Methods and results: A PBPK model in Simcyp (Massoud et al, 2009) software was set up and validated for a CYP3A4 and CYP2D6 substrate (SARXX) that exhibited a low clearance and a long terminal half-life in humans. Simulations in CYP2D6 PM and EM subjects assessed the impact of CYP3A4 inhibition through mechanism-based inhibition (e.g. erythromycin) and through the effect of a strong reversible inhibitor dosing regimen (200 mg bid versus 400 mg o.d. ketoconazole, 1 week) on the pharmacokinetics of SARXX. With a mechanism-based CYP3A4 inhibitor, even if the pharmacokinetic profile of this substrate is not covered by the inhibitor concentration, the inhibition is maintained suggesting that for such inhibition mechanism, the administration frequency is less critical. For a such combined CYP2D6 and CYP3A4 substrate (with low hepatic first pass-effect and long terminal half-life), eryhthomycin, considered as moderate CYP3A4 inhibitor provided higher inhibition compared to ketoconazole, considered as strong inhibitor, whatever the frequency of dosing (see table 1).
Conclusion: The in vivo CYP3A4 inhibitors classification, proposed several years ago, with the corresponding classical study designs (e.g. 400 mg od ketoconazole as strong inhibitor; 500 mg tid erythromycin, as moderate inhibitor) is based on the effect towards the CYP3A4 probe substrate midazolam (high first pass effect and short terminal half-life). This classification cannot be applied totally for CYP3A4 substrates with a low first pass effect and long terminal half-life. Mechanism types of the inhibitor, in addition to the pharmacokinetic features of both substrate and inhibitor have to be considered when designing a clinical interaction study to investigate the effect of CYP3A4 inhibitors and when classifying CYP3A4 inhibitors.
Zaho et al, J. Clin. Pharmacol, 49, 351-359, 2009.
Massoud et al, Expert Opinion, Drug Metabol, Tox, 5(2), 211-223, 2009 Table 1: Simulated steady-state AUC0-24 interactions ratios in CYP2D6 EM and PM after repeated co-administration of SARXX with ketoconazole (400 mg o.d. or 200 mg b.i.d.) or erythromycin 500 mg t.i.d.
Table 1: Simulated steady-state AUC0-24 interactions ratios in CYP2D6 EM and PM after repeated co-administration of SARXX with ketoconazole (400 mg o.d. or 200 mg b.i.d.) or erythromycin 500 mg t.i.d.
|Dosing regimen||AUC0-24 |
interaction ratio estimate [CI90%]
|CYP2D6 EM||CYP2D6 PM|
|Ketoconazole||400 mg OD||1.38|
|200 mg BID||1.52|
|Erythromycin||500 mg TID||1.63|
[1.55 ; 1.72]
[5.23 ; 6.23]