Assessment of the Potential for Veverimer Drug-Drug Interactions

Veverimer is a polymer being developed as a potential treatment for metabolic acidosis in patients with chronic kidney disease. Veverimer selectively binds and removes hydrochloric acid from the gastrointestinal tract, resulting in an increase in serum bicarbonate. Veverimer is not systemically absorbed, so potential drug-drug interactions (DDIs) are limited to effects on the absorption of other oral drugs through binding to veverimer in the gastrointestinal tract or increases in gastric pH caused by veverimer binding to hydrochloric acid. In in vitro binding experiments using a panel of 16 test drugs, no positively charged, neutral or zwitterionic drugs bound to veverimer. Three negatively charged drugs (furosemide, aspirin, ethacrynic acid) bound to veverimer; however, this binding was reduced or eliminated in the presence of normal physiological concentrations (100-170 mM) of chloride. Veverimer increased gastric pH in vivo by 1.5-3 pH units. This pH elevation peaked within 1 hour and had returned to baseline after 1.5-3 hours. Omeprazole did not alter the effect of veverimer on gastric pH. The clinical relevance of in vitro binding and the transient increase in gastric pH was evaluated in human DDI studies using two drugs with the most binding to veverimer (furosemide, aspirin) and two additional drugs with pH-dependent solubility effecting absorption (dabigatran, warfarin). None of the four drugs showed clinically meaningful DDI with veverimer in human studies. Based on the physicochemical characteristics of veverimer and results from in vitro and human studies, veverimer is unlikely to have significant DDIs.


SIF, simulated intestinal fluid
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Veverimer is being developed as a once-daily treatment for metabolic acidosis in patients with CKD. Veverimer is an orally administered, non-absorbed, insoluble, free-amine polymer that combines high capacity and selectivity to bind and remove hydrochloric acid (HCl) from the gastrointestinal (GI) tract, resulting in an increase in serum bicarbonate (Bushinsky et al., 2018;Wesson et al., 2019b;Wesson et al., 2019a). Acid binding and removal using a non-absorbed polymer is a novel approach to treating metabolic acidosis. Within the GI tract, the polymer restores the ability to excrete acid from the body. This mechanism of action is fundamental to the effectiveness of veverimer in treating metabolic acidosis and is distinct from the mechanisms of other drugs, such as proton pump inhibitors (PPIs) and histamine H 2 -receptor antagonists, that affect gastric pH but do not have an effect on systemic acid-base balance. The effect of veverimer on acid binding, as assessed by a change in gastric pH, was evaluated in this study both in the presence or absence of a PPI. The effect of veverimer on a background of PPI use was a relevant question because these drugs affect gastric pH and are commonly used. This article has not been copyedited and formatted. The final version may differ from this version. DMD Fast Forward. Published on May 24, 2021as DOI: 10.1124 at ASPET Journals on July 16, 2021 dmd.aspetjournals.org

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Veverimer was designed to bind HCl with high capacity and specificity. After ingestion, veverimer is protonated, and the positively charged polymer selectively binds the smallest anion in the GI tract, chloride, with little or no binding of other anions (Klaerner et al., 2020). The high HCl binding capacity is a function of the amine content of the polymer, while the high specificity for chloride binding is the result of extensive crosslinking within the polymer beads that excludes anions larger than chloride (e.g., phosphate, citrate, bile acids and short-chain and long-chain fatty acids) and minimizes interaction between the polymer and other concomitantly administered oral drugs (Klaerner et al., 2020).
Polypharmacy is common in CKD and drug-drug interactions (DDIs) are a continuing clinical concern (Rama et al., 2012;Sommer et al., 2020). We used a directed approach based on the known physical and chemical characteristics of veverimer to analyze its potential for DDIs ( Figure 1). Veverimer is too large to be systemically absorbed (Klaerner et al., 2020) 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. In this study we tested the hypothesis that the potential for veverimer to interact with other orally administered drugs is low, consistent with the physical and chemical properties of this novel polymer. This article has not been copyedited and formatted. The final version may differ from this version. DMD Fast Forward. Published on May 24, 2021as DOI: 10.1124 at ASPET Journals on July 16, 2021 dmd.aspetjournals.org Downloaded from

MATERIALS AND METHODS
The protocols for all five clinical trials reported herein were approved by the relevant US institutional review boards (Chesapeake Research Review, Inc. [Columbia, MD] for the furosemide, aspirin and warfarin DDI studies and the gastric pH study and Advarra IRB [Columbia, MD] for the dabigatran DDI study). All participants provided written, informed consent prior to trial initiation. The trials were conducted at Celerion in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The furosemide, warfarin and dabigatran DDI studies and the gastric pH study were conducted in Tempe, AZ, and the aspirin DDI study was conducted in Lincoln, NE.

