Impaired Drug Absorption Due to High Stomach pH - ACS Publications

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IMPAIRED DRUG ABSORPTION DUE TO HIGH STOMACH pH: A REVIEW OF STRATEGIES FOR MITIGATION OF SUCH EFFECT TO ENABLE PHARMACEUTICAL PRODUCT DEVELOPMENT Amitava Mitra, and Filippos Kesisoglou Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/mp400256h • Publication Date (Web): 11 Jul 2013 Downloaded from http://pubs.acs.org on July 20, 2013

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Molecular Pharmaceutics

Graphic for Table of Content Impaired drug absorption due to high stomach pH: A review of strategies for mitigation of such effect to enable pharmaceutical product development Amitava Mitra and Filippos Kesisoglou

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IMPAIRED DRUG ABSORPTION DUE TO HIGH STOMACH pH: A REVIEW OF STRATEGIES FOR MITIGATION OF SUCH EFFECT TO ENABLE PHARMACEUTICAL PRODUCT DEVELOPMENT

Amitava Mitra* and Filippos Kesisoglou

Biopharmaceutics, Product Value Enhancement, Pharmaceutical Sciences and Clinical Supply, Merck & Co. Inc., West Point, PA

*Corresponding Author Amitava Mitra, PhD Merck & Co., Inc West Point, PA-19486, USA Tel.: +1 215 652 8551 Fax: +1 215 993 1245 E-mail: [email protected]

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Abstract Published reports have clearly shown that weakly basic drugs which have low solubility at high pH could have impaired absorption in patients with high gastric pH thus leading to reduced and variable bioavailability. Since such reduction in exposure can lead to significant loss of efficacy, it is imperative to – 1) understand the behavior of the compound as a function of stomach pH to inform of any risk of bioavailability loss in clinical studies and 2) develop a robust formulation which can provide adequate exposure in achlorhydric patients. In this review paper, we provide an overview of the factors that can cause high gastric pH in human, discuss clinical and preclinical pharmacokinetic data for weak bases under conditions of normal and high gastric pH, and give examples of formulation strategies to minimize or mitigate the reduced absorption of weakly basic drugs under high gastric pH conditions. It should be noted that the ability to overcome pH sensitivity issues is highly compound dependent and there are no obvious and general solutions to overcome such effect. Further, we discuss along with several examples, the use of biopharmaceutical tools such as in vitro dissolution, absorption modeling, and gastric pH modified animal models to assess absorption risk of weak bases in high gastric pH and also the use of these tools to enable development of formulations to mitigate such effects.

Keywords: Achlorhydria, pharmacokinetics, famotidine, dissolution, dog study, simulation, modeling.



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INTRODUCTION: Lack of or reduced secretion of gastric acid in the stomach, a condition commonly known as achlorhydria or hypochlorhydria, has been shown to significantly impair absorption of weakly basic drugs which show low solubility at high pH (1). Clinical data for several such compounds e.g. ketoconazole, dipyridamole etc. has shown reduced exposure (Cmax and AUC) and in some cases prolonged Tmax in achlorhydric subjects. The change in gastric pH could be due to several reasons such as use of medications that reduce acid secretion (1), disease (2), ethnicity (3), and/or age (4). Medications that suppress gastric acid secretion or neutralize gastric acid such as proton pump inhibitors (PPI), H2 receptor antagonists (H2RA) and antacids are commonly prescribed to reduce gastric acidity for treatment of diseases such as gastric ulcer (5). PPIs (e.g. omeprazole) suppress gastric acid secretion by blocking the hydrogen/potassium adenosine triphosphatase (ATPase) enzyme system (commonly known as the gastric proton pump) in the gastric parietal cells. H2RAs (e.g. ranitidine) reduce acid secretion by the parietal cells by blocking the action of histamine on these cells. Finally, antacids (e.g. sodium bicarbonate) directly neutralize the gastric acid thus increasing the pH. Since PPIs target the terminal step in acid production they are the most potent acid suppressing agent and are more effective than H2RAs in increasing gastric pH (5). For e.g. omeprazole (PPI) can increase gastric pH to approximately 6.0, whereas cimetidine (H2RA) can increase stomach pH to approximately 4.0.

