A MODEL-BASED ASSESSMENT OF REDISTRIBUTION DEPENDENT ELIMINATION AND BIOAVAILABILITY OF RIFABUTIN

The autoinduction characteristic of rifabutin (RIF) following multiple oral dosing was investigated via pharmacokinetic modeling. A two-comp artment model with first-order absorption was fit to plasma RIF data o btained from a study conducted in healthy normal volunteers following both a single and multiple oral doses. Parameter estimates showed an e limination rate constant (k(10)) of about 0.12-0.14 h(-1) which was in dependent of the single or multiple-dosing condition. The lower-than-e xpected drug accumulation following multiple dosing seems to suggest t hat prolonged dosing perturbs the linear kinetic system. However, this analysis has shown no significant changes (p>0.05) in the rate consta nts describing RIF absorption, tissue distribution/redistribution, and elimination. The mean rate of drug redistribution from the tissue com partment (k(21); 0.04-0.06 h(-1)) was twofold to threefold lower than k(10), and, with a large steady-state distribution volume (V-ss/F afte r a single dose, 1630 L), RIF elimination appears to be dependent on d rug redistribution. This hypothesis was further supported by a signifi cant correlation (p<0.01) between RIF tissue redistribution (k(21)) an d terminal disposition phase rate (lambda(z)) constants. The redistrib ution dependent elimination of RIF also helps explain the stability of the terminal half-life under both single and multiple-dosing paradigm s, Urinary excretion of RIF and its 25-O-deacetyl metabolite totalled less than 7% of the oral dose following single dosing, and decreased t o about 4% after multiple dosing. For individual patients, the decreas e in urinary recovery of the 25-O-deacetyl metabolite was directly pro portional to the decrease in urinary RIF recovery. In addition, both e stimates of the model intercepts (A and B) were lower following multip le dosing, Further analyses revealed a linear relationship between A a nd B intercepts, and also between the urinary RIF recovery and the B i ntercept. These relationships, in conjunction with the lack of signifi cant increase in the rate of elimination, indicate that induction of p resystemic extrahepatic metabolism and/or decrease in the extent of or al absorption may be the primary causes for the lower-than-expected sy stemic RIF plasma levels after multiple oral dosing.