GSK3 Signaling Pathway simvastatin was shown to significantly rease the exposure of these statins

to inhibit UGT1A1 in vitro , it was possible that coadministration of Nobiletin GSK2248761 could rease RAL exposure. Consistent with many drug drug studies, RAL was associated with large intersubject variability . However, the changes observed in RAL PK when coadministered with GSK2248761 were not clinically significant. Thus, no RAL dosage adjustments are required when RAL is coadministered with GSK2248761. The reases in midazolam and dextromethorphan AUC of 50% to 80% when each was coadministered with GSK2248761 indicate GSK2248761 is a weak CYP3A4 and CYP2D6 inhibitor, while the lack of effect of flurbiprofen suggests GSK2248761 does not effect CYP2C9 activity. These data confirm the findings of the phase I trial with ATV and suggest GSK2248761 interaction potential when coadministered with other drugs that are primarily metabolized through CYP450.
Given that midazolam, DRV, and LPV are all predominantly metabolized by CYP3A4, the decrease in LPV exposure is onsistent with the reased midazolam exposure and lack of change in the DRV/RTV exposure. At this time, the mechanism involved GSK3 Signaling Pathway in the reduced LPV/RTV concentrations observed with GSK2248761 coadministration is unknown, and the clinical significance of this interaction remains to be determined. The greater rease in exposure of GSK2248761 after a single dose than after repeated doses may have occurred because the inhibition of CYP3A4 or other enzymes/transporters was counteracted by induction of these enzymes/transporters after repeat dosing.
These reases in GSK2248761 are not considered clinically significant because GSK2248761 doses up to 800 mg QD have been administered to HIV infected subjects electron microscopy without clinically significant drugrelated side effects. Thus, no GSK2248761 dosage adjustments are required when coadministered with DRV/RTV or LPV/RTV. Several antiretroviral agents that affect CYP3A4 are known to influence statin exposure. Efavirenz, a mixed inducer/inhibitor of CYP3A4, was associated with ≥40% reductions in atorvastatin, pravastatin, and simvastatin exposure , while protease inhibitor boosters such as ritonavir and saquinavir have been shown to rease exposure of atorvastatin by 79% and simvastatin by up to 3000% . Due to the magnitude of potential inhibition of simvastatin metabolism , drugs that inhibit CYP3A4 are not recommended for coadministration with simvastatin .
In these studies, coadministration of GSK2248761 with atorvastatin, rosuvastatin, and simvastatin was shown to significantly rease the exposure of these statins. Simvastatin was the most sensitive to inhibition by GSK2248761, consistent with trends noted for other antiretroviral therapies that inhibit CYP3A4. The net atorvastatin related inhibition by GSK2248761 was minimal as the reases in atorvastatin exposure were potentially offset by decreases in exposure of ortho hydroxy the CYP3A4 mediated active metabolite of atorvastatin. Exposures of rosuvastatin were reased by 26% to 32% after coadministration with GSK2248761 relative to rosuvastatin alone. Therefore, atorvastatin and rosuvastatin would be preferable to simvastatin for the treatment of hyperlipidemia in patients receiving GSK2248761 for HIV 1 infection, and monitoring of AEs related to reases in any HMG CoA reductase inhibitor is warranted.