Diseases such as gastric mucosa infection caused by helicobacter pylori can cause transient reduction in gastric acid secretion (2, 6). Gastric biopsies or in-vitro cultured gastric epithelial cells infected with H. pylori has been shown to suppress the H/K ATPase system in the parietal


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cells. Similarly, reduced gastric acid secretion has also been reported in AIDS patients, resulting in their mean gastric pH in fasted state to be approximately 5.9 (7). The reduced gastric acid secretion in AIDS patients has been primarily attributed to decreased secretion of acid (7.4 meq/hour vs. 17.9 meq/hour in healthy subjects), reduced gastric juice volume (116 mL vs. 186.2 mL in healthy subjects) and lower pepsin output (13.3 mg/hour vs. 150.5 mg/hour in healthy subjects), among other pathophysiologies (7, 8). Achlorhydria can also develop due to autoimmune diseases, atrophic gastritis, gastric bypass surgery, stomach cancer, radiation therapy involving the stomach etc.

Gastric acidity has also been shown to vary with ethnicity. For e.g. it has been shown that in the elderly Japanese population the prevalence of achlorhydria is significantly more than in the elderly population in North America (40% vs. 11%) (3, 4). The exact reason for higher percentage of achlorhydrics in Japanese population is unclear but there is good correlation between the number of achlorhydric subjects and those infected with helicobacter pylori, suggesting that the infection is one of the major causes for high gastric pH (3). In addition higher incidence of elevated gastric pH has been reported in elderly subjects as compared to the younger age group. Russell et al reported that approximately 10% of the elderly subjects evaluated, had higher incidence of elevated gastric pH (pH > 5.0) (4). These authors also reported that in approximately half of the elderly subjects studied the gastric pH decreased more slowly than younger subjects after food intake.

In this paper, we review the causes for high gastric pH, the effect of high gastric pH on pharmacokinetics of weak bases, and discuss formulation strategies to minimize or mitigate the



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reduced absorption of weakly basic drugs under high gastric pH conditions. Further, we discuss the use of biopharmaceutical tools such as in vitro dissolution, absorption simulation, and gastric pH modified animal models to assess absorption risk of weak bases in high gastric pH and also to enable development of formulations to mitigate such effects.

EFFECT OF HIGH GASTRIC pH ON FORMULATION BIOPERFORMANCE Several publications have reported low and variable absorption of weakly basic drugs under high gastric pH conditions, which can consequently lead to subtherapeutic exposure (1, 9, 10). Lahner et al has published a comprehensive summary of several clinical studies on the impact of reduced gastric acid secretion on absorption of drugs such as ketoconazole, itraconazole, atazanavir, cefpodoxime, enoxacin, and dipyridamole (1). These drugs have low solubility in high pH, so the impaired absorption is thought to be primarily due to slow and incomplete dissolution of these drugs under high stomach pH conditions. This phenomenon has been demonstrated for ketoconazole tablets among other compounds, which showed greater than 85% dissolution at pH 2 after five minutes, and 100% after 30 minutes. However, as the pH increased the rate and extent of dissolution slowed down significantly, with only approximately 10% dissolution after 60 minutes at or above pH 6 (11, 12). Studies in gastric pH modified dogs (animal models to study achlorhydria effect is discussed in detail in the preclinical in vivo evaluation section later in this article) showed ketoconazole Cmax and AUC reduction by >90% in animals pretreated with famotidine as compared to pentagastrin (12). Consequently, clinical studies have shown significant reduction in ketoconazole AUC (80-95%) and Cmax (80-93%) when co-administered with PPI or H2RA (13, 14). Such a trend has also been shown for posaconazole, where a good correlation was observed for the amount of posaconazole dissolved in the stomach (calculated as


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gastric AUC) and posaconazole exposure at 48 hours (AUC0-48hr), indicating that dissolution in the stomach dictated absorption of posaconazole (15). As a result of this dependence on gastric solubilization, posaconazole Cmax and AUC have been reported to be reduced by approximately 46% and 32%, respectively when codosed with esomeprazole (10). Similar to the dog studies described above for ketoconazole, studies with dipyridamole also showed >85% reduction in Cmax and AUC in famotidine pretreated dogs as compared to pentagastrin pretreated dogs (12). Clinical studies have shown a similar trend in the reduction in AUC and Cmax, as well as prolongation of Tmax for dipyridamole as a function of increase in stomach pH (9). The authors also showed a trend of decrease in dipyridamole Cmax and prolonging of Tmax as a function of increase in median stomach pH. The AUC and Cmax of atazanavir have been reported to be reduced by upto 94% and 91%, respectively, when co-administered with lansoprazole (16). Since such reduction in exposure can lead to significant loss of efficacy, the product label recommends that in treatment naïve patients’ atazanavir should be dosed approximately 12 hours after taking any PPI and co-administration with PPI is contraindicated in treatment experienced patients (17). Such staggered dosing approaches could also be used to mitigate effect of high stomach pH on drug absorption. However, as much as possible the goal is always to mitigate any achlorhydria effect using formulation approaches such that there are no restrictions in the product label.

