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Mechanistic understanding of the effect of PPIs and acidic carbonated beverages on the oral absorption of itraconazole based on absorption-modeling with appropriate in-vitro data Nikoletta Fotaki, and Sandra Klein Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/mp4003249 • Publication Date (Web): 15 Aug 2013 Downloaded from http://pubs.acs.org on August 22, 2013

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Molecular Pharmaceutics

Mechanistic understanding of the effect of PPIs and acidic carbonated beverages on the oral absorption of itraconazole based on absorption-modeling with appropriate in-vitro data Nikoletta Fotaki1, Sandra Klein2

1

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down,

Bath, BA2 7AY, United Kingdom Tel: +44(0)1225 386728 E-mail: [email protected]

2

Ernst Moritz Arndt University Greifswald, Department of Pharmacy, Institute of

Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, Felix-Hausdorff-Strasse 3 17489 Greifswald, Germany Phone: ++49 (0) 3834 86 4897 E-mail: [email protected]

KEYWORDS Itraconazole, PPI, cola, acidic beverage, intragastric pH, gastric emptying, gastric volume, absorption model

ACS Paragon Plus Environment

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ABSTRACT Proton pump inhibitors are potent gastric acid-suppressing agents and are among the most widely sold drugs in the world. However, even though these antisecretory agents are regarded as safe, they can alter the pharmacokinetics of co-administered drugs. Due to the suppression of gastric acid secretion, they can significantly alter the intragastric pH-conditions and are thus likely to affect the bioavailability of co-administered drugs requiring an acidic gastric environment for dissolution and subsequent absorption. Among these drugs, itraconazole, a poorly soluble triazole-type antifungal compound can be found. Based on observations reported in the literature, gastric pH-alterations due to the co-administration of PPIs or acidic beverages can significantly decrease (PPI) or increase (e.g. Coca-Cola®) the bioavailability of this compound. In the present work we estimated the fraction of itraconazole that can be absorbed (fabs) from Sporanox® capsules or an itraconazole-HBenBCD complex formulation after oral admistration with and without co-administration of a PPI or an acidic (carbonated) beverage. For this purpose, the sensitivity of the two formulations towards the impact of various gastric variations (pH, volume and emptying rate) as they can result from such administration conditions was studied using solubility and dissolution experiments and a physiologically based absorption model. Simulating co-administration of the two formulations with a PPI resulted in a significant (~10 fold) decrease in itraconazole fabs, indicating the pH to be essential for in-vivo dissolution and subsequent absorption. The fabs of itraconazole after coadministration of an acidic beverage (Coca-Cola®) was far lower than the fabs obtained for itraconazole alone and did not support the observations reported in the literature. These results clearly indicate that in contrast to PPIs, which seem to affect itraconazole bioavailability mainly via intragastric pH changes, co-administered Coca-


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Cola® is likely to alter a range of gastrointestinal parameters relevant to in-vivo dissolution rather than solely affecting the intragastric pH.

INTRODUCTION Proton pump inhibitors (PPIs) like omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole are currently the most potent gastric acid-suppressing agents in clinical use 1. PPIs are considered to show improved efficacy over histamine H2-receptor antagonists and other drugs 1 and also to be remarkably safe medications for the treatment of acid-related disorders of the upper gastrointestinal tract including peptic ulcers and their complications, functional dyspepsia, gastroesophageal reflux disease (GERD), erosive esophagitis and, anti-inflammatory (NSAID) – induced gastrointestinal (GI) lesions

2-3

. PPIs are commonly prescribed or used as

short-term, self directed, over the counter (OTC) therapy. Therefore, nowadays they are among the most widely sold drugs in the world. By irreversibly inhibiting the proton pump (H+/K+ATPase), an enzyme which causes the parietal cells of the stomach lining to produce acid, PPIs result in a pronounced and long-lasting reduction of gastric acid production. However, even though these antisecretory agents are regarded as safe, particularly due to the significant physiological changes induced by PPIs, recently various safety concerns have been raised 4. According to Heidelbaugh et al. 4 PPIs are considered overutilized when prescribed without an appropriate indication, when patients are left on them ‘indefinitely’ without appropriate indications and when they are continued after being utilized for most cases of hospital stress ulcer prophylaxis. An important fact that should be considered is that patients receiving PPIs are frequently treated with other drugs, too. PPIs as antisecretory agents may then affect the


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absorption, metabolism and renal excretion of the co-medicated compounds 5. Many of these important interactions are a result of competitive inhibition of cytochrome P 450 enzymes 6. However, it is also well known that PPIs can significantly alter the absorption of other drugs via changes in the gastric environment, particularly intragastric pH 6. Inhibition of gastric acid secretion can affect the bioavailability of drugs requiring an acidic gastric environment for dissolution and subsequent absorption. Examples of such drugs include poorly soluble weakly bases, such as the triazole antifungal compounds ketoconazole, itraconazole, voriconazole, posaconazole. As a result of the change of the gastric environment, a serious reduction of the antifungal effect is likely to be observed. Itraconazole is an imidazole/triazole-type antifungal agent which is used for the treatment of a broad spectrum of fungal infections in immunocompromized and non-immunocompromized patients. It is a weakly basic BCS Class II compound (pKa ca. 3.7) 7 being practically insoluble in water 8 . The drug is highly crystalline with a melting point in the range of 166 °C to 170 °C 8 and highly lipophilic with a logP -value of 5.66 at pH 8.1 7. The drug can only be completely ionized at very low pH. For an effective oral itraconazole therapy using solid dosage forms, an acidic environment is required for drug dissolution. Such conditions are likely to be found in the fasted stomach of healthy subjects. Every day approximately 2 to 3 liters of gastric juice are released from the glands in the corporal mucosa 9. In addition to several other components, gastric juice contains an almost isotonic solution of hydrochloric acid

10

which determines the pH conditions in the fasted stomach.

