TABLE 7

Prediction of the increase in midazolam AUC by macrolides using the steady-state enzyme level





Predicted AUC Ratioa

Reported
Pretreatment [I] Imaxb
Imax,uc
Iin,ud
AUC Ratio (mean ± S.D.) Reference


kdeg (min-1)
0.0005
0.00033
0.0005
0.00033
0.0005
0.00033


Erythromycin 500 mg t.i.d. for 6 days 11.9 17.6 3.2 4.3 4.6 6.5 4.4 ± 2.4 Olkkola et al., 1993
500 mg t.i.d. for 5 days 11.9 17.6 3.2 4.3 4.6 6.5 3.8 ± 2.4 Zimmermann et al., 1996
Clarithromycin 500 mg b.i.d. for 7 days 4.9 6.8 2.1 2.7 6.1 8.7 7.0 ± 4.2 Gorski et al., 1998
250 mg b.i.d. for 5 days 3.0 4.0 1.6 1.9 3.6 5.0 3.6 ± 1.7 Yeates et al., 1996
Azithromycin 500 mg o.d. for 3 days 1.0 1.0 1.0 1.0 1.0 1.1 1.3 ± 0.9 Zimmermann et al., 1996

500 mg o.d. for 3 days

1.0
1.0
1.0
1.0
1.0
1.1
1.2 ± 0.7
Yeates et al., 1996
  • a Predicted AUC ratio = (kdeg + kinact × [I]/(Kapp + [I]))/kdeg using Kapp and kinact for the inhibition of midazolam α-hydroxylation by human liver microsomes. Imax, Imax,u or Iin,u for [I].

  • b Imax, maximum concentration of inhibitor in the systemic blood.

  • c Imax,u, maximum unbound concentration of inhibitor in the systemic blood. Imax,u = Imax × fu where fu is unbound fraction.

  • d Iin,u, unbound concentration of inhibitor at the inlet to the liver. Iin,u = (Imax + ka D Fa/Q) × fu where ka is absorption rate constant, D is dose, Fa is fraction absorbed, and Q is hepatic blood flow.