Elevated gastric pH has also been shown to slow gastric emptying. Russell et al (9) showed that in elderly subjects with achlorhydria the time to empty 50% of orange juice from stomach was approximately 40 minutes, which was twice the time taken to empty the same volume in elderly subjects with normal gastric pH. A review of published literature on the effect of PPI on gastric emptying time showed that gastric emptying of solid food is consistently delayed by PPI,



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whereas the effect on emptying of liquids is inconsistent (18). This difference in emptying time of solid and liquid food is thought to be due to differences in the gastric emptying processes for solids and liquids. Gastric emptying of solids involves a process of hydrolytic digestion, which is inhibited by PPIs thus delaying emptying time of solids. In contrast, gastric emptying of liquids depends on the total volume and energy density of gastric contents. PPIs have variable effect on changes in the volume and the energy density thereby affecting gastric emptying in an inconsistent manner. These studies suggest that in addition to changes in AUC and Cmax, high gastric pH could also have an impact on Tmax, as has been shown for dipyridamole (9). This could have clinical efficacy implications especially in indications which require quick onset of action.

Apart from increase in gastric pH, co-dosing with antacids may decrease exposure of drugs which have a propensity to chelate with the multivalent cations (Mg2+, Ca2+, Al3+) in the antacids thus forming insoluble complexes and reducing absorption (19). Such an effect was seen for tetracycline and its analogues, which showed ≥80% reduction in oral bioavailability when coadministered of with antacids (20). Similarly, bisphosphonates have been shown to have a high affinity for calcium and other multivalent cations, and forms insoluble complexes (21). Hence co-administration of antacids could interfere with their absorption. As a result, prescribing information for bisphosphonates such as alendronate recommends that patients should wait at least half an hour after taking bisphosphonates before consuming antacids (22).

In contrast, for weak acids it has been shown that increase in gastric pH could cause an increase in bioavailability due to increased solubilization and dissolution of the dose under high gastric


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pH conditions and thus increases absorption. This has been shown for a number of compounds such as raltegravir (23), alendronate (24), digoxin (25) and nifedipine (26), to name a few. Raltegravir showed 3-fold increase in AUC, 4-fold increase in Cmax and 1.5-fold increase in C12hr, when codosed with omeprazole in healthy subjects (23). Similarly, alendronate bioavailability has been shown to increase by 2-fold when co-dosed with ranitidine (24). A detailed discussion on the effect of decreased gastric acidity on bioavailability of weak acids is out of scope for this review, interested readers should refer to the literatures cited above.

STRATEGIES

TO

MITIGATE

EFFECT

OF

HIGH

STOMACH

pH

ON

FORMULATION BIOPERFORMANCE OF WEAK BASES As described above due to the potential for significant malabsorption of weakly basic drugs under high gastric pH conditions, several approaches have been reported to overcome these interactions and are described below.

Co-administration with acidic beverages The strategy to enhance exposure using acidic beverages has been demonstrated for several compounds (10, 13, 15). The key hypothesis being that these acidic carbonated beverages would transiently reduce the stomach pH and thus aid in the rate and extent dissolution, thereby enhancing absorption. However, another hypothesis has also been proposed by Walravens et al (15), these authors have shown that posaconazole exposure increases significantly when codosed with Coca-Cola in achlorhydric subjects. But they propose that increased solubility of posaconazole in the stomach when dosed with Coca-Cola and prolonged gastric residence of the dose is primarily responsible for enhancement of dissolution rather than reduced stomach pH. In



