.13 ([Berlin 2015](#5-references))                          | Solubility in Fed State Simulated Intestinal Fluid    |
 
-With regard to UGT1A1 inhibition, atazanavir inhibited 17β-Estradiol glucuronidation in recombinant UGT1A1 by a mixed-type mechanism (in-house data, [Jungmann 2019](#5-References)):
+With regard to UGT1A1 inhibition, atazanavir inhibited 17β-Estradiol glucuronidation in recombinant UGT1A1 by a mixed-type mechanism (in-house data, [Jungmann 2019](#5-references)):
 
 | **Parameter**    | **Unit** | **Value** | Source                         | **Description**                      |
 | :--------------- | -------- | --------- | ------------------------------ | ------------------------------------ |
-| K<sub>i</sub>    | µmol/L   | 0.22      | [Jungmann 2019](#5-References) | Inhibition constant                  |
-| Alpha            |          | 4.5       | [Jungmann 2019](#5-References) | Alpha value in mixed-type inhibition |
-| fu<sub>mic</sub> | %        | 0.863     | [Fricke 2020](#5-References)   | determined *in vitro* at 0.22 µmol/L |
+| K<sub>i</sub>    | µmol/L   | 0.22      | [Jungmann 2019](#5-references) | Inhibition constant                  |
+| Alpha            |          | 4.5       | [Jungmann 2019](#5-references) | Alpha value in mixed-type inhibition |
+| fu<sub>mic</sub> | %        | 0.863     | [Fricke 2020](#5-references)   | determined *in vitro* at 0.22 µmol/L |
 
 ### 2.2.2 Clinical data
 
@@ -27,12 +27,12 @@ The following publications were found and used for model building and evaluation
 
 | Publication                                           | Study description                                            |
 | :---------------------------------------------------- | :----------------------------------------------------------- |
-| [Acosta 2007](#5-References)                          | 300 mg atazanavir BID, Period 1                              |
-| [Agarwala 2003](#5-References)                        | 400 mg atazanavir QD, Day 6                                  |
-| [Agarwala 2005a](#5-References)                       | 400 mg atazanavir QD, 400 mg AM                              |
-| [Agarwala 2005b](#5-References)                       | 400 mg atazanavir QD, 400 mg (Treatment A)                   |
-| [Martin 2008](#5-References)                          | 400 mg atazanavir QD, monotherapy                            |
-| [Zhu 2010](#5-References)                             | 300 mg atazanavir QD                                         |
-| [Zhu 2011](#5-References)                             | 400 mg atazanavir QD, 400 mg QPM and QAM                     |
-| [US Food and Drug Administration 2002](#5-References) | Study AI424-004 (p. 94): 400 mg atazanavir single dose (treatment A);<br />Study AI424-014 (p. 77): 400 mg atazanavir single dose (young females & males);<br />Study AI424-015 (p. 81): 400 mg atazanavir single dose (normal subjects);<br />Study AI424-028 (p. 128): 200, 400, and 800 mg atazanavir QD (A-D Day6);<br />Study AI424-029 (p. 47): 400 mg [<sup>14</sup>C]atazanavir single dose;<br />Study AI424-040 (p. 64): 200, 400, and 800 mg atazanavir QD;<br />Study AI424-056 (p. 134): 300 mg atazanavir QD (without ritonavir, Day 10);<br />Study AI424-076 (p. 178): 400 and 800 mg atazanavir QD |
+| [Acosta 2007](#5-references)                          | 300 mg atazanavir BID, Period 1                              |
+| [Agarwala 2003](#5-references)                        | 400 mg atazanavir QD, Day 6                                  |
+| [Agarwala 2005a](#5-references)                       | 400 mg atazanavir QD, 400 mg AM                              |
+| [Agarwala 2005b](#5-references)                       | 400 mg atazanavir QD, 400 mg (Treatment A)                   |
+| [Martin 2008](#5-references)                          | 400 mg atazanavir QD, monotherapy                            |
+| [Zhu 2010](#5-references)                             | 300 mg atazanavir QD                                         |
+| [Zhu 2011](#5-references)                             | 400 mg atazanavir QD, 400 mg QPM and QAM                     |
+| [US Food and Drug Administration 2002](#5-references) | Study AI424-004 (p. 94): 400 mg atazanavir single dose (treatment A);<br />Study AI424-014 (p. 77): 400 mg atazanavir single dose (young females & males);<br />Study AI424-015 (p. 81): 400 mg atazanavir single dose (normal subjects);<br />Study AI424-028 (p. 128): 200, 400, and 800 mg atazanavir QD (A-D Day6);<br />Study AI424-029 (p. 47): 400 mg [<sup>14</sup>C]atazanavir single dose;<br />Study AI424-040 (p. 64): 200, 400, and 800 mg atazanavir QD;<br />Study AI424-056 (p. 134): 300 mg atazanavir QD (without ritonavir, Day 10);<br />Study AI424-076 (p. 178): 400 and 800 mg atazanavir QD |