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.

Expanded distribution of an investigational drug in parallel with ongoing controlled clinical trials: the didanosine model.

The purpose of the didanosine Expanded Access Program was to provide a needed antiretroviral agent to individuals who were unable to tolerate other therapy for human immunodeficiency virus infection or in whom such therapy was failing. The logistics of establishing this program are described, and the results of on-site auditing that confirmed the validity of the data obtained through this program are presented.

The didanosine Expanded Access Program: safety analysis.

The didanosine Expanded Access Program was designed by the Bristol-Myers Squibb Company (Princeton, NJ) to provide didanosine for treatment of patients who could not be enrolled in clinical trials. This program consisted of two protocols: a treatment IND (investigational new drug) protocol for patients intolerant of zidovudine and an open-label protocol for patients whose clinical condition was deteriorating despite continued therapy with zidovudine. Information from the safety data base derived from study of the first 7,806 patients enrolled has shown that the major adverse events associated with didanosine therapy are pancreatitis (which can be life-threatening), peripheral neuropathy, and diarrhea. Pancreatitis was reported for 5% of the patients. Those with a history of pancreatitis were more likely to develop pancreatitis. In contrast to zidovudine, didanosine has been found to be minimally myelosuppressive. In general, hematologic parameters remained stable, especially for patients who entered the program with normal baseline values. The results of this program suggest that patients pretreated with zidovudine for prolonged periods are able to tolerate didanosine well.