Pharmacokinetic interaction of megestrol acetate with zidovudine in human immunodeficiency virus-infected patients.
This nonrandomized, two-period crossover study was performed to assess whether concomitant administration of megestrol acetate influences the steady-state pharmacokinetics of zidovudine and its inactive 5'-O-glucuronide metabolite. Twelve HIV-positive, asymptomatic male volunteers received a 100-mg oral capsule dose of zidovudine at least 30 min before meals five times a day at 0700, 1100, 1500, 1900, and 2300 h on study days 1 to 3 and a single 100-mg dose at 0700 h on day 4. On days 5 to 17, 800 mg of megestrol acetate, as a 40-mg/ml aqueous suspension, was administered orally immediately before the 0700 h dose of zidovudine. On days 5 to 16, zidovudine was also administered at 1100, 1500, 1900, and 2300 h. Serial blood samples were collected for 12 h after the single 100-mg dose of zidovudine on days 4 and 17; trough samples were also obtained just before the 0700 h dose on days 2 to 4 and 15 to 17. Levels of zidovudine and its glucuronide in plasma were assayed by a validated radioimmunoassay. Statistical analysis of trough plasma level data indicated that steady-state levels of zidovudine and its glucuronide in plasma had been attained when pharmacokinetic assessments were made on days 4 and 17. When megestrol acetate and zidovudine were coadministered for 13 days, differences of -14, -6.5, and -4.6% in mean zidovudine peak concentration and areas under the curve at 0 to 4 and 0 to 12 h, respectively, +22.5% in mean trough concentration, +2.6% in mean plasma half-life, and no change in median time to peak were observed compared to conditions when zidovudine was administered alone; for zidovudine 5'-O-glucuronide the respective differences were -9, -7.3, -4.4, +2.3, and +10% and no change. None of the differences were statistically significant (P > 0.05). Concomitant therapy with megestrol acetate, at the dose employed to treat anorexia, cachexia, or an unexplained, significant weight loss in AIDS patients, did not alter the steady-state pharmacokinetics of zidovudine or its 5'-O-glucuronide metabolite.
Van Harken
D R
DR
Division of Oncology and Immunology, Bristol-Myers Squibb Company, Plainsboro, New Jersey 08536, USA. donald_vanharken@ccmail.bms.com
Pei
J C
JC
Wagner
J
J
Pike
I M
IM
D000284:Administration, Oral; D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D019167:Appetite Stimulants / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D015658:HIV Infections / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D008297:Male; D019290:Megestrol Acetate / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D011863:Radioimmunoassay; D015215:Zidovudine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D019167:Appetite Stimulants; D015215:Zidovudine; C055886:3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine; D019290:Megestrol Acetate