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Fixes #10 Update evaluation plan (#11)
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Co-authored-by: Yuri05 <Yuri05@github.com>
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Yuri05 and Yuri05 committed Aug 27, 2024
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0 Digoxin.json → Digoxin-Model.json
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2 changes: 1 addition & 1 deletion Evaluation/Input/Content/References.md
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**Greiner 1999** Greiner, B. et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J. Clin. Invest. 104, 147–53 (1999).

**Gurley 2008** Gurley, B.J., Swain, A., Williams, D.K., Barone, G. & Battu, S.K. Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John’s wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol. Nutr. food Res. 52, 772–9 (2008).
**Gurley 2008b** Gurley, B.J., Swain, A., Williams, D.K., Barone, G. & Battu, S.K. Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John’s wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol. Nutr. food Res. 52, 772–9 (2008).

**Hanke 2018** Hanke N, Frechen S, Moj D, Britz H, Eissing T, Wendl T, Lehr T. PBPK Models for CYP3A4 and P-gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin. CPT Pharmacometrics Syst Pharmacol.. 2018 Oct;7(10):647-659.

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4 changes: 2 additions & 2 deletions Evaluation/Input/Content/Section1_Introduction.md
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The presented model building and evaluation report evaluates the performance of a PBPK model for digoxin in adults.

Digoxin is a cardiac glycoside used to treat atrial fibrillation, atrial flutter and heart failure.
Digoxin is transported by P-glycoprotein 1 (P-gp), also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) poly-glycoprotein. P-gp and mainly excreted unchanged via the kidneys with a small fraction eliminated via biliary excretion and only a very low degree of hepatic metabolism ([Greiner 1999, Ochs 1878 ](#References)).
Digoxin is transported by P-glycoprotein 1 (P-gp), also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) poly-glycoprotein. P-gp and mainly excreted unchanged via the kidneys with a small fraction eliminated via biliary excretion and only a very low degree of hepatic metabolism ([Greiner 1999, Ochs 1978 ](#References)).
Many other substrates of P-gp are metabolized by CYP3A4, setting digoxin apart as an
exception and thereby turning it into a model victim drug of P-gp-mediated DDIs.

Digoxin is reported to have a large volume of distribution due to extensive tissue binding and to be mainly excreted unchanged to urine (50 - 70%) while the remainder of a dose is eliminated by hepatic metabolism and biliary excretion ([Ochs 1878, Bauer 2008](#References))]. The final digoxin model applies target-binding, transport by P-gp in various organs including gut, liver and kidney, an unspecific hepatic metabolic clearance and glomerular filtration, and adequately described the pharmacokinetics of digoxin in adults.
Digoxin is reported to have a large volume of distribution due to extensive tissue binding and to be mainly excreted unchanged to urine (50 - 70%) while the remainder of a dose is eliminated by hepatic metabolism and biliary excretion ([Ochs 1978, Bauer 2008](#References))]. The final digoxin model applies target-binding, transport by P-gp in various organs including gut, liver and kidney, an unspecific hepatic metabolic clearance and glomerular filtration, and adequately described the pharmacokinetics of digoxin in adults.

The digoxin model is a whole-body PBPK model, allowing for dynamic translation between individuals. The digoxin report demonstrates the level of confidence in the digoxin PBPK model with the OSP suite with regard to reliable predictions of digoxin PK in adults during model-informed drug development.

