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Bioequivalence and Food effect of heat-stressed and non-heat-stressed Dapagliflozin Tablets
Poster Presentations fed state; a low fat breakfast was provided in Part A1 and a high breakfast in Part B2. Results: In both parts, the new formulation substantially increased DRL-17822 exposure in fasted state, characterised by Cmax, AUC0-t and AUC0-∞, compared to the current formulation. Following high fat breakfast, DRL-17822 exposure was significantly less using the new formulation compared to the current formulation (P < 0.01). In addition, the new formulation resulted in similar ratios fed/fasted for AUC0-t in following both types of breakfast while the current formulation had a higher ratio after high fat breakfast compared to a low fat breakfast (Table 1, similar ratios were seen for Cmax and AUC0-∞). Conclusion: The new formulation had favourable pharmacokinetic characteristics compared to the current formulation, showing a food effect of only 3-fold, which may relate in more predictable effect profile. Table 1. Statistical analysis results AUC0-t (ng*h/mL) for contrast fed/ fasted new formulation vs. fed/fasted current formulation.
Fed state conditions Low fat breakfast (Part A) High fat breakfast (Part B)
P-value 0.08 < .0001
3.30 2.82
6.37 13.48
93.1% 377.6%
90% CI Lower
Upper
4.4% 231.3%
257.0% 588.6%
References 1. http://www.ncbi.nlm.nih.gov/pubmed/21347617 2. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ UCM126833.pdf
Bioequivalence and Food effect of heat-stressed and non-heat-stressed Dapagliflozin Tablets D.W. Boulton1; S. Griffen2; F. LaCreta1; X. Liu1; C. Smith3; C. Hines3; K. Volk1; and R. Tejwani1 1 Bristol-Myers Squibb Company, Princeton, NJ, USA; 2JDRF, New York, NY, USA; and 3PPDI, Richmond, VA, USA Background: Stability and pharmacokinetic testing are essential to assure drug potency, safety and efficacy. Dapagliflozin, T2DM medication, may convert from crystalline to amorphous forms during storage. To assess the clinical impact of this form change, in vivo evaluation of dapagliflozin tablets was undertaken. Materials and Methods: Two open-label crossover, single-dose studies to assess dapagliflozin pharmacokinetics from heat-stressed (HS) and non-heat-stressed (NH) dapagliflozin tablets were conducted in healthy subjects. The first assessed fasted-state bioequivalence of 10 mg tablets (N = 29). The second evaluated fed and fasted-state effect on 2.5 mg tablets (N = 28). Results: Under fasting conditions, 90% CIs of the geometric mean ratios of AUC0-inf, AUC0-t and Cmax for the HS 2.5 and 10 mg tablets were within 80%–125%, indicating bioequivalence with NH tablets (Table). In the fed versus fasting state for the 2.5 mg tablets, AUCs were similar, time to Cmax was prolonged by 1.25 hours and Cmax decreased by approximately 50% for HS and NH tablets; this is not clinically significant. No serious adverse events were reported. Conclusions: Under fasting conditions, HS and NH 2.5 mg and 10 mg dapagliflozin tablets are bioequivalent. The non-meaningful food
August 2015
Dapagliflozin Dose 2.5 mg
Pharmacokinetic Parameter Cmax (ng/mL)
AUC0-t (ng·h/mL)
AUC0-inf (ng·h/mL)
10 mg
Cmax (ng/mL) AUC0-t (ng·h/mL) AUC0-inf (ng·h/mL)
Back transformed Second Estimate First LSM of LSM of of the difcontrast contrast ference
effect may support patients’ adherence to diabetes treatment through convenience of administration irrespective of meals.