Anionic Probes
Since the free-amine veverimer polymer becomes positively charged upon binding to hydrogen ions, negatively charged probe molecules of increasing molecular weight (36.5-234.2 Da; Supplemental Table S1) were used to assess the role of size exclusion in binding of molecules to veverimer. Veverimer (450 mg) was incubated in 20 mM aqueous solutions (100 mL) of individual probe molecules for 0.5, 2, 4, 6 and 24 hours. Phosphoric acid and HCl incubation periods were limited to 6 hours and 4 hours, respectively. At each time point, a 400 µL aliquot was filtered, diluted 10-fold and analyzed by ion chromatography to calculate the number of millimoles of acid bound per gram of veverimer.

In Vitro Assessment of Direct Drug Binding to Veverimer: Test Drug Panel
An in vitro test system was designed to assess the potential for binding interactions between veverimer and a set of test drugs that included 14 oral medications used in patients with CKD, as well as two water-soluble vitamins ( Table 1). The test drug panel included prototypical drugs from 14 distinct drug classes that ranged in size from 129 to 482 Da, were positively charged (N=5), neutral/zwitterionic (N=4) or negatively charged (N=7), and comprised all four Biopharmaceutics Classification System (BCS) classes, covering a range of solubilities and permeabilities.
In vitro binding assays were conducted using seven matrices mimicking the pH and ionic conditions of the GI tract: simulated gastric fluid (SGF) with or without additional 60 mM HCl and without pepsin (pH 1 to 1.2); 50, 100 or 200 mM acetate buffer (pH 4.5); and simulated intestinal fluid (SIF) with or without an additional 50 mM PO 4 and without pancreatin (pH 6.8).
The matrices with higher buffering capacity (SGF+60 mM HCl, 100 mM and 200 mM acetate buffer, SIF+50 mM PO 4 ) were used to maintain the pH of the incubation mixture around the target pH values of 1.2, 4.5 and 6.8, respectively, in the presence of 9.0 mg/mL veverimer. The likelihood of identifying a drug interaction would be greatest at a high concentration of veverimer (4.5 g or 9.0 g) and a low concentration of the test drug. The maximum clinical dose of veverimer is anticipated to be 9 g QD. A volume of one liter was used for dispersion of an orally administered drug in the upper GI tract. (Read et al., 1980;Metcalf et al., 1987;Thelen et al., 2011).
Binding to veverimer was assessed in six replicates by measuring free test drug concentration after a 3-hour incubation on a benchtop shaker at 37°C in the presence or absence of veverimer (4.5 mg/mL or 9.0 mg/mL). After incubation, samples were allowed to settle for 5 minutes and were filtered with a 0.45 micrometer polyvinylidene fluoride (PVDF) filter plate unit (allopurinol, aspirin, gliclazide, metoprolol tartrate, lisinopril, riboflavin, thiamine hydrochloride, and trimethoprim) or a 0.45 micrometer PVDF syringe filter (amlodipine besylate, ethacrynic This article has not been copyedited and formatted. The final version may differ from this version. is the t-value for a two-sided 90% confidence interval with DF degrees of freedom. Assuming equal variances between the two populations, the standard deviation of the difference between the means is: where 1 2 is the variance of n 1 observations from population 1 and 2 2 is the variance of n 2 observations from population 2 and DF = n 1 + n 2 -2. Results from these in vitro studies informed the selection of drugs for human DDI studies.

