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544 High dose medroxyprogesterone acetate (MPA) in cancer patients: Plasmatic levels determined by an HPLC method
POSTER
543
SESSION
: Posters PO01 - PO03
19%
The Comparative Bioavailability of Two International MedroxyprogesteroneAcetate (MPA) Sterile Suspension Products After Oral and Intramuscular Administration. E. J. Antal, C. E. Wright XII, E. M. Block, and K. S. Albert. The Upjohn Company, Kalamazoo, Michigan, USA The bioavailability of two internationallymarketed MPA intramuscular suspensions (Farlutal, depot, Farmitalia, and OEPO-PROVERA@, Upjohn) were compared after both oral and intramuscular administration. Prior to initiating these studies, the physical characteristics (particle size) of each product were evaluated utilizing Scanning Electron Microscopy. DEPO-PROVERA displayed characteristicsof a well controlled micronization process. In contrast, Farlutal depot appears to be subjected to a less efficient micronization which resulted in larger more irregularly shaped particles. In the first clinical study, 500 mg oral doses of both products were administered after an overnight fast to 7E healthy male volunteers by crossover design. Significantly greater area under the serum MPA level curves from 0 to 144 hours and maximum MPA serum concentrations were observed following DEPO-PROVERA indicating greater extents of absorption. In the second study, 500 mg intramuscular doses of both products were administered to 21 healthy male volunteers by a non-crossover design. The average maximum serum MPA levels were 6% greater following D~PO-PROVED with borderline statistical significance fp=.09f being observed. It can be concluded that for MPA, manufacturing variations which result in different bulk drug characteristics, &translate into bioavailabilitv differences.
544
HIGH DOSE ~DRO~ROG~S~RO~ ACETATE (MPA) IN CANCER PATIEhTS: PLASMATIC LEVELS DETE~INED BY AN HPLC ~THOD G. Milano, M. Namer, J.L. Boublil, N. Renbe, C,M. Lalanne Centre Antoine-Lacassagne, 36 Voie Romaine, 06054 Nice Cldex, France The present report concerns an HPLC method for the separation and quantification of WA in plasma. The chromatographic technique involves rapid, quantitative and reproducible extraction on SEP-PAK cartridges (Waters Assoc.). The internal standard was 19-N-progesterone. The column (Rad-Pak cartridges Cl8 5 urn,Waters) was inserted in a radial compression system (RCM 100, Waters). Peaks were quantifiable after UV detection at 254 nm. Analysis was rapid, with retention times ol 8 min. 30 sec. for MPA and 9 min. 40 sec. for the internal standard. The calibration curve for plasma was linear from 20 to 500 nglml (r10.987). The limit of detection was 4 nglml. The coefficients of variation for intra- (6 samples) and inter- (6 samples) assay reproducibility were 3.2% and 8.6% respectively. Blood levels of MPA were measured for 14 cancer patients (13 breast cancers, 1 kidney cancer) receiving high dose chronic treatment. Injectable MPA taken orally gives blood levels, at the steady state, equal to one half those obtained with the same dose given IM. In order to lower inter- and intra-individualvariations in drug blocd levels, it was found advisable to administer the product per os in 2 daily doses (8 am and 8 pm). Patients with liver metastases exhibited the highest circulating MPA levels.
545
MPA PLASMA LEVELS AND RESPONSE RATE IN BREAST CANCER V.P. Fosser, A. Fornasiero, 0. Daniele and M.V. Fiorentino. Medical Oncology Dept., Padua General Hospital, 35100 Padova, Italy. 64 postmenopausal pts with advanced recurrent breast cancer were randomly assigned to high dose-MPA i.m., i-m. + p.o. or p.o. alone. MPA plasma levels were determined every two weeks during the first month and monthly thereafter by GLC method. Responses were evaluated after 4 months, according to UICC criteria. Groups were comparable regarding predominant metastatic sites, age and previous treatments. MPA when the i.m. route (+ p.0.) was employed, reaching 85 weeks while the oral routeis top level was 57 n&ml. Responses by treatment Response by MPA levels CR PR NC P MPA levels CR PR NC P MPA i.m. 3 4 7 3 -40 n&ml 1146 MPA i.m. + p-0. 1 6 5 5 40-80 5 13 5 MPA p.o. 197 X0 ng/ml 3 3 3Conclusion: P.O. administration achieves lower plasma levels and l/17 response; No significant differences are detectable between i.m. and i.m. + p.o. groups, both for plasma levels and response (7/17 both). There is a clear trend in favour of better results with higher plasma levels. No toxicity, was noted. Karnofsky index improved in 32/51 pts and pain relief was recorded in 19129 pain suffering patients.