Dependent on the concentration of hydrochloric acid in the gastric juice, an acid environment typically prevails in the fasted stomach. During the last decades various experiments have been performed to measure both pH and transit times in the human GI tract using radiotelemetric


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methods. The publication of Arullani et al.

11

was one of the first papers that reported results

from pH measurements using the Heidelberg capsule. In a collective of 9 healthy subjects an average gastric pH of 1.7 was measured. Subsequent studies using the Heidelberg capsule or a gastric tube were able to confirm that the fasted gastric pH falls in the range of pH 1-3 with values of 1.5-2.5 occurring most frequently 12-15. Results from a more recent study published by Kalantzi et al.

16

were also in good agreement with these observations. In this study

16

twenty

healthy human subjects received 250 mL of water, representing the typical fluid volume to be administered with a solid oral dosage form in a clinical study. Subsequently, samples were aspirated from the gastric antrum over 60 min and analyzed for several physicochemical parameters including pH. Despite a significant interindividual variability, the median gastric pH value was 2.4 twenty minutes after administration of water and stabilized to 1.7 at later time points. Thus, a gastric pH of 1-3 after administration of itraconazole with a glass of water in fasted conditions, should be expected. As indicated above, itraconazole is used for the treatment of a broad spectrum of fungal infections.

Such

infections

are

immunodeficiency syndrome (AIDS)

common 17

in

compromised

patients

with

acquired

. In these patients, impaired gastric acid secretion

resulting in fasted gastric pH values > pH 5, as a result of abnormalities in parietal cell function, is commonly observed

17-18

. Such so-called hypochlorhydria also is frequently associated with

ageing or can be a result of medication with e.g. antacids, H2-receptor antagonists or PPIs. In true hypochlorhydria fasted gastric pH values can sometimes be as high as pH 7

19

. Since PPI

medication is tailored to prevent tissue damage and symptom generation in the distal esophagus, gastric acidity is intended to be controlled to above pH 4 20. With most of the current drugs and


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dosing regimens, it is possible to achieve this goal and to measure gastric pH values above pH 4 for 12 or even 24 hours after single dose administration 20-21. All gastric pH alterations due to true or induced hypochlorhydria are expected to significantly alter gastric dissolution of itraconazole. With a pKa of 3.7, the drug will not dissociate to a relevant extent and consequently not well dissolve at pH > 3.7. Accordingly, in above discussed conditions absorption and bioavailability of itraconazole is likely to be impaired. The evidence of impaired drug absorption of itraconazole and other poorly soluble triazole-type antifungal agents related to the use of co-administered PPIs has been addressed in several pharmacokinetic studies, e.g. 22-23 and is frequently discussed in the literature, e.g. 24. Results of these studies clearly showed that acid suppression reduces absorption of these poorly soluble weak bases, resulting in markedly lower AUC and Cmax values observed in the respective patients. Based on the physicochemical properties of itraconazole and other triazoles with similar properties and the observations made in pharmacokinetic studies

22-24

, it was hypothesized that

“acidifying” the gastric environment by co-administering an acidic beverage would be a way to increase the bioavailability of these poorly soluble drugs. Therefore, a series of additional studies addressing this question by co-administering triazole antifungals with an acidic carbonated beverage such as Coca-Cola® have been performed

17, 25-27

. Compared to administration of the

respective dosage forms with water, administration of the same dose with a corresponding volume of Coca-Cola® resulted in enhanced exposure of all poorly soluble triazole compounds. In the literature, the impact of co-administered PPIs and acidic carbonated beverages on the bioavailability of itraconazole in healthy subjects is mainly attributed to the gastric pH changes.


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However, with a detailed look at the study results, it is likely that various other processes could have an impact on the bioavailability of itraconazole. Since PPIs reduce gastric (hydrochloric acid) secretion, besides affecting intragastric pH they might also have an effect on the overall fluid volume (resting volume + secretion in response to dosage form administration with a glass of water) available for gastric dissolution. In contrast, co-administration of the dosage form with a glass of Coca-Cola® (pH 2.4-2.7

28-29

) to healthy

subjects is not likely to result in significant intragastric pH-changes, but might increase gastric secretion and slow down gastric emptying as a result of the carbohydrate content 30. The objective of the present work was to study the sensitivity of two different itraconazole formulations towards the impact of gastric pH, -volume and –emptying rate using data from solubility and dissolution experiments and a physiologically based absorption model.

MATERIALS AND METHODS 1. Design of the study

Published data for solubility and dissolution of two different itraconazole formulations, Sporanox® capsules (Janssen Pharmaceutica N.V., Beerse, Belgium) and itraconazole hydroxybutenyl-β-cyclodextrin (HBenBCD) complex, were used for the calculations and simulations

31-32

. In-vitro solubility and dissolution and in-vivo bioavailability data for

Sporanox® capsules were used to establish and validate an absorption model which was then used to estimate the impact of co-administered PPIs on the bioavailability of the Sporanox® product and the itraconazole-HBenBCD complex formulation

32

. For the latter formulation, we


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also tried to estimate how co-administration of an acidic carbonated beverage might impact the bioavailability of itraconazole.

