Evaluation of the bioequivalence of tablets and capsules containing the novel anticancer agent R115777 (Zarnestra) in patients with advanced solid tumors

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 27; no. 1; pp. 61 - 65
• Main Authors: CRUL, M, DE KLERK, G. J, SWART, M, WEINER, L, PALMER, P. A, BOL, C. J, BEIJNEN, J. H, SCHELLENS, J. H. M
• Format: Journal Article
• Language: English
• Published: Genève Médecine et hygiène 01.01.2002
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Biological Availability; Capsules; Chemotherapy; Chromatography, High Pressure Liquid; Cross-Over Studies; Drug Administration Schedule; Female; Humans; Male; Medical sciences; Middle Aged; Neoplasms - blood; Neoplasms - drug therapy; Pharmacology. Drug treatments; Quinolones - administration & dosage; Quinolones - blood; Quinolones - pharmacokinetics; Tablets; Antineoplastic agent; Human; Lung disease; Solid tumor; Pharmaceutical technology; Bioequivalence; Respiratory disease; Treatment efficiency; Elimination; Oral administration; Bioavailability; Malignant tumor; Bronchopulmonary; Chemotherapy; Absorption; Treatment; Distribution; Dosage form; Bronchus disease; Tablet; Hard capsule; Pharmacokinetics
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/BF03190407

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.