2 changes: 1 addition & 1 deletion Evaluation/Input/Content/Section2.2_Data_used.md
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Expand Up @@ -39,7 +39,7 @@ The following publications were found in adults for model building and evaluatio
| [Eckermann 2012](#References) | Eckermann, G., Lahu, G., Nassr, N. & Bethke, T.D. Absence of pharmacokinetic interaction between roflumilast and digoxin in healthy adults. J. Clin. Pharmacol. 52, 251–7 (2012). |
| [Friedrich 2011](#References) | Friedrich, C. et al. Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers. Eur. J. Drug Metab. Pharmacokinet. 36, 17–24 (2011). |
| [Greiner 1999](#References) | Greiner, B. et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J. Clin. Invest. 104, 147–53 (1999). |
| [Gurley 2008](#References) | Gurley, B.J., Swain, A., Williams, D.K., Barone, G. & Battu, S.K. Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John’s wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol. Nutr. food Res. 52, 772–9 (2008). |
| [Gurley 2008b](#References) | Gurley, B.J., Swain, A., Williams, D.K., Barone, G. & Battu, S.K. Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John’s wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. Mol. Nutr. food Res. 52, 772–9 (2008). |
| [Hayward 1978](#References) | Hayward, R.P., Greenwood, H. & Hamer, J. Comparison of digoxin and medigoxin in normal subjects. Br. J. Clin. Pharmacol. 6, 81–6 (1978). |
| [Jalava 1997 ](#References) | Jalava, K.M., Partanen, J. & Neuvonen, P.J. Itraconazole decreases renal clearance of digoxin. Ther. Drug Monit. 19, 609–13 (1997). |
| [Johne 1999](#References) | Johne, A. et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin. Pharmacol. Ther. 66, 338–45 (1999). |
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22 changes: 11 additions & 11 deletions Evaluation/Input/evaluation_plan.json
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"Projects": [
{
"Id": "Digoxin",
"Path": "../../Digoxin.json",
"Path": "../../Digoxin-Model.json",
"BuildingBlocks": []
}
],
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"Project": "Digoxin",
"Simulation": "Digoxin colon, 0.5 mg",
"Output": "Organism|PeripheralVenousBlood|Digoxin|Plasma (Peripheral Venous Blood)",
"ObservedData": "Ochs 1975 - 0.5mg Patient 1 with normal colon mucosa - Digoxin - IV - 0.5 mg - Plasma - indiv.",
"ObservedData": "Ochs 1975 - 0.5mg Patient 1 with normal colon mucosa - Digoxin - Intracolonic - 0.5 mg - Plasma - indiv.",
"Color": "#000000"
},
{
"Project": "Digoxin",
"Simulation": "Digoxin colon, 0.5 mg",
"Output": "Organism|PeripheralVenousBlood|Digoxin|Plasma (Peripheral Venous Blood)",
"ObservedData": "Ochs 1975 - 0.5mg Patient 2 with normal colon mucosa - Digoxin - IV - 0.5 mg - Plasma - indiv.",
"ObservedData": "Ochs 1975 - 0.5mg Patient 2 with normal colon mucosa - Digoxin - Intracolonic - 0.5 mg - Plasma - indiv.",
"Color": "#000000"
},
{
"Project": "Digoxin",
"Simulation": "Digoxin colon, 0.5 mg",
"Output": "Organism|PeripheralVenousBlood|Digoxin|Plasma (Peripheral Venous Blood)",
"ObservedData": "Ochs 1975 - 0.5mg Patient 3 with normal colon mucosa - Digoxin - IV - 0.5 mg - Plasma - indiv.",
"ObservedData": "Ochs 1975 - 0.5mg Patient 3 with normal colon mucosa - Digoxin - Intracolonic - 0.5 mg - Plasma - indiv.",
"Color": "#000000"
},
{
"Project": "Digoxin",
"Simulation": "Digoxin colon, 0.5 mg",
"Output": "Organism|PeripheralVenousBlood|Digoxin|Plasma (Peripheral Venous Blood)",
"ObservedData": "Ochs 1975 - 0.5mg Patient 4 with normal colon mucosa - Digoxin - IV - 0.5 mg - Plasma - indiv.",
"ObservedData": "Ochs 1975 - 0.5mg Patient 4 with normal colon mucosa - Digoxin - Intracolonic - 0.5 mg - Plasma - indiv.",
"Color": "#000000"
},
{
"Project": "Digoxin",
"Simulation": "Digoxin colon, 0.5 mg",
"Output": "Organism|PeripheralVenousBlood|Digoxin|Plasma (Peripheral Venous Blood)",
"ObservedData": "Ochs 1975 - 0.5mg Patient 5 with normal colon mucosa - Digoxin - IV - 0.5 mg - Plasma - indiv.",
"ObservedData": "Ochs 1975 - 0.5mg Patient 5 with normal colon mucosa - Digoxin - Intracolonic - 0.5 mg - Plasma - indiv.",
"Color": "#000000"
},
{
"Project": "Digoxin",
"Simulation": "Digoxin colon, 0.5 mg",
"Output": "Organism|PeripheralVenousBlood|Digoxin|Plasma (Peripheral Venous Blood)",
"ObservedData": "Ochs 1975 - 0.5mg Patient 6 with normal colon mucosa - Digoxin - IV - 0.5 mg - Plasma - indiv.",
"ObservedData": "Ochs 1975 - 0.5mg Patient 6 with normal colon mucosa - Digoxin - Intracolonic - 0.5 mg - Plasma - indiv.",
"Color": "#000000"
},
{
"Project": "Digoxin",
"Simulation": "Digoxin colon, 0.5 mg",
"Output": "Organism|PeripheralVenousBlood|Digoxin|Plasma (Peripheral Venous Blood)",
"ObservedData": "Ochs 1975 - 0.5mg Patient 7 with normal colon mucosa - Digoxin - IV - 0.5 mg - Plasma - indiv.",
"ObservedData": "Ochs 1975 - 0.5mg Patient 7 with normal colon mucosa - Digoxin - Intracolonic - 0.5 mg - Plasma - indiv.",
"Color": "#000000"
},
{
"Project": "Digoxin",
"Simulation": "Digoxin colon, 0.5 mg",
"Output": "Organism|PeripheralVenousBlood|Digoxin|Plasma (Peripheral Venous Blood)",
"ObservedData": "Ochs 1975 - 0.5mg Patient 8 with normal colon mucosa - Digoxin - IV - 0.5 mg - Plasma - indiv.",
"ObservedData": "Ochs 1975 - 0.5mg Patient 8 with normal colon mucosa - Digoxin - Intracolonic - 0.5 mg - Plasma - indiv.",
"Color": "#000000"
}
]
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"Project": "Digoxin",
"Simulation": "Digoxin iv, 1.0 mg, Bolus",
"Output": "Organism|PeripheralVenousBlood|Digoxin|Plasma (Peripheral Venous Blood)",
"ObservedData": "Kramer 1979 - 1mg iv bolus - Digoxin - IV - 1 mg - Serum - agg. (n=12)",
"ObservedData": "Kramer 1979 - 1mg iv bolus - Digoxin - IV - 1 mg - Plasma - agg. (n=12)",
"Color": "#FF0000"
},
{
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"Project": "Digoxin",
"Simulation": "Digoxin po, 0.25 mg",
"Output": "Organism|PeripheralVenousBlood|Digoxin|Plasma (Peripheral Venous Blood)",
"ObservedData": "Gurley 2008 - Control (Perpetrator Placebo) - Digoxin - PO - 0.25 mg - Serum - agg. (n=18)",
"ObservedData": "Gurley 2008b - Control (Perpetrator Placebo) - Digoxin - PO - 0.25 mg - Serum - agg. (n=18)",
"Color": "#005295"
},
{
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