Comparison of midazolam (MDZ) and simvastatin (SV) as cytochrome P450 (CYP) 3A probes during baseline (BAS), inhibition (INHIB), and induction (INDUC)

MDZ is a validated CYP3A biomarker but disadvantages make it a suboptimal probe. The FDA has suggested the use of SV as a CYP3A biomarker to assess drug interactions (DIs). SV is a P‐glycoprotein (PGP) substrate and its metabolism is mainly via CYP3A with CYP2C8 having a minor role. The aim of this study was to compare SV with MDZ before and after INHIB and INDUC of CYP3A enzyme activity in a fixed sequential, open label, 3‐way crossover study. 19 adults (9M/10F, mean age 38.2±8.7 yr) randomly received single doses of oral MDZ 0.075mg/kg and SV 40mg, 1 to 3d apart, during 3 phases [BAS, INHIB with ketoconazole 400mg x 10d, & INDUC with rifampin 600mg x 9d]. The washout period between phases was 1 & 2 wk after BAS & INHIB, respectively. Area under the plasma concentration time curve (AUC) for MDZ & SV was calculated by a noncompartmental model using WinNonlin®. Log transformed AUCs were evaluated by Pearson correlation (r). Mean increases in AUC from BAS to INHIB were 883%±304% (MDZ) & 1335%±747% (SV). Mean decreases from BAS to INDUC were 87%±4% (MDZ) & 89%±11% (SV). Correlation of AUCs for MDZ vs SV at BAS was r=0.56 (p=0.01); during INHIB, r=0.43 (p=0.07); during INDUC, r=0.36 (p=0.15). SV metabolism may not be influenced only by altered CYP3A activity but by altered CYP2C8 and/or PGP activity during INHIB and INDUC. SV is not a useful biomarker compared to the validated probe MDZ for studying CYP3A DIs due to its lack of CYP3A specificity. Clinical Pharmacology & Therapeutics (2004) 75 , P96–P96; doi: 10.1016/j.clpt.2003.11.365