2. In-vitro data

Dissolution experiments had been performed in a Mini-Paddle apparatus

31-32

. Dissolution of a

100 mg itraconazole dose was studied in 250 mL of simulated gastric fluid without pepsin (SGF) pH 1.2 and acetate buffer pH 5.0 to simulate pH conditions of a healthy and a hypoacidic stomach, respectively. Moreover, with the itraconazole-HBenBCD complex formulation a dissolution experiment was performed in SGF pH 2.0 to simulate gastric pH-conditions in a healthy subject after coadministration of the dosage form with an acidic carbonated beverage, e.g. Coca-Cola®. For each of the formulations studied itraconazole solubility was calculated from the dissolution profile. Since in all experiments, the plateau phase of the dissolution profile was reached within the first 60 min, the amount dissolved after 60 min (Figure 1) was assumed to reflect the maximum amount of drug that can dissolve in the respective test medium.


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Figure 1: Itraconazole solubility in different gastric media as obtained from drug concentration in the plateau phase (> 60 min) of the dissolution profiles.

3. Treatment of in-vivo data

The mean plasma concentration versus time profiles of itraconazole after oral administration of a 100 mg Sporanox® capsule with 100 mL of water to 12 subjects in the fasting state were obtained from the literature 33. Cumulative fraction absorbed vs. time plots of itraconazole were estimated with deconvolution of the mean plasma data after oral administration using the mean oral solution data as weighting function

34

. Numerical deconvolution was performed with

PCDCON 35. 4. Absorption model

Bioavailability after oral administration is defined by the fraction of the dose entering the cellular space of the enterocytes from the gut lumen (fraction absorbed; fabs), the fraction of the drug entering the enterocytes that escapes first pass gut wall metabolism (FG) and the fraction of drug entering the liver that escapes first pass hepatic metabolism and biliary secretion (FH)

36

.

Alterations of the gastric environment from the co-administration of a PPI or an acidic beverage would mainly affect the fraction absorbed. The fraction of itraconazole absorbed after oral administration of Sporanox® capsule and of an itraconazole HBenBCD complex formulation in the fasting state under several conditions was simulated. The advanced dissolution, absorption and metabolism (ADAM) model implemented within the SimCYP Population-based ADME Simulator (SimCYP version 12, SimCYP Ltd, Sheffield, UK) was used for the simulations. In the ADAM model, drug particles, dissolved drug and water/or other administered fluid move through a series of nine compartments starting with


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the stomach and ending with the colon (details of the ADAM model can be found in the review by Jamei et al. 36).

Figure 2: Schematic of the absorption models used and the variables tested to obtain the simulated fraction absorbed vs. time profiles after administration of itraconazole formulations.

The schematic of the absorption model built in this study for the simulation of the fraction absorbed and the variables tested is presented in Figure 2. The physiological properties for a healthy adult population (age 18-65 years old) built in the SimCYP simulator and appropriate modifications in order to simulate conditions of co-administration of PPIs and co-administration of an acidic beverage were used. Physicochemical properties of itraconazole (such as MW, pKa, logP) were obtained from the substrate database provided in the SimCYP simulator. The solubility values (Figure 1) and % dissolved vs time profiles at pH 1.2, pH 2 and pH 5 described previously

31-32

were used. A virtual population of similar size as the observed data after

administration of the Sporanox® formulation 33 (n=12) was used in order to take into account the variability of the physiological processes (such as gastric pH, gastric emptying rate).

4.1. Simulations of itraconazole fraction absorbed under acidic gastric conditions


10

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Simulations were performed assuming administration of a 100 mg Sporanox® capsule in healthy fasted volunteers with the use of: i) solubility data only in pH 1.2 and ii) solubility and dissolution data in pH 1.2. The sensitivity of the simulated fraction absorbed to variation in solubility and dissolution in acidic pH, and also to change of initial volume of stomach fluid that reflects the change in the secretion rate observed after co-administration of a PPI

37-38

were

studied with a sensitivity analysis of these variables for a range of values [solubility: 0 - 0.5 mg/mL; cumulative % dissolved after 60 min: 0 - 100 %; initial volume of stomach fluid 1 - 150 mL]. Fraction absorbed of itraconazole after oral administration of 100 mg of the itraconazoleHBenBCD complex formulation in the same population was simulated with the use of solubility and dissolution data of this formulation in pH 1.2 (Figure 1) 31-32.

4.2. Simulations of itraconazole fraction absorbed after co-administration of a PPI

Simulations were performed assuming administration of a 100 mg Sporanox® capsule and of 100 mg of the itraconazole-HBenBCD complex formulation in healthy fasted volunteers at a relatively high gastric pH (pH 5) that could result from the co-administration of the PPI. The gastric pH in the physiological parameters was set to the value of pH 5, and the corresponding solubility and dissolution data at pH 5 for each formulation (Figure 1) were used

31-32

. The

sensitivity of the simulated fraction absorbed to change of initial volume of fluid in the stomach that reflects the change in the secretion rate observed after co-administration of a PPI

37-38

was

studied. The sensitivity of the simulated fraction absorbed to change of initial volume of stomach fluid was studied with a sensitivity analysis for the range of 1 - 150 mL.

