Ketoconazole pharmacokinetics during chronic dosing in adults with haematological malignancy.
Ketoconazole pharmacokinetics were determined in nine adults with haematological malignancy after one week on a 200 mg daily dose and later after one week on a 400 mg daily dose. The area under the serum concentration time curve (AUC) reached 12.3 +/- 7.7 mg/l.h (mean +/- S.D.) on the 200 mg dose and increased to 23.0 +/- 18.2 mg/l.h on the 400 mg dose (p less than 0.05). The half-life of ketoconazole was 3.1 +/- 1.9 h on the 200 mg dose and 3.5 +/- 1.7 h on the 400 mg dose. Peak concentrations were 3.2 +/- 1.8 mg/l and 4.6 +/- 3.2 mg/l on the 200 mg and 400 mg doses, respectively. Trough ketoconazole concentrations were undetectable 24 h after either dose. There was no correlation between the leucocyte count and any pharmacokinetic parameter for ketoconazole. Variation in AUC was 20-fold on the 200 mg daily dose and 8-fold on the 400 mg per day regimen. Measurement of serum levels during ketoconazole treatment appears necessary in view of the unpredictable concentrations achieved. Once-a-day dosage regimens of ketoconazole in immunocompromised patients may be inappropriate. Future clinical trials should adopt a two or three times a day dosing regimen, as this may confer a pharmacokinetic and therapeutic advantage.
Stockley
R J
RJ
Daneshmend
T K
TK
Bredow
M T
MT
Warnock
D W
DW
Richardson
M D
MD
Slade
R R
RR
D000328:Adult; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D007108:Immune Tolerance; D007654:Ketoconazole / Q000097:blood*; D007700:Kinetics; D007945:Leukemia, Lymphoid / Q000097:blood*; D015470:Leukemia, Myeloid, Acute / Q000097:blood*; D008228:Lymphoma, Non-Hodgkin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood*
D007654:Ketoconazole