Effect of Veverimer on Gastric pH in Healthy Volunteers with and without Omeprazole
An open-label, in-patient, randomized, crossover, 2-stage study in healthy volunteers was conducted to assess the effect of veverimer on gastric pH (Supplemental Figure S1).  Stage 2; subjects who withdrew from the study after Stage 1 were replaced to ensure that the same number of subjects (N = 40) participated in each stage. The sample size was estimated based on the integrated acidity variability when no drug is administered to show no difference and ensure that the effect observed with veverimer was due to the drug administration and not the natural variability of the pH levels in healthy subjects. The number of subjects enrolled was based on in-house data and conservative assumptions regarding intra-and inter-subject coefficients of variation in order to obtain a power of at least 80%, which was defined as the probability of having a 90% confidence interval (CI) for a treatment ratio within 80.00 -125.00%.
Both Stage 1 and Stage 2 had a randomized (1:1:1:1), 4-period, 4-way crossover design. One of four study drug treatments was administered on Day 1 of each of four treatment periods in each stage. Periods 1 and 2, and Periods 3 and 4, were each conducted over two consecutive days; Period 2 and Period 3 were separated by a 1-day rest period. As prespecified in the protocol, after completion of Period 4 in Stage 1 and review of the preliminary intragastric pH data, the decision was made to conduct Stage 2.
Stage 2 began with a 6-day Run-in Period (Days -6 to -1), during which subjects received omeprazole once daily (QD In Stage 1 of the study, subjects received the following treatments:  In Stage 2 of the study, subjects received the following treatments:  Treatment E: Water Fasted. Ninety (90)  Safety was monitored throughout the study with clinical laboratory evaluations, reporting of AEs, physical examination, vital signs, and 12-lead electrocardiograms (ECGs).
Information on subject disposition is provided in Supplemental Table S2. Demographics and key baseline information for the study population are presented in Supplemental Table S3.
Most subjects were white (80.0% in Stage 1; 77.5% in Stage 2) and approximately half were of Hispanic or Latino ethnicity (57.5% in each stage). Most subjects were female (67.5% in Stage 1; 65.0% in Stage 2), and the mean age was 33.4 years in Stage 1 and 35.5 years in Stage 2 Results from this study informed the selection of additional drugs for human DDI studies.

