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Bioequivalence and differences between solid and liquid formulations of oral bisphosphonates
604
Abstracts
5 days and 1 month after induction, reaching the control values 2 months postinduction. In conclusion, the alteration in duodenal antioxidant system, evidenced by a decrease in GSH and increase in the CAT activity, could impact on calcium absorption and thus contribute to bone demineralization.
doi:10.1016/j.bone.2012.12.039
Z-scoring of pQCT-assessed, reference distribution/quality curves in the human tibia to evaluate the efficiency of bone mechanostat R. Cointry, P. Reina, L. Nocciolino, I. Grappiolo, S. Feldman, J.L. Ferretti, R. Capozza Faculty of Medicine, National University of Rosario, Argentina The efficiency of bone mechanostat to control bone stiffness/strength could be assessed as the adequacy of the spatial distribution of bone tissue as a function of its stiffness at any given skeletal site. With that purpose we determined pQCT indicators of cortical tissue distribution (d, bending and torsion moments of inertia, MIs) and quality (q, vDMO -CtD-, a correlate of tissue stiffness) at every 5% of the tibia height in 42 normal men and women. The analysis of the highly-significant d/q curves obtained at every studied site allowed selecting the standard, 38% site as adequate to test the d/q relationship for clinical applications. Aiming to obtain suitable reference d/q curves for comparative diagnosis, we measured the same indicators at the 38% site in a larger sample of healthy men and pre- and post-MP women (n= 60, 80, 120) aged 25–85 years, and Zscored the observed d/q relationships for each group. Then we plotted d/q data obtained in 36 chronic cirrhotic and 60 dialyzed men and women with reference to their sex controls. The healthy post-MP women showed significantly lower d/q Z-scores (similar MIs for lower CtD values) than the reference pre-MP women. Both cirrhotic and dialyzed patients showed significantly lower d/q Z-scores (lower values of both MIs and CtD) than their respective references. Results show that cortical tissue distribution (i.e. the efficiency of cortical modeling drifts modulation in response to local strains induced by mechanical usage) tends to decay as a function of tissue deformability in post-MP women and in patients with metabolic osteopenia (i.e. under the effect of non-mechanical, metabolic disturbances) as expected according to the Mechanostat Theory.
doi:10.1016/j.bone.2012.12.040
Bioequivalence and differences between solid and liquid formulations of oral bisphosphonates C. Gómez Acotto, C. Antonelli, D. Flynn, D. Mc Daid, E.J.A. Roldán Dpt. Phospho-Calcium, Maimonides Univ., Buenos Aires, Argentina Xeolas Ltd, Dublin, Ireland Oral bisphosphonates have low bioavailability together with a short absorption time, limited by food or beverages ingestion, which means that the absorption occurs only during the 30–60 min of post-intake fast. In practice this creates a number of difficulties against the treatment outcomes. In a regulatory trial with 106 healthy men aged 26.7 ± 8 years, alendronate 70 mg reference tablets (At) and an oral solution 70 mg/100 ml of orange aspect (Ab) were compared within EMA regulations. Alendronate urinary excretion was assessed with HPLC (Shimadzu LC-10AS), being 124.4 μg after At and 121.9 μg after Ab, recovered during 36 h, with a variation margin of 82–106% within bioequivalence (ANOVA y Hodges–Lehmann). During the 1st-hour recovery, which is the clinical critical time, alendronate concentration was 190 ± 302 μg/ml At, and 177 ± 205 μg/ml Ab, not significant between means (p = 0.73), but variance was − 32% for Ab, F test p b 0.05). In a 2nd study with healthy volunteers aged 52 (39–68 years), minimum contrast amounts were added to the forms for the video-deglutition followup (Pinnacle DC1000 MPEG 2; n = 72). The time to achieve the stomach with At was 31 s stand, and 73 s in bed-rest, and of 7 s and 8.4 s respectively after Ab (tail of the bolus). While variance after At surpassed the confident follow-up time of 480 s, the same was of 72 and 60 s with Ab. Gastric disaggregation of At was below 4 min in both positions with a position variance of 14 and 23 min, including 1 case of no disaggregation and 1 that lasted 17 min; and 3 others that show esophagi fragmentation. Conversely, mean Ab passage to duodenum (head of bolus) was 2 min with both positions with maximum variance of 7.4 min in stand. Results show that Ab disposes alendronate in the adequate absorption site within 10 min. Instead, most At cases disaggregate properly but some do it prematurely (adverse events?) or even very delayed (no absorption) in coincidence with the less variation show in the 1st hour of the BE trial. It is concluded that Ab minimizes kinetics aspects during absorption and may predict more confident therapeutic outcomes in daily practice.
