Article Figures & Data
Figures
- Fig. 1.
Strategy to assess potential for veverimer drug-drug interactions. We used a directed approach based on the known physical and chemical characteristics of veverimer to analyze its potential for DDIs. Veverimer is too large to be systemically absorbed; therefore, its potential for DDIs is limited to effects on the absorption of other orally administered drugs either through 1) binding to veverimer or 2) transient increases in gastric pH caused by veverimer binding to HCl. To identify candidate drugs for testing with veverimer in human DDI studies, we conducted in vitro studies to identify the characteristics most likely to lead to binding to veverimer, and we evaluated the effect of veverimer on gastric pH in healthy volunteers. Results from these studies informed the selection of drugs for human DDI studies.
- Fig. 2.
Binding of negatively charged probes to veverimer. (A) Binding kinetics for negatively charged probes. (B) Binding of the probe molecules to veverimer as a function of size. N = 9, mean ± S.D.
- Fig. 3.
In vitro binding of test drugs to veverimer. The potential for binding interactions with veverimer was assessed in vitro using a set of test drugs that included 14 oral medications and two water-soluble vitamins and test matrices mimicking the pH of various GI compartments. (A) 4.5 mg/mL veverimer in SGF; (B) 9.0 mg/mL veverimer in SGF + 60 mM HCl; (C) 4.5 mg/mL veverimer in 50 mM acetate buffer; (D) 9.0 mg/mL veverimer in 100 mM acetate buffer; (E) 4.5 mg/mL veverimer in SIF; (F) 9.0 mg/mL veverimer in SIF + 50 mM PO4. The dashed line represents the threshold for test drug interaction with veverimer. PO4, phosphate. N = 6, mean ± 90% confidence interval.
- Fig. 4.
In vitro binding of test drugs to veverimer in the presence of physiologically relevant concentrations of chloride. Five representative test drugs from the set of 14 oral medications, one each with a positive (trimethoprim) or neutral (allopurinol) charge and three with a negative charge (aspirin, ethacrynic acid, and furosemide) were assessed for veverimer binding in six test matrices supplemented with 100 mM chloride. (A) 4.5 mg/mL veverimer in SGF + 100 mM chloride; (B) 9.0 mg/mL veverimer in SGF + 100 mM chloride; (C) 4.5 mg/mL veverimer in 50 mM acetate buffer with 100 mM chloride; (D) 9.0 mg/mL veverimer in 100 mM acetate buffer with 100 mM chloride; (E) 4.5 mg/mL veverimer in SIF with 100 mM chloride; (F) 9.0 mg/mL veverimer in SIF + 50 mM PO4 with 100 mM chloride. The dashed line represents the threshold for test drug interaction with veverimer. PO4, phosphate. N = 6, mean ± 90% confidence interval.
- Fig. 5.
Effect of veverimer on gastric pH in the absence and presence of a proton pump inhibitor. The magnitude and duration of effect of veverimer on gastric pH was measured continuously in vivo in healthy volunteers using a microelectrode pH probe. Ingestion of veverimer or water occurred at ?hour 0, just after initiation of pH monitoring. In experiments assessing the fed condition, breakfast was eaten within 15 minutes prior to hour 0. Other meal/snack times occurred at ?hour 4, hour 9 (or 10), and hour 13. Omeprazole was administered at hour 9. (A) Veverimer versus water control under fasted conditions (without PPI); (B) veverimer versus water control under fed conditions (without PPI); (C) veverimer versus water control under fasted conditions (with PPI); (D) veverimer versus water control under fed conditions (with PPI).
- Fig. 6.
Effects of veverimer on the pharmacokinetic exposures of other orally administered medications. The effect of veverimer on the bioavailability of test drugs chosen to represent medications most likely to interact with veverimer via direct binding (furosemide, aspirin) or via indirect effects on gastric pH (furosemide, warfarin, dabigatran) was assessed in healthy volunteers.