Human DDI Studies
To characterize the potential for clinically relevant DDIs due to binding of other orally administered drugs to veverimer, human DDI studies were conducted with the two drugs that This article has not been copyedited and formatted. The final version may differ from this version. showed the highest binding with veverimer in vitro: aspirin and furosemide. Given the transient effect of veverimer on gastric pH, human DDI studies were also conducted to evaluate the potential for veverimer to affect the bioavailability of drugs with pH-dependent solubility; the victim drugs evaluated in these studies were the weak acids furosemide and warfarin, and the weak base dabigatran (Supplemental Table S4).
Human DDI studies were open-label, in-patient, randomized, crossover studies that examined the effect of veverimer on the pharmacokinetic (PK) profile of each of the four victim drugs. The treatments administered comprised: victim drug alone, victim drug coadministered with veverimer, and victim drug separated from veverimer by 1 -3 hours, and subjects were randomly assigned to treatment sequence (Supplemental Figure S2 and Figure S3). Key entry criteria for the studies are provided in Supplemental Section 3.1.2.1.
In order to maximize the possibility of observing binding to veverimer, the highest anticipated daily dose of veverimer (9 g) and the lowest feasible clinical dose of the victim drugs were administered (20 mg furosemide, 81 mg aspirin, 2 mg warfarin, 150 mg dabigatran). Study treatments were administered during treatment periods in which subjects were confined in a CRU where they were fed a standardized diet, with an out-patient washout period between treatment periods and a 14-day follow-up period after the final study treatment. In each treatment period, serial blood samples for PK analysis were collected following administration of the victim drug; the sampling time periods and washout periods between treatments were based on the half-lives of the victim drugs ( All DDI studies included assessment of the safety and tolerability of veverimer when coadministered with the victim drug. Safety was evaluated from 12-lead ECGs, measurements of vital signs and clinical laboratory parameters, assessment of AEs, and physical examinations.
Information on the disposition of subjects in the human DDI studies is summarized in Supplemental Table S6. A total of 52 subjects were randomized, enrolled, and received at least one dose of study drug in the furosemide DDI study. The furosemide PK analysis set comprised 51 subjects; one subject vomited during administration of the first dose of veverimer in Treatment Period 1 and was withdrawn from the study. Per protocol, because the subject did not have ≥ 2 consecutive time points with measurable furosemide concentrations, he was excluded from the furosemide PK analysis set.
In the aspirin DDI study, a total of 51 subjects were randomized, enrolled, and received at least one dose of study drug and were included in the aspirin PK analysis set. Forty-eight (48) subjects completed the study; 3 subjects withdrew early for diverse reasons (i.e., mild headache, difficulty with study blood draws, personal reasons). In the warfarin DDI study, a total of 15 subjects were randomized, enrolled, received at least one dose of study drug, and completed the study. The warfarin PK and PD analysis sets comprised 15 subjects who complied sufficiently with the protocol and displayed evaluable PK and PD profiles, respectively. A subset analysis was prespecified that excluded obviously aberrant PK profiles based on the presence of outlier values in one or more of the key PK parameters, defined as those falling below the first quartile or above the third quartile by more than 1.5 times the interquartile range, in the event that outlier values were noted for the PK parameters AUC 0-t , AUC 0-inf or C max , for R-or S-warfarin. The initial PK and statistical assessments included a PK profile for one subject (Treatment A [warfarin alone]) that diverged dramatically from the remainder of the data. It was readily apparent on visual inspection of the concentration-time profiles that there was a unique issue in this individual on this dosing occasion (i.e., the subject did not appear to have ingested the drug), and that this profile should be excluded from the analysis. A cause for the effective absence of warfarin blood levels in this subject on this occasion could not be identified. The decision to perform subset analyses with the aberrant Treatment A profile removed from the warfarin PK analysis set was supported by the statistical assessment described above.
In the warfarin DDI study, Plasma R-and S-warfarin levels were below the limit of quantitation (BLQ) (i.e., < 1.00 ng/mL) in all samples collected prior to dosing in Period 1. Quantifiable Rand S-warfarin concentrations were observed in all predose plasma samples in Periods 2 and 3, consistent with carryover from the prior dose. This suggests that the 21-day wash out period was insufficient. However, individual predose concentrations were low, ranging from approximately 1.5% to 6.8% of the subsequent C max for R-warfarin, with nine instances exceeding 5%. For Swarfarin, predose concentrations ranged from approximately 2.0% to 8.6% of C max , with four This article has not been copyedited and formatted. The final version may differ from this version. instances exceeding 5%. Therefore, it is highly improbable that the measurable predose concentrations had a discernable impact on the PK data.
In the dabigatran DDI study, a total of 84 subjects were randomized, enrolled, and received at least one dose of study drug. Of the 84 subjects in the dabigatran PK analysis set, 81 subjects (96.4%) completed the study, receiving all doses of each study drug; three subjects had incomplete PK data: 1 subject was discontinued for a protocol violation and had no PK data for Treatment D; 2 subjects withdrew early causing one to miss Treatment D and the other to miss Treatments C and D. The available data for all subjects were included in the PK analyses.
Demographic and baseline characteristics of the subjects enrolled in the DDI studies are summarized in Supplemental Table S7. The average age of the subjects in the studies ranged from 33-39 years and the study populations ranged from 47-80% male. The majority (80-90%) of the patients studied were white; 2-79% were Hispanic or Latino; and 6-13% were black or African American.
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Binding of Veverimer to Anionic Probes and Representative Test Drugs In Vitro
The binding kinetics for the anionic probe molecules to veverimer are shown in Figure 2A and binding of the probe molecules to veverimer as a function of size is illustrated in Figure 2B.
The rate of binding, as well as the total amount of probe bound to the polymer, was inversely proportional to the size of the probe, suggesting that smaller negatively charged molecules preferentially bound to the polymer over larger negatively charged molecules. Anionic probe molecules >200 Da did not bind to veverimer.
In in vitro binding experiments using a panel of 16 test drugs, none of the five test drugs that are positively charged across the physiological pH range of the GI tract (i.e., amlodipine, metformin, metoprolol, thiamine and trimethoprim) bound to veverimer under any condition (Figure 3).
Similarly, none of the four test drugs that are neutral or zwitterionic (i.e., allopurinol, riboflavin, spironolactone and lisinopril) bound to veverimer under any condition (Figure 3). The remaining seven test drugs (aspirin, ethacrynic acid, furosemide, valsartan, rosuvastatin, warfarin and gliclazide) are weak acids; of these, only furosemide, aspirin and ethacrynic acid bound to veverimer and these only did so in the acetate buffer (pH 4.5) matrix. Under the pH conditions of the SGF matrix (pH 1-1.2), the weak acids are neutral (Table 1), and none bound to veverimer (Figure 3). Although the weak acids are negatively charged in the SIF matrix (pH 6.8), none bound to veverimer, likely because 50-100 mM of the small anion, phosphate, was available to compete for veverimer binding sites (Figure 3).
In the presence of physiologically relevant concentrations of chloride (100 mM) the three test drugs (aspirin, ethacrynic acid, furosemide) that bound to veverimer in acetate buffer were unable to bind, likely due to preferential binding of the small chloride ion (Figure 4). Drugs previously shown not to bind veverimer (allopurinol, trimethoprim) also did not bind to the polymer in the presence of 100 mM chloride.