doi:10.1016/j.bone.2012.12.041
Abstracts
5 days and 1 month after induction, reaching the control values 2 months postinduction. In conclusion, the alteration in duodenal antioxidant system, evidenced by a decrease in GSH and increase in the CAT activity, could impact on calcium absorption and thus contribute to bone demineralization.
doi:10.1016/j.bone.2012.12.039
Z-scoring of pQCT-assessed, reference distribution/quality curves in the human tibia to evaluate the efficiency of bone mechanostat R. Cointry, P. Reina, L. Nocciolino, I. Grappiolo, S. Feldman, J.L. Ferretti, R. Capozza Faculty of Medicine, National University of Rosario, Argentina The efficiency of bone mechanostat to control bone stiffness/strength could be assessed as the adequacy of the spatial distribution of bone tissue as a function of its stiffness at any given skeletal site. With that purpose we determined pQCT indicators of cortical tissue distribution (d, bending and torsion moments of inertia, MIs) and quality (q, vDMO -CtD-, a correlate of tissue stiffness) at every 5% of the tibia height in 42 normal men and women. The analysis of the highly-significant d/q curves obtained at every studied site allowed selecting the standard, 38% site as adequate to test the d/q relationship for clinical applications. Aiming to obtain suitable reference d/q curves for comparative diagnosis, we measured the same indicators at the 38% site in a larger sample of healthy men and pre- and post-MP women (n= 60, 80, 120) aged 25–85 years, and Zscored the observed d/q relationships for each group. Then we plotted d/q data obtained in 36 chronic cirrhotic and 60 dialyzed men and women with reference to their sex controls. The healthy post-MP women showed significantly lower d/q Z-scores (similar MIs for lower CtD values) than the reference pre-MP women. Both cirrhotic and dialyzed patients showed significantly lower d/q Z-scores (lower values of both MIs and CtD) than their respective references. Results show that cortical tissue distribution (i.e. the efficiency of cortical modeling drifts modulation in response to local strains induced by mechanical usage) tends to decay as a function of tissue deformability in post-MP women and in patients with metabolic osteopenia (i.e. under the effect of non-mechanical, metabolic disturbances) as expected according to the Mechanostat Theory.
doi:10.1016/j.bone.2012.12.040
Bioequivalence and differences between solid and liquid formulations of oral bisphosphonates C. Gómez Acotto, C. Antonelli, D. Flynn, D. Mc Daid, E.J.A. Roldán Dpt. Phospho-Calcium, Maimonides Univ., Buenos Aires, Argentina Xeolas Ltd, Dublin, Ireland Oral bisphosphonates have low bioavailability together with a short absorption time, limited by food or beverages ingestion, which means that the absorption occurs only during the 30–60 min of post-intake fast. In practice this creates a number of difficulties against the treatment outcomes. In a regulatory trial with 106 healthy men aged 26.7 ± 8 years, alendronate 70 mg reference tablets (At) and an oral solution 70 mg/100 ml of orange aspect (Ab) were compared within EMA regulations. Alendronate urinary excretion was assessed with HPLC (Shimadzu LC-10AS), being 124.4 μg after At and 121.9 μg after Ab, recovered during 36 h, with a variation margin of 82–106% within bioequivalence (ANOVA y Hodges–Lehmann). During the 1st-hour recovery, which is the clinical critical time, alendronate concentration was 190 ± 302 μg/ml At, and 177 ± 205 μg/ml Ab, not significant between means (p = 0.73), but variance was − 32% for Ab, F test p b 0.05). In a 2nd study with healthy volunteers aged 52 (39–68 years), minimum contrast amounts were added to the forms for the video-deglutition followup (Pinnacle DC1000 MPEG 2; n = 72). The time to achieve the stomach with At was 31 s stand, and 73 s in bed-rest, and of 7 s and 8.4 s respectively after Ab (tail of the bolus). While variance after At surpassed the confident follow-up time of 480 s, the same was of 72 and 60 s with Ab. Gastric disaggregation of At was below 4 min in both positions with a position variance of 14 and 23 min, including 1 case of no disaggregation and 1 that lasted 17 min; and 3 others that show esophagi fragmentation. Conversely, mean Ab passage to duodenum (head of bolus) was 2 min with both positions with maximum variance of 7.4 min in stand. Results show that Ab disposes alendronate in the adequate absorption site within 10 min. Instead, most At cases disaggregate properly but some do it prematurely (adverse events?) or even very delayed (no absorption) in coincidence with the less variation show in the 1st hour of the BE trial. It is concluded that Ab minimizes kinetics aspects during absorption and may predict more confident therapeutic outcomes in daily practice.
doi:10.1016/j.bone.2012.12.041