Tables
Test Drug (Conc.; µg/mL) Class BCS Class MM pKa Charge at pH 1.2 4.5 6.8 Positively charged test drugs Amlodipine (5) Calcium channel blocker I 408.9 9.21B + + + Metformin (500) Biguanide III 129.2 2.94B, 13.7B + + + Metoprolol (25) β blocker I 267.4 9.61B + + + Thiamine (1) Vitamin B1 III 265.4 4.8B + + + Trimethoprim (100) Antibiotic II 290.3 7.14B + + + Neutral/zwitterionic test drugs Allopurinol (100) Xanthine oxidase inhibitor I 136.1 9.31A N N N Lisinopril (5) ACE inhibitor III 405.5 1.63A, 3.13A, 7.13B, 10.75B + Z Z Riboflavin (1.2) Vitamin B2 I 376.4 9.69A N N N Spironolactone (25) Aldosterone antagonists II 416.6 n/a N N N Negatively charged test drugs Aspirin (81) Platelet aggregation inhibitor I 180.2 3.50A N – – Ethacrynic acid (25) Diuretic NA 303.1 3.50A N – – Furosemide (20) Diuretic IV 330.7 3.62A, 10.16A N – – Gliclazide (40) Sulfonylurea II 323.4 5.80A N N N/– Rosuvastatin (5) HMG COA reductase inhibitor III 481.5 4.6A N N/– – Valsartan (40) Angiotensin II antagonist III 435.5 3.9A 4.7A N – – Warfarin (1) Antithrombotic II 308.3 4.94A N N/– – –, negative; +, positive; ACE, angiotensin-converting enzyme inhibitor; BCS, Biopharmaceutics Classification System; HMG COA, hydroxymethylglutaryl-coenzyme A; N, neutral; NA, not applicable; Z, zwitterionic.
- TABLE 2
Pharmacokinetic analyses: ANOVA comparison of geometric least-squares-mean ratios (90% confidence intervals)
Analyte Parameter Concomitant Administration 1-Hour Separation 2-Hour Separation 3-Hour Separation Acetylsalicylic acid
Cmax (ng/mL)
AUC0-t (hour·ng/mL)
AUC0-inf (hour·ng/mL)94.4% (86.0%, 103.5%)
85.1% (81.4%, 89.0%)
85.1% (81.4%, 89.0%)NA NA 94.3% (85.9%, 103.4%)
98.3% (94.0%, 102.7%)
98.2% (94.0%, 102.7%)Salicylic acid
Cmax (ng/mL)
AUC0-t (hour·ng/mL)
AUC0-inf (hour·ng/mL)103.7% (100.3%, 107.2%)
91.8% (90.0%, 93.5%)
91.7% (90.0%, 93.5%)NA NA 101.4% (98.0%, 104.8%)
97.9% (96.0%, 99.8%)
97.5% (95.6%, 99.4%)Furosemide
Cmax (ng/mL)
AUC0-t (hour·ng/mL)
AUC0-inf (hour·ng/mL)99.5% (89.8%, 110.3%)
91.1% (87.5%, 94.9%)
89.9% (86.5%, 93.5%)NA NA 107.3% (96.8%, 118.9%)
101.3% (97.3%, 105.6%)
99.9% (96.1%, 103.9%)R-Warfarin
Cmax (ng/mL)
AUC0-t (hour·ng/mL)
AUC0-inf (hour·ng/mL)105.5% (99.6%, 111.7%)
100.9% (98.2%, 103.7%
100.6% (95.9%, 105.6%NA NA 100.7% (95.1%, 106.7%)
99.7% (97.0%, 102.5%)
99.7% (95.0%, 104.6%)S-Warfarin
Cmax (ng/mL)
AUC0-t (hour·ng/mL)
AUC0-inf (hour·ng/mL)107.3% (96.5%, 119.3%)
98.0% (93.5%, 102.6%)
98.5% (93.2%, 104.2%)NA NA 101.5% (91.3%, 113.0%)
98.9% (94.4%, 103.6%)
98.1% (92.8%, 103.8%)Free dabigatran
Cmax (ng/mL)
AUC0-t (hour·ng/mL)
AUC0-inf (hour·ng/mL)87.8% (81.3%, 94.8%)
82.4% (77.3%, 87.8%)
82.6% (77.6%, 87.9%)93.6% (84.0%, 104.0%)
88.5% (80.3%, 97.6%)
88.5% (80.4%, 97.5%)111.0% (103.0%, 120.0%)
94.5% (88.7%, 101.0%)
94.6% (88.9%, 101.0%)NA Total dabigatran
Cmax (ng/mL)
AUC0-t (hour·ng/mL)
AUC0-inf (hour·ng/mL)88.3% (81.5%, 95.7%)
82.4% (77.1%, 88.0%)
82.8% (77.7%, 88.2%)95.6% (86.0%, 106.0%)
89.1% (80.9%, 98.1%)
89.2% (81.1%, 98.0%)115.0% (107.0%, 125.0%)
97.9% (91.6%, 105.0%)
98.0% (91.9%, 104.0%)NA NA, not applicable.
