Etoposide combined with interferon alfa-2b: novel exploitation of established etoposide pharmacokinetics and pharmacodynamics.
OBJECTIVE
To construct an efficient pilot study design to determine whether interferon alfa-2b modifies the pharmacokinetics and pharmacodynamics of continuous-infusion etoposide.


METHODS
A two-stage randomized 2 X 2 factorial design was used to evaluate interferon alfa-2b at two doses (2 or 10 MU/m2/day SQ for 3 days) and two schedules (interferon alfa-2b administered before or concurrent with 72-hour continuous-infusion etoposide). Etoposide was administered at 75, 100, or 125 mg/m2/day. In lieu of comparing the experimental arms to an etoposide-alone control arm to determine effect of interferon alfa-2b dose and schedule, a novel analytic approach was used. The effect of interferon alfa-2b on etoposide-induced leukopenia was assessed indirectly by comparison of the observed white blood cell (WBC) nadir to the nadir predicted from an established pharmacodynamic model for single agent etoposide.


RESULTS
Based on 29 patients, dose-normalized 24-hour total and estimated free etoposide concentrations did not differ with interferon alfa-2b dose or schedule. Patients treated with interferon alfa-2b before etoposide had, on average a WBC nadir 545 +/- 225 cells microliter lower than that predicted by a pharmacodynamic model for etoposide alone. An optimal nonlinear model for leukopenia was defined by interferon alfa-2b schedule in addition to 24-hour etoposide concentration.


CONCLUSIONS
A novel study design and statistical analysis provided an efficient preliminary evaluation of the combination of interferon alfa-2b with etoposide in a modest number of patients. Exploitation of a previously validated pharmacodynamic model allowed evaluation of interferon alfa-2b effect and eliminated the need for an etoposide-alone control arm. The pharmacokinetics of continuous-infusion etoposide at doses from 75 to 125 mg/m2/day appear to be unchanged by interferon alfa-2b at the doses and schedules tested and the combination appears to be feasible. We hypothesize that leukopenia may be enhanced when interferon alfa-2b is administered before etoposide, especially at a higher dose of interferon alfa-2b.
Mick
R
R
Department of Medicine, University of Chicago Medical Center, IL 60637, USA.
Vokes
E E
EE
Lestingi
T M
TM
Gray-Stern
W
W
Fleming
G F
GF
Schilsky
R L
RL
Ratain
M J
MJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D005047:Etoposide / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D007970:Leukopenia / Q000139:chemically induced; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D005047:Etoposide