Results. Subject Disposition and Demographics Of 37 enrolled subjects, 23 (62.2%) completed the study

Transcription

1 Poster 5-20 Effect of Gastric ph on the Bioavailability of in Healthy Subjects James Longstreth, PhD, Marijke H. Adams, PharmD, PhD, 2 Vasi Sperry, PhD, 3 Dan Kajdasz, PhD, 3 Carol R. Reed, MD 3 Longstreth & Associates, Inc., Mundelein, IL; 2 MH Adams & Associates, Inc., Davie, FL; 3 PGxHealth LLC, a division of Clinical Data, Inc., New Haven, CT Background Figure. Study design and dosing schedule. Results Conclusions, a new molecule, is a dual-acting selective and potent serotonin A receptor partial agonist and reuptake inhibitor (SPARI) in clinical development for the treatment of major depressive disorder (MDD),2 The solubility of vilazodone is greatest at an acidic ph (pk = 7.) a The efficacy of vilazodone 40 mg/day in the treatment of MDD has been demonstrated in 2 Phase 3, randomized, double-blind, placebocontrolled, 8-week trials. 3,4 The long-term tolerability of vilazondone has been examined, and its effectiveness was described in an open-label, multicenter, 52-week study 5 Higher than normal gastric ph may occur because of concomitant administration of medications (eg, histamine H2-receptor antagonists, proton pump inhibitors), comorbid disorders (eg, pernicious anemia, chronic Helicobacter pylori infection), or surgical procedures (eg, vagotomy, gastrectomy) It is, therefore, important to determine whether higher than normal gastric ph affects the bioavailability of vilazodone Objectives 40 mg 40 mg Pharmacokinetic Sampling Day Main Eligibility Criteria The study included healthy adult men and women whose body mass index was between 8 and 35 kg/m 2 Exclusion criteria included: Inpatient Outpatient Inpatient Outpatient Safety Assessments Safety was assessed by monitoring adverse events (AEs), clinical laboratory evaluations, electrocardiograms (ECGs), and vital signs Subjects who experienced vomiting within 0 hours after vilazodone dosing were discontinued from the study Subject Disposition and Demographics Of 37 enrolled subjects, 23 (62.2%) completed the study 4 subjects (37.8%; 2/2 women and 2/6 men) discontinued because of AEs Baseline characteristics of the safety population () and the PK-evaluable population () were similar except for the distribution of sexes (Table ) Table. Demographic and Baseline Characteristics of the Safety and PK-Evaluable Populations Safety Population PK-Evaluable Population Characteristic Sex, n (%) Female 2 (56.8) 9 (39.) Male 6 (43.2) 4 (60.9) Age, y, mean (SD) 36. (0.3) 38. (.2) Race, n (%) White 36 (97.3) 22 (95.7) Black (2.7) (4.3) Weight, kg, mean (SD) 72.7 (0.2) 75.0 (9.5) BMI, kg/m 2, mean (SD) 27.5 (3.2) 27.7 (3.4) PK parameters for vilazodone alone were similar to those for vilazodone with increased gastric ph (Table 2) Table 2. Mean (SD) PK s for and With 40 mg + 40 mg 40 mg AUC 0-24, h ng/ml (37.6) (50.3), h ng/ml (672.8) (839.6), h ng/ml 20.7 (69.3) (855.4) C, ng/ml 06.5 (28.9) 5.9 (46.0) t, h 5.8 (.8) 5.5 (.9) t ½, h 25.4 (.8) 27.0 (9.4) λ z, /h (0.0623) ( ) CL/F, L/h 2. (7.) 20.2 (0.7) Accumulation factor.6 (0.22).66 (0.24) The relative bioavailability of vilazodone associated with increased gastric ph compared with that of vilazodone alone was not statistically significantly different (Table 3) 90% CIs for the ratios of the means lay completely within the prespecified 0.80 to.25 interval (Table 3) -induced increases in gastric ph had no effect on the bioavailability or PK of a single 40-mg dose of vilazodone These findings suggest that dose reductions would be unnecessary in patients with a high likelihood of having reduced gastric acidity The high rate of vomiting in this trial reinforces the importance of titrating vilazodone to the minimally effective dose of 40 mg/day. References Hughes ZA, Starr KR, Langmead CJ, et al. Neurochemical evaluation of the novel 5-HT A receptor partial agonist/serotonin reuptake inhibitor, vilazodone. Eur J Pharmacol. 2005;50: Dawson LA, Watson JM. : a 5-HT receptor agonist/serotonin A 3. transporter inhibitor for the treatment of affective disorders. CNS Neurosci Ther. 2009;5:07-7. Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR. Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70: Primary To determine the effect of increased gastric ph on the relative bioavailability of the 40-mg oral tablet formulation of vilazodone Secondary To evaluate the effect of increased gastric ph on the safety and tolerability of oral vilazodone in healthy adult volunteers Methods Ethical Conduct The study was conducted in accordance with Good Clinical Practice guidelines described in the International Conference on Harmonization (ICH) Guideline E6, other applicable ICH guidelines, and the US Code of Federal Regulations (CFR), Title 2 6 The study protocol was approved by the institutional review board at the investigational site according to specifications outlined in the US CFR All subjects provided voluntary written informed consent before any study procedures were performed Study Design Phase, open-label, 2-period crossover, single-center study ( Figure ) On day, each subject received a single dose of vilazodone 40 mg; vilazodone pharmacokinetics (PK) were followed for 44 hours On days 3 to 8, subjects received pantoprazole 40 mg/day; on day 9, subjects received vilazodone 40 mg plus pantoprazole 40 mg; vilazodone PK were followed for 44 hours is a proton pump inhibitor that inhibits gastric acid secretion by 85% 7 All doses were administered after a light breakfast History of clinically significant cardiac, gastrointestinal, renal, or hepatic disease Use of an acid-suppressing medication within 2 weeks before day Use of any serotonergic migraine medication or cytochrome P450 3A4 inhibitor within 30 days before day Pharmacokinetic Evaluation Blood samples for PK assessments were drawn at 5 minutes before and at 0.5,, 2, 3, 4, 5, 6, 8, 0, 2, 6, 24, 48, 72, 96, 20, and 44 hours after each dose of vilazodone The following plasma PK parameters of vilazodone were determined: C : imum plasma concentration t : time to imum plasma concentration AUC 0-24 time 0 to 24 hours AUC 0-tlqc time 0 to the last quantifiable concentration AUC 0- time 0 to infinity, estimated by extrapolation CL/F: oral clearance, estimated by dose/auc0- Accumulation factor, estimated by AUC / 0-24 λ z : terminal rate constant t ½ : elimination half-life Statistical Analysis Study populations The primary analysis population was the PK-evaluable population, which included all subjects who received study medication and for whom plasma PK evaluations were completed for both treatment periods The safety population, which was used for all safety analyses, consisted of all subjects who received dose of vilazodone PK analysis PK parameters of interest were calculated and summarized for each vilazodone dose, where appropriate, by noncompartmental analysis Analysis of variance was performed on the natural logarithms of AUC0-tlqc, AUC, and C, with treatment received (vilazodone 0- alone, vilazodone with pantoprazole) as a fixed effect The point estimate and 90% confidence interval (CI) for the least squares mean (LSM) difference between treatments in PK parameters on the log scale were exponentiated to obtain estimates for ratios of geometric LSM on the original scale to evaluate the impact of reduced gastric acidity on absorption of vilazodone Pharmacokinetic Assessments Plasma concentration-time curves were nearly superimposable for vilazodone alone and vilazodone with increased gastric ph (Figure 2) Figure 2. (A, B) Mean plasma concentration versus time curves for vilazodone alone and vilazodone with pantoprazole. A B Dose : 40 mg alone (n=23) Dose 2: 40 mg + pantoprazole 40 mg qd (n=23) Linear Scale Semi-Logarithmic Scale Table 3. Relative Bioavailability for With Compared With Geometric LSM Ratio 90% CI, h ng/ml ,.64, h ng/ml ,.65 C, ng/ml ,.39 Safety Assessments: Adverse Events An overview of treatment-emergent AEs (TEAEs) is provided in Table 4 Most TEAEs were mild; none were assessed as severe Study drug was discontinued in 4 (35.