4.3. Simulations of itraconazole fraction absorbed after co-administration of an acidic beverage


11


Simulations were performed assuming administration of 100 mg of the itraconazole-HBenBCD complex formulation in healthy fasted volunteers with a gastric pH of 2 that could result from the co-administration of 250 mL of an acidic beverage. Solubility and dissolution data obtained in SGF pH 2 (Figure 1) for this formulation were used 31-32. Simulations were also performed with a gastric emptying time of 1 h (in place of the value of 0.4 h used for all other simulations described above) in order to take into account the prolonged gastric emptying that is observed after administration of an caloric acidic beverage 39.

RESULTS Figure 3 shows the cumulative fraction of itraconazole dissolved vs time profile in the gut lumen of humans that is the fraction of dose entering the enterocytes (fraction absorbed in the ADAM model) as well as the simulated cumulative fractions absorbed vs time based on absorption modeling. The simulated profiles estimated by using only solubility data of Sporanox® under conditions simulating the gastric environment (pH 1.2) overpredict the fraction of itraconazole dissolved. The simulated profiles estimated by using solubility and dissolution data of Sporanox® in pH 1.2 predict successfully the in-vivo dissolution of itraconazole.

1.0

Itraconazole Fraction Absorbed

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0.8

0.6

0.4 In vivo (observed) 0.2

Predicted based on Solubility Predicted based on Solubility and Dissolution

0.0 0

2

4

6

8

10

Time (h)


12

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Figure 3: In-vivo (---) and simulated itraconazole cumulative fraction absorbed vs time profiles after oral administration of a 100 mg Sporanox® capsule in 12 healthy volunteers.

Based on the successful prediction of the observed data, this model was selected to test the effect of different gastric parameters on the absorption of itraconazole. The absorption model was further tested with sensitivity analysis in order to assess the changes in the fraction absorbed as a function of solubility and dissolution in gastric fluids (Figure 4). Formulation properties, as revealed by the fraction dissolved in combination with solubility properties, would define the optimal area for achieving the highest fraction absorbed, as would be expected for a BCS Class II compound such as itraconazole 31.

Figure 4: Theoretical relationship between fraction of itraconazole absorbed, cumulative % dissolved in pH 1.2 at 60 min and solubility at pH1.2.

The predicted fraction absorbed of itraconazole after oral administration of one 100 mg Sporanox® tablet with 100 mL of water in the population model for the 12 volunteers reveals variability in the range of 41 % - 62 % of the dose to be entering the enterocytes with the observed fraction absorbed in the in-vivo study 33 to be in this window (Figure 5, left panel). The effect that a PPI would have on the fraction absorbed of itraconazole after oral administration of


13


Sporanox® is presented in Figure 5, right panel. In this case, the population absorption model built based on the gastric pH and on the solubility and the dissolution of the Sporanox® capsule

1.0


in this pH (pH 5) (Figure 1) predicts that 5 % - 8 % of the administered dose will be absorbed.

1.0



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0.8

0.6

0.4

0.2

0.0

0.8

0.6

0.4

0.1 0.08 0.06 0.04 0.02 0 0

1

2 Time (h)

3

4

0.2

0.0 0

2

4

6

8

10

0

2

Time (h)

4

6

8

10

Time (h)

Figure 5: Mean and individual simulated cumulative fraction itraconazole absorbed (n=12) after administration of a 100 mg Sporanox® capsule in the fasted state at acidic (pH 1.2) (left panel) and at elevated (pH 5.0) gastric pH (right panel); in-vivo cumulative fraction absorbed after administration of a 100 mg Sporanox® capsule (---).

Apart from the increase in the gastric pH, administration of PPIs is related to changes in the gastric secretion rate

37-38

. In the SimCYP simulator the gastric juice secretion (plus saliva

secretion) is defined by the initial volume in the stomach (50 mL in healthy population) and the first order rate of gastric emptying (0.4 h in healthy population). The impact of the change of the initial volume in the stomach, reflecting the change in the gastric secretion rate (by keeping the gastric emptying time constant at 0.4 h) on the fraction of itraconazole absorbed after administration of Sporanox® without and with co-administration of a PPI as assessed in the population model developed is minimal (Figure 6).


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1

Itraconazole fraction absorbed

Sporanox gastric pH1.2 0.8

Sporanox gastric pH5

0.6

0.4

0.2

0 0

50

100

150

Initial Volume in Stomach (mL)

Figure 6: Impact of the change of the initial volume in the stomach on the fraction of itraconazole absorbed after administration of Sporanox® assessed by sensitivity analysis.

In the in-vitro studies

32

the itraconazole-HBenBCD complex formulation had shown better

solubility and dissolution rate in acidic pH compared to the Sporanox® capsule. The population absorption model was used to predict the fraction absorbed after oral administration of 100 mg of this formulation without and with co-administration of a PPI (Figure 7). A clear increase in the % absorbed is observed when the pH of the stomach is acidic leading to a range of 79 % - 103 %

1.0


whereas in pH 5 similar absorption profiles with Sporanox® are obtained (range 7 % - 10 %).