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case of ketoconazole it was shown that in healthy volunteers its AUC and Cmax dropped by approximately 80% when co-administered with omeprazole (13). However, when ketoconazole was dosed with Coca-Cola in presence of omeprazole the AUC was approximately 65% and Cmax approximately 59% of the control (i.e. ketoconazole dosed without omeprazole). Similar data has been published for other antifungals such as posaconazole, Krishna et al (10) has reported a reduction in Cmax and AUC by approximately 50% and 34%, respectively when codosed with esomeprazole. However, when taken with ginger ale posaconazole exposure increased after comedication with esomeprazole (Cmax and AUC reduction by 38% and 25%, respectively). Polster et al (27) used an in-vitro artificial stomach-duodenum (ASD) model to investigate whether dosing an oncology compound, which had very low solubility at pH >2, with acidic beverage would reduce the large variability seen in Phase I studies. The ASD studies showed that coformulating the compound with captisol and dosing with Sprite was an effective way to increase duodenal concentrations of the compound, as well as to reduce the differences in the duodenal concentrations for different gastric pH. Most of these studies using acidic beverages to mitigate the achlorhydria effect have shown partial improvement in bioavailability. The primary reason for this could that the acidic beverages are not able to fully reduce the stomach pH to normal conditions. Walravens et al (15) have shown that after esomeprazole treatment the stomach pH of health subjects’ increases to approximately 6-7. Intake of 330 mL Coca-Cola after esomeprazole treatment only transiently (for 1.5 hours) decreases the stomach pH to 4-5.5 but the stomach pH doesn’t go down to normal conditions (i.e. ~pH 2.0). Hence this strategy could only be considered marginally effective in improving absorption.


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Pretreatment with organic acid Pretreatment of achlorhydric patients with an organic acid supplement such as glutamic acid to reduce the gastric pH has also been published. Russell et al (9) showed that pretreatment of achlorhydric elderly subjects with glutamic acid hydrochloride resulted in higher dipyridamole AUC and Cmax, as compared to subjects who were not pretreated with the acid. In this study two consecutive doses of two 340 mg glutamic acid hydrochloride capsules were given – the first dose was 10 minutes prior and the second dose was concurrently with dipyridamole. Gastric pH was also measured in these studies, which showed that glutamic acid pretreatment reduced the median gastric pH significantly as compared to the achlorhydric subjects (1.6 vs. 6.6, respectively after 1 hour post dose). Although the study showed that pretreatment with organic acid could compensate for reduced gastric acidity, this might not be a practical approach to make a viable commercial product, for e.g. from patient convenience and compliance perspective. In such a pretreatment based dosing regimen the patient will have to remember to take the acidifier prior to every dose and so compliance might be an issue. Certain strategies could be implemented to improve compliance such as co packaging of the acidifier and the drug product but that makes product development more complicated.

Development of solid dosage formulation containing organic acid Another approach is to formulate the solid dosage form using an acid as a pH-modifier to enhance dissolution of the compound by decreasing microenvironmental pH in the stomach and thus enhance bioavailability. This concept is based on the hypothesis that for compounds with pH-dependent solubility profile, the solubility of the drug in the diffusion layer at the surface of



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the dissolving particle is the primary driver for the rate of dissolution, rather than solubility in the bulk medium (28). Hence, attempts have been made to reduce pH in the vicinity of the dissolving drug particle by addition of an acid in the formulation and thus increasing the dissolution rate even when the pH of the bulk medium is unfavorably high for dissolution of the weakly basic compound.

Merck compound A is a weakly basic, BCS class II molecule for oncology with a steep pH dependent solubility profile, the compound does not have any appreciable solubility above pH 2 (29). In patients coadministered with omeprazole the non-acidified dry filled capsule (DFC) formulation of the free base form of compound A showed approximately 20-fold reduced exposure as compared to patients without PPI, along with high variability and less than dose proportional increase in exposure. This clinical experience was in agreement with data in famotidine/pentagastrin dog model, where this formulation showed approximately 15-fold lower exposure under high gastric pH conditions (reference F1 DFC in Table 2). In-order to mitigate this achlorhydria effect several formulations with or without an acidifier were developed. The bioperformance of these formulations in high gastric pH conditions were assessed by in vitro dissolution, in gastric pH modified dog model and using absorption modeling to predict human bioperformance. Dissolution studies in pH 3.0 media demonstrated that the formulation incorporating citric acid as an acidifier showed the greatest amount dissolved. Similarly in famotidine pretreated dog studies, it was shown that the acidified formulations gave higher exposure than the non-acidified formulations. Absorption simulation based on the dissolution data and the dog data predicted that the citric acid based dry filled capsule formulation using hydrochloride salt of compound A would have the best bioperformance in achlorhydric patients


