Evaluation of the bioequivalence of tablets and capsules containing the novel anticancer agent R115777 (Zarnestra) in patients with advanced solid tumors.
R115777 (Zamestra) is a novel anticancer agent, currently undergoing phase III clinical testing. An open, cross-over trial was performed in 24 patients with solid tumors to compare the bioavailability of a new tablet formulation with the standard capsule formulation. Both dosage forms were administered once daily in doses of 300 or 400 mg. Patients received R115777 as a capsule on day I and as a tablet on day 2, or vice versa. Blood samples were drawn up to 24 hours after drug intake and R115777 levels were measured using a validated high performance liquid chromatography (HPLC) method. The following pharmacokinetic parameters were determined and compared for the two formulations: time to maximal plasma concentration (Tmax), half-life (t 1/2), maximal plasma concentration (Cmax) and area under the curve at twenty-four hours (AUC24h). For the latter two parameters, 90% classical confidence intervals of the ratio tablet/capsule were calculated after a log-transformation, using an Analysis of Variance (ANOVA). For t 1/2 and Tmax, no statistically significant differences were found between tablet and capsule. The point estimates of the ratio's of the log-normalized Cmax and AUC24h were 0.94 and 0.92, respectively, and the 90% confidence intervals were 0.81-1.09 and 0.83-1.03, which is within the critical range for bioequivalence of 0.80-1.25. In conclusion, the established pharmacokinetic parameters demonstrate that the capsule and tablet formulations of R115777 are interchangeable.
Crul
M
M
The Netherlands Cancer Institute, Department of Medical Oncology, Amsterdam.
de Klerk
G J
GJ
Swart
M
M
Weiner
L
L
Palmer
P A
PA
Bol
C J
CJ
Beijnen
J H
JH
Schellens
J H M
JH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D015363:Quinolones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets
D000970:Antineoplastic Agents; D002214:Capsules; D015363:Quinolones; D013607:Tablets; C402769:tipifarnib