1.0



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.8

0.6

0.4

0.2

0.0

0.8

0.6

0.4

0.1 0.08 0.06 0.04 0.02 0 0

1

2 Time (h)

3

4

0.2

0.0

0

2

4

6

8

10

0

2

Time (h)

4

6

8

10

Time (h)

Figure 7: Mean and individual simulated cumulative fraction itraconazole absorbed (n=12) after administration of a 100 mg itraconazole-HBenBCD complex formulation in the fasted state at acidic (pH 1.2) (left panel) and at elevated (pH 5.0) gastric pH (right panel); in-vivo cumulative fraction absorbed after administration of a 100 mg Sporanox® capsule (- - -).


15


Based on the established absorption model, co-administration of the itraconazole HBenBCD complex formulation with 250 mL of an acidic beverage, such as Coca-Cola® (resulting in an intragastric pH of ~2) would lead to a fraction absorbed in the range of 24 % - 28 % (Figure 8, left panel). A longer gastric emptying time (1 h) that would be expected in this case 40 results in a slower absorption rate with no significant change in the cumulative fraction absorbed (25 % - 30 %) (Figure 8, right panel).

1.0

Itraconazole Fraction absorbed

1.0

Itraconazole Fraction absorbed

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0.8

0.6

0.4

0.2

0.0

0.8

0.6

0.4

0.2

0.0 0

2

4

6

8

10

0

2

Time (h)

4

6

8

10

Time (h)

Figure 8: Individual simulated cumulative fraction itraconazole absorbed (n=12) after administration of a 100 mg itraconazole-HBenBCD complex formulation with 250mL of an acidic beverage (pH 2.0) with gastric emptying time of 0.4 h (left panel) and 1 h (right panel) in the fasted state; mean simulated cumulative fraction absorbed after administration of 100 mg itraconazole-HBenBCD complex formulation at acidic (pH 1.2) gastric pH with 100 mL of water and gastric emptying time of 0.4 h (-).

DISCUSSION Itraconazole, a weakly basic 7, lipophilic triazole-type antifungal agent is practically insoluble in water and dilute acidic conditions 8. The drug can only be ionized at very low pH. Therefore, prerequisite for a sufficient oral bioavailability of the compound after administration to fasted patients is dissolution in the acidic environment of the fasted stomach that represents the only site in the human GI tract where the pH can be low enough to ensure itraconazole´s ionization.


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According to several studies reported in the literature

22-24, 41

, itraconazole bioavailability is

impaired when an acidic gastric environment is not longer guaranteed. Lim et al. 22 studied the impact of co-adminstration of famotidine, an H2-receptor antagonist, on oral fasted bioavailability of a 200 mg dose of itraconazole (Sporal® = Thai brand name of Sporanox®). A significant (~ 50 %) decrease in both the median peak serum concentration (Cmax) and the median integrated concentration (AUC0-48) of itraconazole with famotidine was found when itraconazole was co-administered with famotidine compared to administration of itraconazole alone. Similar observations, namely a 66 % and 64 % reduction in Cmax and AUC024,

respectively were made by Jaruratanasirikul and Sriwiriyajan 23, who studied the effect of co-

administration of omeprazole on the pharmacokinetics of a single dose of 200 mg oral itraconazole (Sporanox®). It needs to be pointed out that in both studies

22-23

, itraconazole was

administered immediately after a standard breakfast, indicating that, since after food intake, gastric pH is not in the acidic range anymore, the reduced itraconazole’s bioavailability should not be attributed solely to gastric acid secretion-inhibiting effect of the co-administered compounds. In the leaflet of Sporanox® (itraconazole) capsules 7, it is indicated that several studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased and that there is a risk of reduced plasma concentrations of itraconazole when Sporanox® capsules are administered concomitantly with H2-receptor antagonists or PPIs. Further information given in the Sporanox® leaflet indicates that additional studies have shown that fasted itraconazole absorption in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors, was increased when Sporanox® capsules were administered with a cola beverage.


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Page 18 of 28

In a study enrolling 18 male AIDS patients receiving single 200-mg doses of Sporanox® capsules under fasted conditions with 8 ounces (~236.6 mL) of water or 8 ounces (~236.6 mL) of a cola beverage in a crossover design, Lange et al. studied the bioavailability of itraconazole as a result of the co-administered fluid composition. Compared to co-administration with water, the overall absorption of itraconazole was increased, but highly variable when Sporanox® capsules were coadministered with a cola beverage, with AUC0-24 and Cmax increasing 75% ± 121% and 95% ± 128%, respectively

7, 17

. Results from a study, in which 100 mg Sporal® (Thai brand name of

Sporanox®) capsules were administered to 8 fasted healthy subjects together with either 325 mL of water or Coca-Cola® 25,were in good agreement with these observations, since also in healthy subjects, Coca-Cola® was effective in enhancing the absorption of itraconazole. Similar observations were made by Bae et al.