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and also had the highest probability of meeting the target Ctrough needed for efficacy in humans. The bioperformance of this formulation was evaluated in oncology patients with and without concomitant administration of omeprazole. The study showed that exposure from this formulation did not meaningfully change in the presence of PPI as compared to that in non-PPI patients (AUC ratio = 0.95 and Cmax ratio = 0.93). Further the Ctrough target was achieved in all patients with or without omeprazole co-administration with the acidified formulation. Although these human data confirmed that the formulation incorporating citric acid was successful in overcoming the achlorhydria effect for compound A, it should be noted that the choice of acidifier and overall formulation design is primarily dependent on the properties of the molecule being evaluated.

Similarly, Badawy et al (30) has reported that co-formulating a weak base compound (BMS561389) with tartaric acid showed enhanced dissolution in pH 5.5 media as compared to the nonacidified tablet formulation. Also, in famotidine pretreated dog studies the acidified formulation showed approximately 20-30% reduction in Cmax and AUC, as compared to in pentagastrin pretreated dogs. In contrast, the non-acidified tablet showed >80% reduction in Cmax and AUC in dogs with high stomach pH.

Taniguchi et al (31) developed dipyridamole formulations with ten different acidifiers using wet granulation technology. Based on manufacturability, stability and dissolution behavior of these formulations, the formulation containing p-toluenesulfonic acid as pH-modifier was selected for preclinical in-vivo evaluation. In PK studies in omeprazole pretreated rats, the non-acidified dipyridamole formulation exhibited significantly poor systemic exposure, Cmax and AUC0-3hr



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reduction by 53% and 38% as compared to that in normal rats. However, the acidified formulation showed marked improvement in dipyridamole exposure in omeprazole pretreated rats and there was no significant change in Cmax and AUC0-3hr with between normal and PPI pretreated rats. Controlled release mini-matrix formulation of dipyridamole based on hydroxypropyl methylcellulose and using succinic acid or fumaric acid has also been developed (32). Incorporation of acidifier in the matrix formulations enhanced dipyridamole release in pH 6.8 media as compared to formulations without acidifier. In these studies fumaric acid showed a stronger effect on reducing the microenvironmental pH than succinic acid. Consequently, the fumaric acid based formulation showed higher dipyridamole release in pH 6.8 dissolution media compared to the formulation using succinic acid as acidifier.

As exemplified in this section, incorporation of organic acids into solid dosage formulation has been used extensively. However it should be noted that the ability to overcome pH sensitivity issues is highly compound dependent. Hence appropriate studies should be conducted to choose the adequate acidifier for a particular compound. These studies include evaluation of the ability of an acidifier to enhance dissolution of the compound, physical and chemical stability of the product, and formulation processing, to name a few.

Use of enabled formulations Enabled formulation approaches such as solid dispersions are frequently used to maximize absorption of poorly soluble drugs (33). Solid dispersions have also been shown to minimize effect of achlorhydria for weak bases. A review by Tran et al (34) summarizes the potential advantages of using acidified solid dispersion formulations to enhance dissolution of weak bases.


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The use of amorphous form of the drug along with an acidifier is proposed to have a synergistic effect on enhancing dissolution of the drug even under unfavorable pH conditions. The authors suggest that an optimum pH modifier is one that not only greatly modulates the microenvironment pH of the solid dosage form at the best pH condition for high drug solubility, but also maintains this condition for a sufficiently long time. We have shown previously that an acidified hot melt extrusion formulation (HME) of Merck compound A showed good dissolution in a pH 3 media and also showed high bioavailability in famotidine pretreated dogs (29). Absorption simulations also predicted that the acidified HME formulations would also meet the Ctrough target in human. These studies and data are described in detail in the next sections. Sugawara et al (35), has shown that a hydroxypropyl methylcellulose (HPMC) based solid dispersion of albendazole was able to minimize the effect of high gastric pH on albendazole absorption, in an in vitro system. This group had previously reported that in lansoprazole pretreated rabbits the albendazole solid dispersion had bioavailability of approximately 69% as compared to a physical mixture of albendazole with lactose, which showed 21% bioavailability (36). While this approach is particularly attractive for low solubility compounds, it could also present significant formulation development challenges such as ensuring appropriate mixing of the organic acid with the drug and the polymer to form a homogeneous solid solution as well as achieving adequate stability (particularly physical stability) to provide two years product shelf life.

