Effect of fluoxetine on pharmacokinetics of ritonavir

The potential interaction between fluoxetine, a known inhibitor of cytochro me P-450 isoform 2D6 (CYP2D6), and ritonavir, a human immunodeficiency viru s type 1 protease inhibitor, was evaluated in this open-label study. Sixtee n male and female subjects ranging in age from 18 to 40 years completed the study, Subjects received single doses of 600 mg of ritonavir on days 1 and 10. On study days 3 to 10, all subjects received 30 mg of fluoxetine every 12 h for a total of 16 consecutive doses. Serial blood samples for determi nation of ritonavir concentrations in plasma were collected after the admin istration of ritonavir on days 1 and 10, A limited number of blood samples for determination of fluoxetine and norfluoxetine concentrations were colle cted after administration of the morning dose on day 10. A statistically si gnificant increase (19%) in the ritonavir area under the concentration-time curve (AUC) was observed with concomitant fluoxetine administration, with individual changes ranging from -12 to +56%. The change in the ritonavir AU C with concomitant fluoxetine administration,vas positively correlated with the norfluoxetine 24-h AUC (AUC,,) (r(2) = 0.42), the norfluoxetine/fluoxe tine AUC(24) ratio (r(2) = 0.53), and the fluoxetine elimination rate const ant (r(2) = 0.65), with larger increases in the ritonavir AUC tending to oc cur with higher norfluoxetine concentrations and higher fluoxetine eliminat ion rate constants. The effect of fluoxetine appeared to be larger in subje cts with the CYP2D6 wt/wt genotype. There was little or no effect on the ti me to maximum drug concentration (C-max) in serum, C-max, and the eliminati on rate constant of ritonavir with concomitant fluoxetine administration. C onsidering the magnitude of the change observed, no ritonavir dose adjustme nt is recommended during concomitant fluoxetine administration.