PHARMACOKINETICS OF 2 MULTIPLE-DOSING REGIMENS OF D0870 IN HUMAN IMMUNODEFICIENCY VIRUS-POSITIVE PATIENTS - A PHASE-I STUDY

D0870 is a triazole,vith a broad antifungal spectrum, and it has been shown to have both in vitro and in vivo activities against wild-type a nd fluconazole-resistant strains of Candida albicans. Twenty-two human immunodeficiency virus (HIV)-positive male subjects were enrolled in an open, nonrandomized trial investigating the pharmacokinetics of two different dosing regimens of D0870 and assessing the safety of multip le oral doses of D0870 in HIV-positive subjects and their ability to t olerate multiple oral doses. Nine subjects received an initial loading dose of 50 mg, followed by four once-daily maintenance doses of 10 mg . A further nine subjects received an initial 200-mg loading dose foll owed by four daily maintenance doses of 25 mg. All subjects were fasti ng. A single loading dose of 50 mg of D0870 resulted in a mean maximum concentration in serum (C-max) of 107 +/- 32 ng/ml. Concentrations in plasma were maintained by the 10-mg once-daily dosing regimen as seen by the similar values of the area under the concentration-time curve from 0 to 24 h following dosing on days 1 and 5 and a mean accumulatio n ratio close to unity (0.90). The terminal plasma half-life of D0870 in plasma following dosing on day 5 ranged from 23 to 85 h (mean, 49 h ). A single loading dose of 200 mg of D0870 resulted in a C-max of 431 +/- 186 ng/ml. Concentrations in plasma were again maintained by the 25-mg daily dosing regimen, with the mean accumulation ratio being clo se to unity (1.17). The terminal half-life of D0870 in plasma followin g dosing on day 5 of phase II of the study ranged from 34 to 137 h (me an, 71 h). In addition, the concentrations achieved in the plasma of t hese HIV-positive subjects were similar to the values predicted from s imulations based on data derived from normal, healthy subjects. D0870 was well tolerated. No serious adverse events were experienced during the course of the study, and all volunteers completed the trial. A tot al of 15 adverse events were reported, but none were considered to be related to the administration of D0870 and all had resolved by the end of the trial. No changes in the hematology, clinical chemistry, or ur inalysis parameters were considered to be related to dosing with D0870 . No clinically significant changes in the electrocardiogram parameter s were noted during the trial. The data generated in this trial suppor t further investigation of these regimens with HIV-positive subjects w ith fluconazole-susceptible or -resistant oropharyngeal candidosis.