Predicted vs. observed AUC increases of simvastatin acid after coadministration or dose staggering (12 h apart) with telithromycin based upon combined reversible inhibition/inactivation of intestinal CYP3A4 (fm = 0.4) and hepatic CYP3A4 (fm = 0.83) with inhibition of hepatic OATP1B1 (fe = 0.79)
Numbers in square brackets are the calculated predicted AUCR range using the upper and lower 95% confidence intervals determined for each inhibitory kinetic parameter given in Table 1. To determine the lower predicted AUCR, the upper confidence interval for Ki and KI values and the lower confidence interval for kinact were used for calculations. To determine the upper predicted AUCR, the lower confidence interval for Ki and KI values, and the upper confidence interval for kinact were used for calculations.
| Perpetrator Drug | Dose (mg) | Predicted Fold Increase in AUC due to Inhibition of Composite Pathways | Overall Predicted AUCR | Clinically Observed AUCR | Primary Mechanism of DDI | ||
|---|---|---|---|---|---|---|---|
| Intestinal CYP3A4 (theoretical maximum = 1.67) | OATP1B1 (theoretical maximum = 4.76) | Hepatic CYP3A4 (theoretical maximum = 5.88) | |||||
| mg | |||||||
| Telithromycin (coadministered) | 800 | 1.66 [1.66–1.67] | 1.16 [1.12–1.22] | 5.62 [5.45–5.74] | 10.8 [10.1–11.7] | 9.4a–10.8b | CYP3A4 reversible inhibition/inactivation |
| Telithromycin (12 h apart) | 800 | 1.49 [1.38–1.58]c | 1.01 [1.00–1.01]c | 3.60 [2.79–4.62]c | 5.4 [3.85–7.37] | 4.3a | CYP3A4 inactivation |
↵a Study Number 1065; Drug FDA approval package review 1 (Clinical Pharmacology Biopharmaceutics Review Part 1, accessed via Drugs@FDA database; www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-144_Ketek_BioPharmr_P1.pdf).
↵b Study Number 1048; Drug FDA approval package review 4 (Clinical Pharmacology Biopharmaceutics Review Part 4, accessed via Drugs@FDA database; www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-144_Ketek_BioPharmr_P4.pdf).
↵c Using [C12 h u] plasma concentration for [I].