Concentrations and effects of zopiclone are greatly reduced by rifampicin

Aims The effects of rifampicin on the pharmacokinetics and pharmacodynamics of zopiclone, a non-benzodiazepine hypnotic, were studied. Methods In a randomized, placebo-controlled cross-over study with two phases, eight young healthy volunteers took either 600 mg rifampicin or placebo once daily for 5 days. On the 6th day, 10 mg zopiclone was administered orally. Plasma zopiclone concentrations and effects of zopiclone were measured for 10 h. Results The total area under the plasma zopiclone concentration-time curve after rifampicin was 18.0% (95% CI 13.5 - 22.5%) of that after placebo (86.1 +/- 34.5 ng ml(-1) h vs 473 +/- 114 ng ml(-1) h (mean +/- s.d.); P < 0.001). Rifampicin decreased the peak plasma concentration of zopiclone from 76.9 +/- 27.2 ng ml(-1) to 22.5 +/- 6.0 ng ml(-1) (P < 0.001) and the half-life from 3.8 +/- 0.6 h to 2.3 +/- 0.9 h (P < 0.005). A significant (P < 0.02) reduction in the effects of zopiclone was seen in three of the five psychomotor tests used (digit symbol substitution test, critical flicker fusion test and Maddox wing test) after rifampicin pretreatment. Conclusions The strong interaction of rifampicin with zopiclone is due to enhanced metabolism of zopiclone. Zopiclone may show a reduced hypnotic effect when used concomitantly with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.