%) subjects because of AEs (vomiting in 2 subjects after the first dose of vilazodone, vomiting in subject after the second dose of vilazodone, rash in subject during treatment with pantoprazole alone) Table 4. Overview of AEs n = 25 + n = 24 Total Category, n (%) Subjects with AE 22 (59.5) 2 (8.0) 0 (4.7) 26 (70.3) Subjects with serious AE Subjects who withdrew 2 (32.4) (4.0) (4.2) 3 (35.) because of AE Most common TEAEs after vilazodone administration Vomiting 2 (32.4) 0 (4.2) 3 (35.) Nausea 8 (2.6) 0 2 (8.3) 9 (24.3) Dizziness 8 (2.6) 0 2 (8.3) 9 (24.3) Headache 5 (3.5) (4.0) 0 5 (3.5) Diarrhea 4 (0.8) 0 3 (2.5) 5 (3.5) Study Assessments: Other No clinically relevant changes in laboratory parameters, vital signs, physical examination findings, or ECGs were observed Khan A, Cutler AJ, Kajdasz DK, et al. Efficacy and tolerability of vilazodone, a dual-acting serotonergic antidepressant, in the treatment of patients with major depressive disorder (MDD) 200. Presented at: 63rd Annual Meeting of the American Psychiatric Association; May 22-26, 200; New Orleans, LA. Robinson DS, Kadjdaz DA, Gallipoli S, Whalen H, Wamil A, Reed CR. A -year open-label study assessing the safety and tolerability of vilazodone in patients with major depressive disorder 200. Presented at: 63rd Annual Meeting of the American Psychiatric Association; May 22-26, 200; New Orleans, LA. International Conference on Harmonisation Expert Working Group. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R). International Conference on Harmonisation Steering Committee; 996:-53. E6(R). Accessed October 27, 200 Protonix (pantoprazole sodium) delayed-release tablets [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals. Disclosures Authors of this presentation have the following to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or an indirect interest in the subject matter of this presentation: J. Longstreth: Consultant PGxHealth LLC, a division of Clinical Data Inc., M. H. Adams: Consultant PGxHealth LLC, a division of Clinical Data Inc., V. Sperry: Employee PGxHealth LLC, a division of Clinical Data Inc., D. Kajdasz: Employee PGxHealth LLC, a division of Clinical Data Inc., C. R. Reed: Employee PGxHealth LLC, a division of Clinical Data Inc., Presented at the 45th ASHP (American Society of Health-System Pharmacists) Midyear Clinical Meeting & Exhibition; December 59, 200; Anaheim, CA Supported by PGxHealth LLC, a division of Clinical Data, Inc.

2 Background, a new molecule, is a dual-acting selective and potent serotonin A receptor partial agonist and reuptake inhibitor (SPARI) in clinical development for the treatment of major depressive disorder (MDD),2 The solubility of vilazodone is greatest at an acidic ph (pk = 7.) a The efficacy of vilazodone 40 mg/day in the treatment of MDD has been demonstrated in 2 Phase 3, randomized, double-blind, placebocontrolled, 8-week trials. 3,4 The long-term tolerability of vilazondone has been examined, and its effectiveness was described in an open-label, multicenter, 52-week study 5 Higher than normal gastric ph may occur because of concomitant administration of medications (eg, histamine H2-receptor antagonists, proton pump inhibitors), comorbid disorders (eg, pernicious anemia, chronic Helicobacter pylori infection), or surgical procedures (eg, vagotomy, gastrectomy) It is, therefore, important to determine whether higher than normal gastric ph affects the bioavailability of vilazodone Objectives Primary To determine the effect of increased gastric ph on the relative bioavailability of the 40-mg oral tablet formulation of vilazodone Secondary To evaluate the effect of increased gastric ph on the safety and tolerability of oral vilazodone in healthy adult volunteers Methods Ethical Conduct The study was conducted in accordance with Good Clinical Practice guidelines described in the International Conference on Harmonization (ICH) Guideline E6, other applicable ICH guidelines, and the US Code of Federal Regulations (CFR), Title 2 6 The study protocol was approved by the institutional review board at the investigational site according to specifications outlined in the US CFR All subjects provided voluntary written informed consent before any study procedures were performed Study Design Phase, open-label, 2-period crossover, single-center study ( Figure ) On day, each subject received a single dose of vilazodone 40 mg; vilazodone pharmacokinetics (PK) were followed for 44 hours On days 3 to 8, subjects received pantoprazole 40 mg/day; on day 9, subjects received vilazodone 40 mg plus pantoprazole 40 mg; vilazodone PK were followed for 44 hours is a proton pump inhibitor that inhibits gastric acid secretion by 85% 7 All doses were administered after a light breakfast Presented at the 45th ASHP (American Society of Health

