By simulating the simultaneous administration of CYP3A4 substrate with ritonavir by PK-Sim, the CYP3A4 concentration in the liver has been reduced to 0.01-0.15. I then modeled the co-administration of CYP3A4 substrates with ritonavir and clarithromycin, which resulted in a significant increase in the exposure of ritonavir + clarithromycin combined with CPY3A4 substrates compared to co-administration with ritonavir.
Then, I modified the CYP3A4 substrate in the model so that no enzyme metabolized it, and the simulation came out with higher exposure than the co-administration of the three drugs.
However, there is no clinical data available for validation at this time. Still, my colleagues and I agree that the PBPK simulation results of two strong inhibitors of CYP3A4 combined with a CYP3A4 substrate may have overestimated the exposure of the CYP3A4 substrate.
Is there a reasonable explanation for this? Or am I overlooking the details of simulating co-administration in PK-sim?
By simulating the simultaneous administration of CYP3A4 substrate with ritonavir by PK-Sim, the CYP3A4 concentration in the liver has been reduced to 0.01-0.15. I then modeled the co-administration of CYP3A4 substrates with ritonavir and clarithromycin, which resulted in a significant increase in the exposure of ritonavir + clarithromycin combined with CPY3A4 substrates compared to co-administration with ritonavir. Then, I modified the CYP3A4 substrate in the model so that no enzyme metabolized it, and the simulation came out with higher exposure than the co-administration of the three drugs. However, there is no clinical data available for validation at this time. Still, my colleagues and I agree that the PBPK simulation results of two strong inhibitors of CYP3A4 combined with a CYP3A4 substrate may have overestimated the exposure of the CYP3A4 substrate. Is there a reasonable explanation for this? Or am I overlooking the details of simulating co-administration in PK-sim?