42

who investigated the effects of a co-administered

vitamin C beverage (composition not mentioned) or cola on the pharmacokinetics of itraconazole after a single 200-mg dose of Sporanox® capsules in healthy volunteers. Both co-administration with a vitamin C beverage or cola significantly enhanced itraconazole bioavailability, resulting in significantly higher Cmax and AUC values, in comparison with the administration of itraconazole capsules with water. Results from the cited studies clearly indicate that in both the fasted and the fed state coadminstration of a PPI results in an impaired bioavailability of itraconazole. In contrast, coadministration of an acidic (carbonated) beverage seems to have a positive effect on the bioavailability of itraconazole, particularly when the patients suffer from hypochlorhydria 17. All studies addressing the impact of hypochlohydria, H2-receptor antagonists

22

or PPIs

23

on

itraconazole bioavailability were focused on measuring the plasma concentrations of itraconazole rather than monitoring intragastric pH as a surrogate for the effectiveness of the PPI. The study


18

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results clearly indicate that such dosing conditions do impair itraconazole bioavailability, but, since intragastric pH values in the respective subjects were not determined, it was not possible to relate these observations to particular intragastric pH conditions. However from various studies dedicated to monitor intragastric pH after administration of different PPIs, it is clear that even after administering a single PPI dose, the median gastric pH is above pH 4 for many hours

20

indicating that gastric secretion is reduced over a long time period, often throughout the entire day. Nevertheless, there are no data available enabling a quantitative relationship between itraconazole bioavailability and the changes in intragastric pH and gastric volume over time. The same observation applies for studies examining the impact of co-administered acidic (carbonated) beverages on itraconazole bioavailability. The main focus of these studies was also the plasma concentration of itraconazole, whereas the intragastric pH and volume was not measured. Thus, a correlation of intragastric pH and bioavailability could also not be performed. The composition of cola beverages varies between brands and countries. For Coca-Cola® pH values between 2.4 and 2.68 320-436 calories/L

28-29

22, 28-29

, carbohydrate contents of 80-109 g/L

and an osmolarity of 493-688.2 mOsmol/L

28-29

28-29

, a caloric load of

can be found in the

literature. Since, based on the product information the pH of Coca-Cola® falls into the upper range of fasted gastric pH conditions in healthy volunteers, it is not likely that the results from itraconazole bioavailability studies can be interpreted solely from the pH of a co-administrated cola beverage. This will particularly be the case for healthy subjects, where fasted gastric pH can be even lower than that of co-administered cola. The absorption model developed in the present study was aimed to estimate the fraction of itraconazole that can be absorbed (fabs) after oral administration of Sporanox® capsules or an itraconazole-HBenBCD complex formulation with and without co-administration with a PPI or


19


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Page 20 of 28

an acidic (carbonated) beverage. With the validated absorption model, we tried to assess the potential changes of fabs as a function of solubility and dissolution in gastric conditions resulting from these dosing conditions. Simulating co-administration of Sporanox® with a PPI resulted in a significant decrease in itraconazole fabs. In contrast to administration of Sporanox® with water, under conditions of a hypoacidic stomach (pH 5), only 5 – 8 % of the dose was predicted to be absorbed (Figure 5), indicating the pH to be essential for in-vivo dissolution and subsequent absorption. In contrast, and as shown in an additional step, simulating also the smaller intragastric volumes resulting from impaired gastric secretion, seems to have a minor impact on the amount of drug available for absorption when gastric pH is increased (Figure 6). Based on these observations, it is evident that the PPI-induced increase in gastric pH rather than the reduced amount of fluid available in the fasted gastric stomach is the main determinant for the amount of itraconazole that can be dissolved in the stomach. This assumption was also confirmed when simulating the in-vivo performance of the itraconazole-HBenBCD formulation (Figure 7). Whereas under optimal pHconditions, i.e. assuming a very acidic stomach with an intragastric pH of 1.2, in contrast to the observations made for Sporanox® complete drug absorption from the itraconazole-HBenBCD formulation is likely, for the latter formulation fabs was estimated to be a little higher than that of the Sporanox® product when the intragastric pH was set at the value of pH 5. The final modification of the model was intended to address the fabs that could be observed after co-administration of the itraconazole-HBenBCD complex (100 mg dose) with a glass (250 mL) of Coca-Cola® (pH ~ 2.5). As can be seen in Figure 8 (left panel), assuming co-administration of the itraconazole-HBenBCD complex to healthy subjects, simulated by a resulting intragastric pH of 2, would result in a fabs of 25 – 30 %. This result does not support the observations reported in


20

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the literature and thus clearly indicates that in contrast to PPIs, which seem to affect itraconazole bioavailability mainly via intragastric pH changes, co-administered Coca-Cola® is likely to alter a range of gastrointestinal parameters relevant to in-vivo dissolution rather than solely affecting the intragastric pH. As indicated above, classical Coca-Cola® does not represent a simple acidic fluid but is also rich in sugars (calories) and electrolytes which in turn can affect gastric secretion and gastric emptying via osmotic and caloric effects

30, 43-45

. As can be seen in Figure 8, addressing solely

the Coca-Cola® -derived increase in gastric volume (left panel) and residence time (right panel), in addition to the gastric pH is not sufficient to explain the in-vivo observations. These results clearly indicate that the impact of the co-administration of Coca-Cola® on itraconazole´s bioavailability is not a result of the alteration of the gastric pH. Moreover, besides affecting intragastric pH and gastric volumes, co-administered Coca-Cola® seems to affect various additional factors including intraluminal aspects of the small intestine that could impact itraconazole´s oral bioavailability. Furthermore, and as recently disussed for posaconazole 27 the solubility of itraconazole in Coca-Cola® as a result of the overall composition of the drink, is likely to contribute to its in-vivo performance. Thus, it is likely that the “Coca-Cola® effect” is a result of enhanced solubility in the drink itself, an increased gastric volume, prolonged gastric residence and most likely also an increased fluid volume available at the site of drug absorption, overall resulting in an enhanced bioavailability, particularly in those patients suffering from a hypochlorhydric gastric environment.