Effects of Veverimer on Gastric pH with and without 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.  proton pump inhibitor (omeprazole) (Figure 5C and Figure 5D). Supplemental Figure S4 and Figure S5 show the independent effects of food or omeprazole (in the absence of veverimer) on gastric pH.
A total of 12/40 subjects (30%) in Stage 1 and 13/40 subjects (32.5%) in Stage 2 had one or more AEs during the study. No deaths or other SAEs were reported, and no subject discontinued the study due to an AE. The most common AEs observed in the veverimer treatment periods (i.e., reported by more than one subject in either study stage in the Veverimer Fasted and Veverimer Fed treatment periods combined) were headache, nausea and oropharyngeal pain. All AEs were mild (22.5% of subjects in Stage 1 and 30% of subjects in Stage 2) or moderate (7.5% of subjects in Stage 1 and 2.5% of subjects in Stage 2); there were no severe AEs reported for any treatment group. There were no treatment effects noted in this study on clinical laboratory or vital signs parameters, physical examination findings or ECG intervals.

Human Drug-Drug Interaction Studies
Human DDI studies were conducted with drugs that demonstrated the greatest potential for direct interaction with veverimer in vitro (furosemide, aspirin) and those with susceptibility to gastric pH changes (furosemide, warfarin, dabigatran).
No DDIs were observed between veverimer and any of the drugs tested, either with concomitant administration (Figure 6) or with 1-3-hour dosing separation intervals (  Table   S10).
In the furosemide DDI study, there were no deaths, serious AEs or severe treatment-emergent AEs. Three subjects were withdrawn because of treatment-emergent AEs (mild postural dizziness; mild eosinophil count increase and mild white blood cell count increase; mild vomiting). In the aspirin DDI study, there were no deaths, serious AEs or severe treatmentemergent AEs. All treatment-emergent AEs were mild. One subject withdrew because of a mild headache. In the warfarin DDI study, there were no deaths or treatment-emergent AEs leading to discontinuation of study drug. One subject had a serious AE (jaw fracture [due to trauma]) 10 days after study treatment in Period 1. This event was assessed as unrelated to study drug. All other treatment-emergent AEs that occurred were mild or moderate and non-serious. In the dabigatran DDI study, there were no deaths, serious AEs or severe treatment-emergent AEs.
There were no treatment-emergent AEs that led to discontinuation of study drug.