Treatment comparisons HS-fast/NH-fast NH-fed/NH-fast HS-fed/HS-fast HS-fast/NH-fast NH-fed/NH-fast HS-fed/HS fast HS-fast/NH-fast NH-fed/NH-fast HS-fed/HS-fast HS-fast/NH-fast HS-fed/HS-fast HS-fast/NH-fast HS-fed/HS-fast HS-fast/NH-fast HS-fed/HS-fast
Adjusted geometric. mean ratio (%), NH vs HS (90% CI) [N = 25–29] 99.8 (88.4, 112.7) 55.6 (49.3, 62.7) 49.9 (44.2, 56.3) 99.0 (96.2, 101.9) 90.3 (87.8, 92.9) 90.3 (87.7, 93.0) 97.6 (93.7, 101.6) 92.5 (89.4, 95.8) 94.0 (90.2, 97.9) 101.8 (92.3, 112.2) 55.0 (49.9, 60.6) 98.8 (95.9, 101.8) 96.1 (93.2, 99.0) 99.0 (96.0, 102.1) 97.3 (94.3, 100.4)
Small gender differences in Drug concentrations stored in a TDM database F. Sjöqvist; E. Eliasson; and J.D. Lindh Karolinska University Hospital, Stockholm, Sweden Several recent reviews on pharmacological gender differences suggest important effects on pharmacokinetics, with females having slower drug elimination compared to men. However, the evidence referred to is not convincing. Our department has been involved in therapeutic drug monitoring (TDM) since 1970 and presently analyzes 75.000 TDM samples of 100 different drugs annually. Over the years, the methods have been successively refined and now mostly involve LC-mass spectrometry. The drug concentrations are stored in a TDM data bank (Eliasson et al. Eur. J. Clin. Pharmacol. 2013, 69, Suppl 1, S25–S32) containing drug concentrations and essential clinical data. We have used this source to trace possible gender differences in dose-adjusted plasma concentrations of commonly used drugs. Men and women did not differ in age. The most frequently analyzed drugs were immunosuppressants, antiepileptics, antibiotics, antivirals, antipsychotics, and antidepressants. For a large number of these drugs, women achieved higher doseadjusted concentrations compared to men but after adjustment for differences in body-weight, only a small number of drugs (gentamicin, hydroxycarbazepine, isoniazid, perfenazine, and valproic acid) exhibited this pattern. For a majority of drugs (in particular amikacin, ciclosporin, ganciclovir, mycophenolic acid, sertraline, and tacrolimus) the opposite tendency was observed, with slightly lower weight- and dose-adjusted concentrations in women. The overall data, which will be further analyzed statistically, suggest that previously made claims of lower drug clearance in women may be incorrect. If gender differences in drug elimination exist, they are probably negligible compared to interindividual differences due to other genetic and environmental factors.
Impact of medication use on mortality in Belgian community-dwelling oldest Old M. Wauters1; M. Elseviers1; B. Vaes2,3; J. Degryse2,3; O. Dalleur2; R. Vander Stichele1; L. Van Bortel1; and M. Azermai1 1 Ghent University, Ghent, East Flanders, Belgium; 2Université catholique de Louvain, Saint-luc Brussels, Flemish Brabant,
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Fed state conditions Low fat breakfast (Part A) High fat breakfast (Part B)
P-value 0.08 < .0001
3.30 2.82
6.37 13.48
93.1% 377.6%
90% CI Lower
Upper
4.4% 231.3%
257.0% 588.6%
References 1. http://www.ncbi.nlm.nih.gov/pubmed/21347617 2. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ UCM126833.pdf
Bioequivalence and Food effect of heat-stressed and non-heat-stressed Dapagliflozin Tablets D.W. Boulton1; S. Griffen2; F. LaCreta1; X. Liu1; C. Smith3; C. Hines3; K. Volk1; and R. Tejwani1 1 Bristol-Myers Squibb Company, Princeton, NJ, USA; 2JDRF, New York, NY, USA; and 3PPDI, Richmond, VA, USA Background: Stability and pharmacokinetic testing are essential to assure drug potency, safety and efficacy. Dapagliflozin, T2DM medication, may convert from crystalline to amorphous forms during storage. To assess the clinical impact of this form change, in vivo evaluation of dapagliflozin tablets was undertaken. Materials and Methods: Two open-label crossover, single-dose studies to assess dapagliflozin pharmacokinetics from heat-stressed (HS) and non-heat-stressed (NH) dapagliflozin tablets were conducted in healthy subjects. The first assessed fasted-state bioequivalence of 10 mg tablets (N = 29). The second evaluated fed and fasted-state effect on 2.5 mg tablets (N = 28). Results: Under fasting conditions, 90% CIs of the geometric mean ratios of AUC0-inf, AUC0-t and Cmax for the HS 2.5 and 10 mg tablets were within 80%–125%, indicating bioequivalence with NH tablets (Table). In the fed versus fasting state for the 2.5 mg tablets, AUCs were similar, time to Cmax was prolonged by 1.25 hours and Cmax decreased by approximately 50% for HS and NH tablets; this is not clinically significant. No serious adverse events were reported. Conclusions: Under fasting conditions, HS and NH 2.5 mg and 10 mg dapagliflozin tablets are bioequivalent. The non-meaningful food
August 2015
Dapagliflozin Dose 2.5 mg
Pharmacokinetic Parameter Cmax (ng/mL)
AUC0-t (ng·h/mL)
AUC0-inf (ng·h/mL)
10 mg
Cmax (ng/mL) AUC0-t (ng·h/mL) AUC0-inf (ng·h/mL)
Back transformed Second Estimate First LSM of LSM of of the difcontrast contrast ference
effect may support patients’ adherence to diabetes treatment through convenience of administration irrespective of meals.
