Rifabutin absorption in the gut unaltered by concomitant administration of didanosine in AIDS patients.
Didanosine (ddI) is currently used in the management of patients infected by the human immunodeficiency virus. Rifabutin (RBT) is being extensively used for prophylaxis against Mycobacterium avium complex (MAC) infections. Due to its acid-labile characteristics, ddI must be administered with a buffer. Recent reports have indicated that absorption of ketoconazole, ciprofloxacin, and dapsone, etc., in the gut is altered by concomitant ddI dosing. We have assessed whether concomitant dosing of ddI as antiretroviral therapy modifies RBT absorption in the gut, its steady-state pharmacokinetics, and/or safety in 15 patients with AIDS. Of the 15 patients enrolled, 12 completed the study and 3 receiving 600 mg of RBT with concomitant ddI administration withdrew prematurely from the study. Steady-state RBT pharmacokinetics were assessed on day 13 (ddI plus RBT) and day 16 (RBT alone). The ddI doses (adjusted for body weight) were 167 to 375 mg twice daily, while RBT was administered as a single 300- or 600-mg daily dose. No statistically significant (P > 0.05) differences were seen in RBT absorption parameter estimates between days 13 and 16: maximum concentration in plasma (Cmax; 511 +/- 341 ng/ml versus 525 +/- 254 ng/ml) and the time at which Cmax was observed (3.0 versus 2.5 h). The mean RBT estimates for area under the concentration-time curve from 0 to 24 h (AUC(0-tau)) (5,650 versus 5,023 ng x h/ml) and for oral clearance (1.28 versus 1.18 liter/h/kg) on both study days were also similar. Assessment based on urinary recovery of RBT (3.1 versus 3.7 mg) and its predominant deacetyl metabolite, LM565 (1.6 versus 1.4 mg), showed no apparent effect of ddI. The fraction of the RBT dose converted to LM565, as suggested by the ratio of AUC of the metabolite to AUC of the parent drug, was also unaltered (0.15 versus 0.12). A ratio analysis (day 13/day 16) of the RBT pharmacokinetic estimates showed that the 95% confidence intervals for all parameters were inclusive of one. Furthermore, the brief interruption of ddI therapy over this short study period at steady state produced no clinically significant changes in body weight, hematology, and renal and pancreatic functions. Therefore, concomitant administration of ddI appears not to affect RBT absorption in the gut and its disposition or safety in patients with AIDS.
Li
R C
RC
Department of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin. ronli@cuhk.edu.hk
Narang
P K
PK
Sahai
J
J
Cameron
W
W
Bianchine
J R
JR
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics*; D016049:Didanosine / Q000627:therapeutic use*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D015270:Mycobacterium avium-intracellulare Infection / Q000517:prevention & control; D017828:Rifabutin / Q000009:adverse effects / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D000904:Antibiotics, Antitubercular; D017828:Rifabutin; D016049:Didanosine