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
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.