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Brand Name(s) include: Daraprim
Disease: Malaria
Drug Class: Antimalarials
Date Updated: November 2021
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Note: Kp scalar used |
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The current model does not mechanistically describe the absorption of pyrimethamine as the ADAM model over-predicts the extent of absorption. Although pyrimethamine is described as well absorbed in some literature, further analysis of the IV and PO data did not support this. |
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Updates in V19 |
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Prepared: June 2023 The RES-Eltrombopag_V21 model has been developed primarily as an inhibitor of hepatic OATP1B1 and OATP1B3, and intestinal BCRP using the New GI physiology in Simcyp V21 with altered GI tract population inputs that became default in V22. The file is verified as tablet in the fasted state as that formulation was used in the Rosuvastatin DDI (Allred et al., 2011). The PK for Eltrombopag was evaluated at 25mg, 50mg and 75mg SD; 50mg QD, 100mg QD, 150mg QD, and 200mg QD. Note, the Rosuvastatin DDI with 75mg QD was used to fit the BCRP component in Rosuvastatin V21 file using the New GI physiology. The BCRP component of Rosuvastatin was then verified with other BCRP-Inhibitors available on the members area (as specified in the attached document) or within the Simcyp Simulator. Allred, A. J., C. J. Bowen, J. W. Park, B. Peng, D. D. Williams, M. B. Wire, and E. Lee. 2011. “Eltrombopag Increases Plasma Rosuvastatin Exposure in Healthy Volunteers.” Journal Article. Br J Clin Pharmacol 72 (2): 321–29.
The RES-Darolutamide_V21 model has been developed primarily as inhibitor of hepatic OATP1B1 and OATP1B3, and intestinal BCRP using the New GI physiology in Simcyp V21 with altered GI tract population inputs that became default in V22. Darolutamide shows dose proportional PK between 100 to 700 mg BID. It is a BSCII compound, where the metabolite is a potent BCRP-inhibitor too. Darolutamide is possibly a weak CYP3A inducer in the clinic. The back-conversion of Keto-darolutamide to Darolutamide is efficiently catalyzed via cytosolic AKR1C3 (in vitro). This back-conversion is also observed in incubations of feces under anaerobic conditions (in vitro). In the compound fit-for-purpose compound file, the back-conversion was fixed to recover the concentration time profile for the 600 mg BID as this was the dose for the reported Rosuvastatin DDI. Note that two workspaces need to be run to simulate the Darolutamide DDI and then the results have to be combined. This is due to having to switch the position of Darolutamide and rosuvastatin (limitations on functionality on inhibitory metabolite in the Simcyp Simulator currently).
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