3 Figure. Study design and dosing schedule. Inpatient Outpatient Inpatient Outpatient 40 mg 40 mg Pharmacokinetic Sampling Day Main Eligibility Criteria The study included healthy adult men and women whose body mass index was between 8 and 35 kg/m 2 Safety Assessments Safety was assessed by monitoring adverse events (AEs), clinical laboratory evaluations, electrocardiograms (ECGs), and vital signs Exclusion criteria included: History of clinically significant cardiac, gastrointestinal, renal, or hepatic disease Use of an acid-suppressing medication within 2 weeks before day Use of any serotonergic migraine medication or cytochrome P450 3A4 inhibitor within 30 days before day Pharmacokinetic Evaluation Blood samples for PK assessments were drawn at 5 minutes before and at 0.5,, 2, 3, 4, 5, 6, 8, 0, 2, 6, 24, 48, 72, 96, 20, and 44 hours after each dose of vilazodone The following plasma PK parameters of vilazodone were determined: C : imum plasma concentration t : time to imum plasma concentration AUC 0-24 time 0 to 24 hours AUC 0-tlqc time 0 to the last quantifiable concentration AUC 0- time 0 to infinity, estimated by extrapolation CL/F: oral clearance, estimated by dose/auc0- Subjects who experienced vomiting within 0 hours after vilazodone dosing were discontinued from the study Statistical Analysis Study populations The primary analysis population was the PK-evaluable population, which included all subjects who received study medication and for whom plasma PK evaluations were completed for both treatment periods The safety population, which was used for all safety analyses, consisted of all subjects who received dose of vilazodone PK analysis PK parameters of interest were calculated and summarized for each vilazodone dose, where appropriate, by noncompartmental analysis Analysis of variance was performed on the natural logarithms of AUC0-tlqc, AUC, and C, with treatment received (vilazodone 0- alone, vilazodone with pantoprazole) as a fixed effect The point estimate and 90% confidence interval (CI) for the least squares mean (LSM) difference between treatments in PK parameters on the log scale were exponentiated to obtain estimates for ratios of geometric LSM on the original scale to evaluate the impact of reduced gastric acidity on absorption of vilazodone Accumulation factor, estimated by AUC / 0-24 λ z : terminal rate constant t ½ : elimination half-life th-system Pharmacists) Midyear Clinical Meeting & Exhibition; December 59, 200; Anaheim, CA

4 Suppo Results Subject Disposition and Demographics Of 37 enrolled subjects, 23 (62.2%) completed the study 4 subjects (37.8%; 2/2 women and 2/6 men) discontinued because of AEs Baseline characteristics of the safety population () and the PK-evaluable population () were similar except for the distribution of sexes (Table ) Table. Demographic and Baseline Characteristics of the Safety and PK-Evaluable Populations Safety Population PK-Evaluable Population Characteristic Sex, n (%) Female 2 (56.8) 9 (39.) Male 6 (43.2) 4 (60.9) Age, y, mean (SD) 36. (0.3) 38. (.2) Race, n (%) White 36 (97.3) 22 (95.7) Black (2.7) (4.3) Weight, kg, mean (SD) 72.7 (0.2) 75.0 (9.5) BMI, kg/m 2, mean (SD) 27.5 (3.2) 27.7 (3.4) Pharmacokinetic Assessments Plasma concentration-time curves were nearly superimposable for vilazodone alone and vilazodone with increased gastric ph (Figure 2) Figure 2. (A, B) Mean plasma concentration versus time curves for vilazodone alone and vilazodone with pantoprazole. A Dose : 40 mg alone (n=23) Dose 2: 40 mg + pantoprazole 40 mg qd (n=23) Linear Scale PK parameters for vilazodone alone were similar to those for vilazodone with increased gastric ph (Table 2) Table 2. Mean (SD) PK s for and With 40 mg + 40 mg 40 mg AUC 0-24, h ng/ml (37.6) (50.3), h ng/ml (672.8) (839.6), h ng/ml 20.7 (69.3) (855.4) C, ng/ml 06.5 (28.9) 5.9 (46.0) t, h 5.8 (.8) 5.5 (.9) t ½, h 25.4 (.8) 27.0 (9.4) λ z, /h (0.0623) ( ) CL/F, L/h 2. (7.) 