Acidic salts of weak bases The use of acidic salts of weakly basic compounds has also been investigated to mitigate slow dissolution at high stomach pH. Dickinson et al (37) has shown that the use of fumarate salt of a



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weakly basic compound (AZD8055) resulted in similar in-vitro dissolution at gastric pH of 2 and 5, whereas dissolution of the freebase form was upto 80% lower at pH 5 and highly variable as compared to dissolution at pH 2. Subsequent clinical studies in achlorhydric patients showed that the fumarate salt tablet gave approximate dose proportional increase in exposure and had similar exposure as from a solution formulation. However, the inter-individual variability for the fumarate salt tablet was fairly high. Similarly, we have also reported that a capsule formulation containing hydrochloride salt of Merck compound A showed higher dissolution in pH 3 media than a formulation containing free base form of the compound (29). In agreement with the invitro data, studies in famotidine pretreated dogs showed that the hydrochloride salt containing formulation gave higher exposure than the freebase form. These studies and others have shown that selecting an appropriate salt form could be a viable approach to mitigate the achlorhydria effect. However, identification of a salt form that has adequate stability, formulation processability

and

shows

adequate

bioperformance

could

be

a

key

challenge.

EVALUATION OF FORMULATIONS

In vitro evaluation In vitro evaluations in the form of either solubility and/or dissolution experiments is an important and often the first step of formulation evaluation in industrial settings. In vitro experiments allow for the rapid screening of multiple formulations early on to allow only for the most promising candidates to proceed forward, as well as allow for monitoring of formulation performance during scale up after the performance of the formulation has been confirmed in the clinic. However, while the composition of both stomach and intestinal fluids has been extensively


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studied under both fasted and fed state conditions (38, 39), a detailed characterization of the stomach content after natural or pharmacologically induced achlorhydric conditions is not available in the literature and a universally acceptable biorelevant medium is missing. Thus reported in vitro methods for evaluation of formulations developed to overcome the effect of stomach acid altering agents vary.

In a previous report (29), in our lab we demonstrated how the use of a low buffer capacity pH 3.0 HCl/NaCl media allowed us to identify new formulations with potential for mitigating the PPI interaction that was previously seen for a BCS II weak base drug candidate. For the specific compound (Compound A) of interest with pKa of 2.4 and 3.9, selection of a pH target of 3.0 for the dissolution medium allowed us to test formulation behavior in the most sensitive part of the pH solubility curve (significant change in solubility was observed from 0.2 mg/mL at pH 2.0 vs. 0.001 mg/mL at pH 4.0). The relatively low buffer capacity of the system further probably facilitated the ability to more clearly observe the impact of inclusion of acidifying agents in the formulation. Finally, it should be noted that pH 3.0 is at the lower end of the pH range that would be observed after administration of a PPI or H2RA. However this pH was acceptable for Compound A since this compound showed significant drop in solubility between pH 2.0 (0.2 mg/mL) and 4.0 (0.001 mg/mL), but beyond pH 4.0 there was no further reduction in solubility. The choice of dissolution media pH should be made on a case-by-case basis depending of the pH-solubility profile of the compound.

In some cases testing in standard compendial media with pH in the intestinal pH range has also been proven to identify formulations with improved dissolution characteristics against the



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unfavorable pH for drug solubility. Badawy et al (30) utilized dissolution at pH 5.5 acetate buffer in a USP II system to screen formulations for BMS-561389 HCl salt. With pKa values of 2.2 and 7.4, the selection of pH 5.5 represented the lower part of the pH solubility curve and allowed the authors to differentiate between formulations incorporating different levels of acidifying excipients (tartaric acid, citric acid and succinic acid) vs. the effect of incorporating polymers (PVP) or using a beta-cyclodextrin. Similarly, Taniguchi et al (31) or Onoue et al (40) simply utilized dissolution in standard 50 mM phosphate buffer (pH 6.8) as a screening tool to study the impact of incorporation of an acidifying agent in formulations of dipyridamole and screen different levels of the acidifier (eg. fumaric acid in the case of Onoue et al). While such systems that are closer to the media for simulating intestinal contents are likely not fully biorelevant for simulating dissolution in the achlorhydric stomach, depending on the properties of the compound and the formulations tested may provide a directional read when screening within formulations of similar compositions and of common mechanism of dissolution (eg. formulations with acidifying agents).