Treatment comparisons HS-fast/NH-fast NH-fed/NH-fast HS-fed/HS-fast HS-fast/NH-fast NH-fed/NH-fast HS-fed/HS fast HS-fast/NH-fast NH-fed/NH-fast HS-fed/HS-fast HS-fast/NH-fast HS-fed/HS-fast HS-fast/NH-fast HS-fed/HS-fast HS-fast/NH-fast HS-fed/HS-fast
Adjusted geometric. mean ratio (%), NH vs HS (90% CI) [N = 25–29] 99.8 (88.4, 112.7) 55.6 (49.3, 62.7) 49.9 (44.2, 56.3) 99.0 (96.2, 101.9) 90.3 (87.8, 92.9) 90.3 (87.7, 93.0) 97.6 (93.7, 101.6) 92.5 (89.4, 95.8) 94.0 (90.2, 97.9) 101.8 (92.3, 112.2) 55.0 (49.9, 60.6) 98.8 (95.9, 101.8) 96.1 (93.2, 99.0) 99.0 (96.0, 102.1) 97.3 (94.3, 100.4)
Small gender differences in Drug concentrations stored in a TDM database F. Sjöqvist; E. Eliasson; and J.D. Lindh Karolinska University Hospital, Stockholm, Sweden Several recent reviews on pharmacological gender differences suggest important effects on pharmacokinetics, with females having slower drug elimination compared to men. However, the evidence referred to is not convincing. Our department has been involved in therapeutic drug monitoring (TDM) since 1970 and presently analyzes 75.000 TDM samples of 100 different drugs annually. Over the years, the methods have been successively refined and now mostly involve LC-mass spectrometry. The drug concentrations are stored in a TDM data bank (Eliasson et al. Eur. J. Clin. Pharmacol. 2013, 69, Suppl 1, S25–S32) containing drug concentrations and essential clinical data. We have used this source to trace possible gender differences in dose-adjusted plasma concentrations of commonly used drugs. Men and women did not differ in age. The most frequently analyzed drugs were immunosuppressants, antiepileptics, antibiotics, antivirals, antipsychotics, and antidepressants. For a large number of these drugs, women achieved higher doseadjusted concentrations compared to men but after adjustment for differences in body-weight, only a small number of drugs (gentamicin, hydroxycarbazepine, isoniazid, perfenazine, and valproic acid) exhibited this pattern. For a majority of drugs (in particular amikacin, ciclosporin, ganciclovir, mycophenolic acid, sertraline, and tacrolimus) the opposite tendency was observed, with slightly lower weight- and dose-adjusted concentrations in women. The overall data, which will be further analyzed statistically, suggest that previously made claims of lower drug clearance in women may be incorrect. If gender differences in drug elimination exist, they are probably negligible compared to interindividual differences due to other genetic and environmental factors.
Impact of medication use on mortality in Belgian community-dwelling oldest Old M. Wauters1; M. Elseviers1; B. Vaes2,3; J. Degryse2,3; O. Dalleur2; R. Vander Stichele1; L. Van Bortel1; and M. Azermai1 1 Ghent University, Ghent, East Flanders, Belgium; 2Université catholique de Louvain, Saint-luc Brussels, Flemish Brabant,
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