Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV infection: dosage requirements and pharmacokinetic studies

Citation
Gd. Morse et al., Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV infection: dosage requirements and pharmacokinetic studies, ANTIVIR RES, 45(1), 2000, pp. 47-58
Citations number
24
Categorie Soggetti
Microbiology
Journal title
ANTIVIRAL RESEARCH
ISSN journal
01663542 → ACNP
Volume
45
Issue
1
Year of publication
2000
Pages
47 - 58
Database
ISI
SICI code
0166-3542(200001)45:1<47:CPITOA>2.0.ZU;2-C
Abstract
Rationale: To determine the dosage requirements and pharmacokinetics of ate virdine, a non-nucleoside reverse transcriptase inhibitor and its N-dealkyl ated metabolite (N-ATV) during phase I studies in patients receiving atevir dine alone or in combination with zidovudine. Design: Two open label, phase I studies conducted by the adult AIDS Clinical Trials Group (ACTG) in whic h atevirdine was administered every 8 h with weekly dosage adjustments to a ttain targeted trough plasma atevirdine concentrations. Setting: Five Adult AIDS Clinical Trials Units. Patients: Fifty patients (ACTG 199, n = 20 and ACTG 187; n = 30) with HIV-1 infection and less than or equal to 500 CD4lymphocytes/mm(3). Intervention: ACTG 199: 12 weeks of therapy with atevird ine (dose-adjusted to achieve plasma trough atevirdine concentrations of 5- 10 mu M) and zidovudine (200 mg every 8 h). ACTG 187: 12 weeks of atevirdin e monotherapy with atevirdine doses adjusted to achieve escalating, targete d trough plasma concentration ranges (5-13, 14-22, and 23-31 mu M). il Meas urements: ACTG 199. atevirdine, N-ATV and zidovudine trough determinations weekly (all patients) and intensive pharmacokinetics (selected patients) Dr ier to and at 6 and 12 weeks during combination therapy. ACTG 187. atevirdi ne and N-ATV trough concentrations over a 12 week period. Intensive pharmac okinetic studies were conducted prior to and at 4 and/or 8 weeks during ate virdine monotherapy in female patients, Results: Atevirdine plasma concentr ations demonstrated considerable interpatient variability which was minimiz ed by the adjustment of maintenance doses (range: 600-3900 mg/day) to achie ve the desired trough concentrations. In ACTG 187, the mean number of weeks to attain the target value, and the percentage of patients who attained th e target, was group I (5-11 mu M): 2.7 +/- 2.4 weeks (92%); group II (12-21 mu M): 2.6 +/- 1.8 (64%); and group III (22-31 mu M): 7.0 +/- 5.6 weeks (2 7%). In ACTG 199 it was 3.2 +/- 5.2 weeks (95%) to achieve a 5-10 mu M trou gh. Atevirdine demonstrated a mono- or bi-exponential decline among most of the patients studied after the first dose. During multiple-dosing a number of patterns of atevirdine disposition were observed including; rapid absor ption with C-max at 0.5-1 h, delayed absorption with C-max at 3-4 h; minima l C-max to C-min fluctuation and C-max to C-min ratios of > 4. N-ATV (an in active metabolite) patterns were characterized on day one by rapid appearan ce of the metabolite which peaked at 2-3 h after the dose and declined in a mono- or bi-exponential manner. Al steady-stare N-ATV patterns demonstrate d minimal C-max to C-min fluctuations with some of the patients having more stable plasma N-ATV concentrations, while others had greater fluctuations week to week. Conclusions: Considerable interpatient variability was noted in the pharmacokinetics of atevirdine. The variation in drug disposition wa s reflected in the range of daily doses required to attain the targeted tro ugh concentrations. Atevirdine metabolism did not appear to reach saturatio n during chronic dosing in many of our patients, as reflected by the patter n of N-ATV/ATV ratios in plasma and saturation was not an explanation for t he variation in dosing requirements. No apparent differences were noted bet ween males and females, and atevirdine did not appear to influence zidovudi ne disposition. Published by Elsevier Science B.V.