543
SESSION
: Posters PO01 - PO03
19%
The Comparative Bioavailability of Two International MedroxyprogesteroneAcetate (MPA) Sterile Suspension Products After Oral and Intramuscular Administration. E. J. Antal, C. E. Wright XII, E. M. Block, and K. S. Albert. The Upjohn Company, Kalamazoo, Michigan, USA The bioavailability of two internationallymarketed MPA intramuscular suspensions (Farlutal, depot, Farmitalia, and OEPO-PROVERA@, Upjohn) were compared after both oral and intramuscular administration. Prior to initiating these studies, the physical characteristics (particle size) of each product were evaluated utilizing Scanning Electron Microscopy. DEPO-PROVERA displayed characteristicsof a well controlled micronization process. In contrast, Farlutal depot appears to be subjected to a less efficient micronization which resulted in larger more irregularly shaped particles. In the first clinical study, 500 mg oral doses of both products were administered after an overnight fast to 7E healthy male volunteers by crossover design. Significantly greater area under the serum MPA level curves from 0 to 144 hours and maximum MPA serum concentrations were observed following DEPO-PROVERA indicating greater extents of absorption. In the second study, 500 mg intramuscular doses of both products were administered to 21 healthy male volunteers by a non-crossover design. The average maximum serum MPA levels were 6% greater following D~PO-PROVED with borderline statistical significance fp=.09f being observed. It can be concluded that for MPA, manufacturing variations which result in different bulk drug characteristics, &translate into bioavailabilitv differences.
544
HIGH DOSE ~DRO~ROG~S~RO~ ACETATE (MPA) IN CANCER PATIEhTS: PLASMATIC LEVELS DETE~INED BY AN HPLC ~THOD G. Milano, M. Namer, J.L. Boublil, N. Renbe, C,M. Lalanne Centre Antoine-Lacassagne, 36 Voie Romaine, 06054 Nice Cldex, France The present report concerns an HPLC method for the separation and quantification of WA in plasma. The chromatographic technique involves rapid, quantitative and reproducible extraction on SEP-PAK cartridges (Waters Assoc.). The internal standard was 19-N-progesterone. The column (Rad-Pak cartridges Cl8 5 urn,Waters) was inserted in a radial compression system (RCM 100, Waters). Peaks were quantifiable after UV detection at 254 nm. Analysis was rapid, with retention times ol 8 min. 30 sec. for MPA and 9 min. 40 sec. for the internal standard. The calibration curve for plasma was linear from 20 to 500 nglml (r10.987). The limit of detection was 4 nglml. The coefficients of variation for intra- (6 samples) and inter- (6 samples) assay reproducibility were 3.2% and 8.6% respectively. Blood levels of MPA were measured for 14 cancer patients (13 breast cancers, 1 kidney cancer) receiving high dose chronic treatment. Injectable MPA taken orally gives blood levels, at the steady state, equal to one half those obtained with the same dose given IM. In order to lower inter- and intra-individualvariations in drug blocd levels, it was found advisable to administer the product per os in 2 daily doses (8 am and 8 pm). Patients with liver metastases exhibited the highest circulating MPA levels.
545
MPA PLASMA LEVELS AND RESPONSE RATE IN BREAST CANCER V.P. Fosser, A. Fornasiero, 0. Daniele and M.V. Fiorentino. Medical Oncology Dept., Padua General Hospital, 35100 Padova, Italy. 64 postmenopausal pts with advanced recurrent breast cancer were randomly assigned to high dose-MPA i.m., i-m. + p.o. or p.o. alone. MPA plasma levels were determined every two weeks during the first month and monthly thereafter by GLC method. Responses were evaluated after 4 months, according to UICC criteria. Groups were comparable regarding predominant metastatic sites, age and previous treatments. MPA when the i.m. route (+ p.0.) was employed, reaching 85 weeks while the oral routeis top level was 57 n&ml. Responses by treatment Response by MPA levels CR PR NC P MPA levels CR PR NC P MPA i.m. 3 4 7 3 -40 n&ml 1146 MPA i.m. + p-0. 1 6 5 5 40-80 5 13 5 MPA p.o. 197 X0 ng/ml 3 3 3Conclusion: P.O. administration achieves lower plasma levels and l/17 response; No significant differences are detectable between i.m. and i.m. + p.o. groups, both for plasma levels and response (7/17 both). There is a clear trend in favour of better results with higher plasma levels. No toxicity, was noted. Karnofsky index improved in 32/51 pts and pain relief was recorded in 19129 pain suffering patients.