Data Supplement
- Supplemental Data -
Mean (SD) Plasma Total Dabigatran Concentration Profile over Time (Linear Scale)Supplemental Methods
Supplemental Table 1 - Anionic Probes (Test Acids).
Supplemental Table 2 - Gastric pH Study Subject Disposition.
Supplemental Table 3 - Gastric pH Study Demographics and Baseline Characteristics
Supplemental Table 4 -Test Drugs with pH-Dependent Solubility
Supplemental Table 5 - Exclusion Criteria for Genotyping
Supplemental Table 6 - DDI Study Subject Disposition
Supplemental Table 7 - DDI Study Demographics and Baseline Characteristics
Supplemental Table 8 - Human DDI Study Pharmacokinetics Analyses - Summary Statistics
Supplemental Table 9 - Summary Statistics for INR AUC0-0168 and INRmax in the Warfarin DDI Study
Supplemental Table 10 - ANOVA Comparison of Geometric Least Square Means for INR AUC0-0168 and INRmax in the Warfarin DDI Study
Supplemental Figure 1 - Gastric pH Study Design Schematic
Supplemental Figure 2 - Drug-Drug Interaction Study Design (Furosemide, Aspirin, Warfarin)
Supplemental Figure 3 - Drug-Drug Interaction Study Design (Dabigatran)
Supplemental Figure 4 - Effect of Food: Water Administered under Fasting vs. Fed Conditions
Supplemental Figure 5 - Effect of Omeprazole: Water Administered under Fasting Conditions Without vs. With Omeprazole
Supplemental Figure 6 - Mean (SD) Plasma Furosemide Concentration Profile over Time (Linear Scale)
Supplemental Figure 7 - Mean Plasma Furosemide Concentration Profile over Time (Log-Linear Scale)
Supplemental Figure 8 - Mean (SD) Plasma Acetylsalicylic Acid Concentration Profile over Time (Linear Scale)
Supplemental Figure 9 - Mean Plasma Acetylsalicylic Acid Concentration Profile over Time (Log-Linear Scale)
Supplemental Figure 10 - Mean (SD) Plasma Salicylic Acid Concentration Profile over Time (Linear Scale)
Supplemental Figure 11 - Mean Plasma Salicylic Acid Concentration Profile over Time (Log-Linear Scale)
Supplemental Figure 12 - Mean (SD) Plasma R-Warfarin Concentration Profile over Time (Linear Scale)
Supplemental Figure 13 - Mean Plasma R-Warfarin Concentration Profile over Time (Log-Linear Scale)
Supplemental Figure 14 - Mean (SD) Plasma S-Warfarin Concentration Profile over Time (Linear Scale)
Supplemental Figure 15 - Mean Plasma S-Warfarin Concentration Profile over Time (Log-Linear Scale)
Supplemental Figure 16 - Mean (SD) Plasma Total Dabigatran Concentration Profile over Time (Linear Scale)
Supplemental Figure 17 - Mean Plasma Total Dabigatran Concentration Profile over Time (Log-Linear Scale)
Supplemental Figure 18 - Mean (SD) Plasma Free Dabigatran Concentration Profile over Time (Linear Scale)
Supplemental Figure 19 - Mean Plasma Free Dabigatran Concentration Profile over Time (Log-Linear Scale)
Supplemental Figure 20 - Mean (SD) International Normalized Ratio over Time (Linear Scale)
Supplemental Figure 21 - Mean International Normalized Ratio over Time (Log-Linear Scale)
- Supplemental Data -
In this issue
Assessment of Potential Veverimer Drug-Drug Interactions