20.2 (0.7) Accumulation factor.6 (0.22).66 (0.24) The relative bioavailability of vilazodone associated with increased gastric ph compared with that of vilazodone alone was not statistically significantly different (Table 3) 90% CIs for the ratios of the means lay completely within the prespecified 0.80 to.25 interval (Table 3) Table 3. Relative Bioavailability for With Compared With Geometric LSM Ratio 90% CI, h ng/ml ,.64, h ng/ml ,.65 C, ng/ml ,.39 Safety Assessments: Adverse Events An overview of treatment-emergent AEs (TEAEs) is provided in Table 4 Most TEAEs were mild; none were assessed as severe Study drug was discontinued in 4 (35.%) subjects because of AEs (vomiting in 2 subjects after the first dose of vilazodone, vomiting in subject after the second dose of vilazodone, rash in subject during treatment with pantoprazole alone) B Semi-Logarithmic Scale Table 4. Overview of AEs n = 25 + n = 24 Total Category, n (%) Subjects with AE 22 (59.5) 2 (8.0) 0 (4.7) 26 (70.3) Subjects with serious AE Subjects who withdrew 2 (32.4) (4.0) (4.2) 3 (35.) because of AE Most common TEAEs after vilazodone administration Vomiting 2 (32.4) 0 (4.2) 3 (35.) Nausea 8 (2.6) 0 2 (8.3) 9 (24.3) Dizziness 8 (2.6) 0 2 (8.3) 9 (24.3) Headache 5 (3.5) (4.0) 0 5 (3.5) Diarrhea 4 (0.8) 0 3 (2.5) 5 (3.5) 0. Study Assessments: Other No clinically relevant changes in laboratory parameters, vital signs, physical examination findings, or ECGs were observed

5 Conclusions -induced increases in gastric ph had no effect on the bioavailability or PK of a single 40-mg dose of vilazodone These findings suggest that dose reductions would be unnecessary in patients with a high likelihood of having reduced gastric acidity The high rate of vomiting in this trial reinforces the importance of titrating vilazodone to the minimally effective dose of 40 mg/day References. Hughes ZA, Starr KR, Langmead CJ, et al. Neurochemical evaluation of the novel 5-HT A receptor partial agonist/serotonin reuptake inhibitor, vilazodone. Eur J Pharmacol. 2005;50: Dawson LA, Watson JM. : a 5-HT receptor agonist/serotonin A transporter inhibitor for the treatment of affective disorders. CNS Neurosci Ther. 2009;5: Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR. Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70: Khan A, Cutler AJ, Kajdasz DK, et al. Efficacy and tolerability of vilazodone, a dual-acting serotonergic antidepressant, in the treatment of patients with major depressive disorder (MDD) 200. Presented at: 63rd Annual Meeting of the American Psychiatric Association; May 22-26, 200; New Orleans, LA. Robinson DS, Kadjdaz DA, Gallipoli S, Whalen H, Wamil A, Reed CR. A -year open-label study assessing the safety and tolerability of vilazodone in patients with major depressive disorder 200. Presented at: 63rd Annual Meeting of the American Psychiatric Association; May 22-26, 200; New Orleans, LA. International Conference on Harmonisation Expert Working Group. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R). International Conference on Harmonisation Steering Committee; 996:-53. E6(R). Accessed October 27, 200 Protonix (pantoprazole sodium) delayed-release tablets [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals. Disclosures Authors of this presentation have the following to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or an indirect interest in the subject matter of this presentation: J. Longstreth: Consultant PGxHealth LLC, a division of Clinical Data Inc., M. H. Adams: Consultant PGxHealth LLC, a division of Clinical Data Inc., V. Sperry: Employee PGxHealth LLC, a division of Clinical Data Inc., D. Kajdasz: Employee PGxHealth LLC, a division of Clinical Data Inc., C. R. Reed: Employee PGxHealth LLC, a division of Clinical Data Inc., orted by PGxHealth LLC, a division of Clinical Data, Inc.