DISCUSSION
Reported here are results from in vitro and in vivo studies that evaluated potential interactions of veverimer with other orally administered drugs. We considered the physicochemical and biopharmaceutical properties and method of use of veverimer to design a rational, sequential and tailored approach that examined possible mechanisms of interaction. Because the polymer is not absorbed from the GI tract, it is unlikely that it would alter the pharmacokinetics of concomitantly administered drugs through inhibition and/or induction of drug metabolizing enzymes or transporters. Potential interactions with veverimer are restricted to those that could affect absorption of other drugs from the GI tract, such as through direct binding or indirect effects on bioavailability resulting from transient increases in gastric pH.
The mechanism by which veverimer transiently reduces acidity in the GI tract after ingestion involves protonation of the polyamine polymer with subsequent binding of chloride and the removal of HCl from the GI tract in the feces (Bushinsky et al., 2018). The highly cross-linked structure of veverimer confers a marked size exclusion selectivity to the negatively charged moieties that bind to the protonated polymer, strongly favoring binding of the smallest anions and restricting binding of larger anions (Klaerner et al., 2020). These properties were affirmed in studies reported here evaluating the in vitro binding of a range of anionic probe molecules and a diverse panel of test drugs clinically relevant to the CKD population. The results of these studies illustrated the predisposition of veverimer to bind negatively charged molecules, with an inverse relationship between size of the anion and its propensity for binding to the polymer (Figure 2); data on furosemide, gliclazide, and warfarin suggested that size is secondary to negative charge in this regard. While binding of aspirin, ethacrynic acid and furosemide to veverimer was significant at pH 4.5 in acetate buffer, it was reduced or eliminated in the presence of This article has not been copyedited and formatted. The final version may differ from this version. physiologically relevant concentrations of chloride (100-170 mM) (Figure 4). This is consistent with results from previous in vitro studies in matrices mimicking the lower GI tract demonstrating that veverimer preferentially bound chloride in the presence of competing organic and inorganic anions (e.g., acetate, phosphate, citrate, taurocholate, oleic acid (Klaerner et al., 2020). In the current study, chloride effectively competed for veverimer binding sites with the three negatively charged test drugs at chloride concentrations normally present in the GI tract, which predicted a low likelihood of clinically meaningful DDIs mediated by direct binding of even the smallest co-administered anionic drugs.
Consistent with the binding properties of veverimer, administration of the drug did not impact absorption of fat-soluble vitamins from the GI tract in rat and dog chronic toxicity studies. Since the essential nutrient requirements of rats and dogs are qualitatively similar to humans, the absence of clinically relevant binding of veverimer to any essential dietary substance in the chronic toxicology studies is expected to extrapolate to humans.
The pharmacodynamic effects of veverimer on gastric acidity were evaluated in human volunteers to elucidate the extent and time course of gastric pH changes mediated by the intended removal of HCl from the GI tract by the polymer. Continuous monitoring of stomach acidity demonstrated a modest and transient increase in gastric pH following oral administration of veverimer. The magnitude of the gastric pH increase observed after ingestion of a meal or when the proton pump inhibitor (PPI) omeprazole was given without food were similar to those seen with veverimer given in the fasted state. All three factors individually appeared to increase mean gastric pH by 2-4 pH units, although the time course of the effect on gastric pH differed.
While omeprazole, which had been dosed to steady-state prior to the test, increased gastric pH throughout the 22-hour monitoring period, the effects of food and veverimer were short-lived This article has not been copyedited and formatted. The final version may differ from this version. (i.e., disappearing within 1-4 hours). In this way, the effect of veverimer on gastric pH more closely resembled the transient effect of food than the long-lasting effect of a PPI. Thus, the mechanism of action of veverimer (i.e., increasing serum bicarbonate by binding and removing HCl from the GI tract), as assessed by its effect on gastric pH, was unaffected by proton pump inhibition. These findings are consistent with clinical trials in patients with CKD and metabolic acidosis which showed that the effect of veverimer on serum bicarbonate was similar in patients who were and were not receiving proton pump inhibitors or H-2 receptor blockers (Wesson et al., 2019b). ). With both free and total dabigatran, GLSM ratio point estimates were reduced by less than 18% when coadministered with veverimer, the effect lessening slightly with a widening of the dose separation interval (e.g., 1 and 2 hours). This minimal reduction is substantially less than that observed when dabigatran was coadministered with the PPI pantoprazole, which diminished dabigatran C max and AUC by 40% and 28%, respectively, changes that are not clinically meaningful (Zhang et al., 2014). Notably, the lack of effect on aspirin, furosemide, warfarin and dabigatran exposures indicates that veverimer does not interact in a clinicallyrelevant manner with small, negatively charged drugs or drugs that have pHdependent solubility, demonstrating the lack of two potential mechanisms by which the veverimer polymer might foster DDIs.
In summary, the potential for DDIs with veverimer was evaluated based on the known site of action and physicochemical structure of the polymer, which restricts the compound to the GI particularly vulnerable to DDIs (Sommer et al., 2020). Based on the physicochemical characteristics of veverimer and the findings from the in vitro and human studies presented here, we conclude that veverimer is unlikely to have clinically significant DDIs.
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FOOTNOTES
This work was funded by Tricida, Inc.
The work was partially published in abstract form at American Society of Nephrology, Kidney Week 2020

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. 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.

DDI = drug-drug interaction
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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.

Figure 1
Veverimer is an orally administered, nonabsorbed, insoluble, free-amine polymer Does veverimer have potential to affect absorption of coadministered drugs?
Does veverimer have potential to affect metabolism and excretion of coadministered drugs?
Need to conduct DDI studies to evaluate potential effect on drug absorption