More complex setups have also been reported. Recently Bhattachar et al (41) described the use of the artificial stomach and duodenum setup, a two compartment dissolution system that simulates the dissolution and flow of compound in the upper GI tract, to study the behavior of LY2157299, a weak base with pKa of 4.34 and 2.81. To simulate the different gastric pH conditions, the authors utilized a 0.01N HCl solution as the normal gastric state fluid and a 0.001N HCl solution (pH 4.5) to simulate the lower gastric acidity state. In this in vitro set-up, the authors were able to observe significant solubility differences in the duodenum compartment (the compartment relevant for drug absorption) between the two gastric acidity states and


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demonstrated recovery of solubilization when they dosed the compound in a phosphoric acid containing suspension in the reduced acidity state.

Set-ups that simulate simultaneous dissolution and absorption have also been proposed. Sugaware et al. (35) reported the use of a two-stage dissolution system coupled with a Caco-2 setup to study the behavior of pH-independent controlled release formulations of two weak bases, albendazole and dipyridamole. To simulate achlorhydric conditions the authors adjusted the pH of the “gastric compartment” to 6.0 (a phosphate/MES based buffer system). Using this setup the authors were able to correctly capture the significant absorption suppression for the APIs under achlorhydric conditions and the significant improvement in absorption under the achlorhydric state with the albendazole solid dispersion and the pH-independent sustainedrelease granules of dipyridamole and the effective mitigation of the achlorhydric effect.

The Simulated Gastro-intestinal Tract Model-1 developed by TNO Nutrition and Food Research (TIM-1) (Zeist, The Netherlands) is a multi-compartment system that simulates the upper GI tract and has been described in detail in the literature. The application of the system as a biorelevant dissolution tool has been documented in a few reports. Recently, Dickinson et al (37) described the use of the system to simulate achlorhydria for AZD8055 a weak base with a pKa of 6.2. The stomach compartment was adjusted to pH 5.0 for the purpose of the simulation and the authors were able to clearly demonstrate both the reduction of drug available for absorption for the free base suspension as well as the much improved dissolution under the modified stomach pH conditions when the fumarate salt form was used. The projections from the in vitro



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experiments were confirmed in the clinic indicating the potential utility of the setup in studying this stomach pH – formulation bioavailability interplay.

In-vivo evaluation The dog represents the most common preclinical animal model that is utilized for formulation screening due to similar GI dimensions to humans that allows easy dosing of common dosage forms and the ease of handling and dosing under either fasted or fed conditions. However one of the limitations is the variable and generally low gastric acid output in fasted state; as a result basal stomach pH can be quite variable within a dog colony and more often higher compared to humans. As shown in Figure 1 (unpublished Merck data), studies in our laboratory where the dog stomach pH was measured using the Medimetrics capsule, pH ranged from 1.0 to above 6.0 among dogs with most of the dogs falling at the two extremes – which makes use of an average pH as indicator of the stomach pH of the dog colony of limited practical value when using animal studies to screen formulations. The variable gastric pH could lead to significant pharmacokinetic variability during screening of formulations, especially when the goal of the formulation screening is to conclusively identify formulations that can mitigate stomach pH-drug interactions in the clinic. To avoid this variability, most studies implement pharmacological treatments to achieve the required stomach pH prior to formulation dosing. The most common approach is the pre-treament with pentagastrin to mimic the normal fasted state in human and the pretreatment with an H2-blocker, most typically famotidine, to mimic the achlorhydric state.

Zhou et al (12) and Fancher et al. (42) have published detailed protocols for lowering and increasing gastric pH in beagle dogs, specifically both manuscripts recommend a 6 ug/kg


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intramuscular injection of pentagastrin to lower gastric pH and an oral administration of 40 mg famotidine to increase gastric pH. In addition Fancher et al (42) has reported that an iv bolus dose of 0.5 mg/kg for famotidine was also effective in increasing the gastric pH for upto 4 hours. While other studies had relied on the measurement of pH via radiotelemetry, Fancher et al (42) has confirmed the effectiveness of these treatments via direct pH measurements of aspirated gastric fluids. Pentagastrin treatment resulted in a reduction of pH from an average value of 5.6 to

Impaired Drug Absorption Due to High Stomach pH - ACS Publications

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