CONCLUSION


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Page 22 of 28

In conclusion, the absorption model developed allows demonstration of the effect of gastric conditions associated with co-administration of PPIs on the absorption of itraconazole. Furthermore, based on the developed absorption model the effect of co-administered acidic carbonated beverages on itraconazole’s absorption cannot be attributed only to the alterations of the gastric acidity and secretions. To better predict the effect of co-administered acidic beverages, appropriate in-vitro data need to be generated taking into account aspects other than only the gastric pH. Formulation properties, as revealed by dissolution characteristics in combination with solubility properties and the physiological parameters in the gastric environment are critical variables for the absorption of itraconazole.

ACKNOWLEDGEMENTS The Department of Pharmacy and Pharmacology at the University of Bath thanks SimCYP Limited (Sheffield, UK) for providing the academic license of the Simcyp Population-based Simulator. Authors would also like to thank Mr C.M Long for performing the numerical deconvolution of the oral Sporanox® data.


22

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AUTHOR INFORMATION

Corresponding Author *Ernst Moritz Arndt University Greifswald, Department of Pharmacy, Institute of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, Felix-Hausdorff-Strasse 3 17489 Greifswald, Germany Phone: ++49 (0) 3834 86 4897 Fax: ++++49 (0) 3834 86 4886 E-mail: [email protected]

Author Contributions Both authors contributed equally to this manuscript and both have given approval to the final version of the manuscript.


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References 1.

Richardson, P.; Hawkey, C. J.; Stack, W. A. Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders. Drugs 1998, 56, (3), 307-35.

2.

Thomson, A. B.; Sauve, M. D.; Kassam, N.; Kamitakahara, H. Safety of the long-term use of proton pump inhibitors. World J Gastroenterol 2010, 16, (19), 2323-30.

3.

Shi, S. J.; Klotz, U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics. European Journal of Clinical Pharmacology 2008, 64, (10), 935-951.

4.

Heidelbaugh, J. J.; Metz, D. C.; Yang, Y. X. Proton pump inhibitors: are they overutilised in clinical practice and do they pose significant risk? Int J Clin Pract 2012, 66, (6), 582-91.

5.

Hansten, P. D. Drug interactions with antisecretory agents. Aliment Pharmacol Ther 1991, 5 Suppl 1, 121-8.

6.

Gerson, L. B.; Triadafilopoulos, G. Proton pump inhibitors and their drug interactions: an evidence-based approach. Eur J Gastroenterol Hepatol 2001, 13, (5), 611-6.

7.

Janssen SPORANOX® (itraconazole) Capsules http://www.janssenpharmaceuticalsinc.com/assets/sporanox.pdf (May 19),

8.

PhEur, European Pharmacopoeia 7th Edition. Council of Europe: 2011; Vol. 7.

9.

Kong, F.; Singh, R. P. Disintegration of solid foods in human stomach. Journal of Food Science 2008, 73, (5), R67-R80.

10.

Thews, G.; Mutschler, E.; Vaupel, P., Gastrointestinaltrakt und Verdauung. In Anatomie, Physiologie, Pathophysiologie des Menschen, 4. ed.; Wissenschaftliche Verlagsgesellschaft mbH: Stuttgart, 1991; pp 271-322.

11.

Arullani, P.; Caprilli, R.; Spaziani, G. [pH changes in the different segments of the small and the large intestine: continuous recording by means of an endoradioprobe]. Arch Ital Mal Appar Dig 1967, 34, (3), 279-89.

12.

Evans, D. F.; Pye, G.; Bramley, R.; Clark, A. G.; Dyson, T. J.; Hardcastle, J. D. Measurement of Gastrointestinal pH Profiles in Normal Ambulant Human-Subjects. Gut 1988, 29, (8), 1035-1041.

13.

Dressman, J. B.; Berardi, R. R.; Dermentzoglou, L. C.; Russell, T. L.; Schmaltz, S. P.; Barnett, J. L.; Jarvenpaa, K. M. Upper gastrointestinal (GI) pH in young, healthy men and women. Pharm Res 1990, 7, (7), 756-61.

14.

Sasaki, Y.; Hada, R.; Nakajima, H.; Fukuda, S.; Munakata, A. Improved localizing method of radiopill in measurement of entire gastrointestinal pH profiles: colonic luminal pH in normal subjects and patients with Crohn's disease. Am J Gastroenterol 1997, 92, (1), 114-8.

Leaflet.


24

Page 25 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


15.

Malagelada, J. R.; Longstreth, G. F.; Summerskill, W. H.; Go, V. L. Measurement of gastric functions during digestion of ordinary solid meals in man. Gastroenterology 1976, 70, (2), 203-10.

16.

Kalantzi, L.; Goumas, K.; Kalioras, V.; Abrahamsson, B.; Dressman, J. B.; Reppas, C. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies. Pharmaceut Res 2006, 23, (1), 165-176.

17.

Lange, D.; Hardin Pavao, J.; Jacqmin, P.; Woestenborghs, R.; Ding, C.; Klausner, M. The effect of coadministration of a cola beverage on the bioavailability of itraconazole in patients with acquired immunodeficiency syndrome. Current Therapeutic Research 1997, 58, (3), 202-212.

18.

Lake-Bakaar, G.; Elsakr, M.; Hagag, N.; Lyubsky, S.; Ahuja, J.; Craddock, B.; Steigbigel, R. T. Changes in parietal cell structure and function in HIV disease. Dig Dis Sci 1996, 41, (7), 1398-408.

19.

Feldman, M.; Barnett, C. Fasting gastric pH and its relationship to true hypochlorhydria in humans. Dig Dis Sci 1991, 36, (7), 866-9.

20.

Hatlebakk, J. G. Review article: gastric acidity--comparison of esomeprazole with other proton pump inhibitors. Aliment Pharmacol Ther 2003, 17 Suppl 1, 10-5; discussion 167.

21.

Pohle, T.; Domschke, W. Gastric function measurements in drug development. Br J Clin Pharmacol 2003, 56, (2), 156-64.

22.

Lim, S. G.; Sawyerr, A. M.; Hudson, M.; Sercombe, J.; Pounder, R. E. Short report: the absorption of fluconazole and itraconazole under conditions of low intragastric acidity. Aliment Pharmacol Ther 1993, 7, (3), 317-21.

23.

Jaruratanasirikul, S.; Sriwiriyajan, S. Effect of omeprazole on the pharmacokinetics of itraconazole. Eur J Clin Pharmacol 1998, 54, (2), 159-61.

24.

Lahner, E.; Annibale, B.; Delle Fave, G. Systematic review: impaired drug absorption related to the co-administration of antisecretory therapy. Aliment Pharmacol Ther 2009, 29, (12), 1219-29.

25.

Jaruratanasirikul, S.; Kleepkaew, A. Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole. Eur J Clin Pharmacol 1997, 52, (3), 235-7.

26.

Krishna, G.; Moton, A.; Ma, L.; Medlock, M. M.; McLeod, J. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother 2009, 53, (3), 958-66.

27.

Walravens, J.; Brouwers, J.; Spriet, I.; Tack, J.; Annaert, P.; Augustijns, P. Effect of pH and comedication on gastrointestinal absorption of posaconazole: monitoring of intraluminal and plasma drug concentrations. Clin Pharmacokinet 2011, 50, (11), 725-34.


25


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 28

28.

Mettler, S.; Rusch, C.; Colombani, P. C. Osmolality and pH of sport and other drinks available in Switzerland. Schweizerische Zeitschrift für Sportmedizin und Sporttraumatologie 2006, 54, (3), 92-5.

29.

Chavalittamrong, B.; Pidatcha, P.; Thavisri, U. Electrolytes, sugar, calories, osmolarity and pH of beverages and coconut water. Southeast Asian J Trop Med Public Health 1982, 13, (3), 427-31.

30.

Rehrer, N. J.; Beckers, E. J.; Brouns, F.; Saris, W. H. M.; Tenhoor, F. Effects of Electrolytes in Carbohydrate Beverages on Gastric-Emptying and Secretion. Med Sci Sport Exer 1993, 25, (1), 42-51.

31.

Taupitz, T.; Dressman, J. B.; Buchanan, C. M.; Klein, S. Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: Itraconazole. Eur J Pharm Biopharm 2013, 83, (3), 378387.

32.

Buchanan, C. M.; Buchanan, N. L.; Edgar, K. J.; Klein, S.; Little, J. L.; Ramsey, M. G.; Ruble, K. M.; Wacher, V. J.; Wempe, M. F. Pharmacokinetics of itraconazole after intravenous and oral dosing of itraconazole-cyclodextrin formulations. J Pharm Sci 2007, 96, (11), 3100-3116.

33.

Yeates, R. A.; Zimmermann, T.; Laufen, H.; Albrecht, M.; Wildfeuer, A. Comparative Pharmacokinetics of Fluconazole and of Itraconazole in Japanese and in German Subjects. Int J Clin Pharm Th 1995, 33, (3), 131-135.

34.

VandeVelde, V. J. S.; VanPeer, A. P.; Heykants, J. J. P.; Woestenborghs, R. J. H.; VanRooy, P.; DeBeule, K. L.; Cauwenbergh, G. F. M. J. Effect of food on the pharmacokinetics of a new hydroxypropyl-beta-cyclodextrin formulation of itraconazole. Pharmacotherapy 1996, 16, (3), 424-428.

35.

Gillespie, W. R. PCDCON: Deconvolution for Pharmacokinetic Applications. , Austin, TX, 1992.

36.

Jamei, M.; Turner, D.; Yang, J. S.; Neuhoff, S.; Polak, S.; Rostami-Hodjegan, A.; Tucker, G. Population-Based Mechanistic Prediction of Oral Drug Absorption. Aaps J 2009, 11, (2), 225-237.

37.

Lind, T.; Cederberg, C.; Ekenved, G.; Haglund, U.; Olbe, L. Effect of omeprazole--a gastric proton pump inhibitor--on pentagastrin stimulated acid secretion in man. Gut 1983, 24, (4), 270-6.

38.

Sud, D.; Joseph, I. M. P.; Kirschner, D. Predicting Efficacy of Proton Pump Inhibitors in Regulating Gastric Acid Secretion. Journal of Biological Systems 2004, 12, (1), 1-34.

39.

Lobo, D. N.; Hendry, P. O.; Rodrigues, G.; Marciani, L.; Totman, J. J.; Wright, J. W.; Preston, T.; Gowland, P.; Spiller, R. C.; Fearon, K. C. Gastric emptying of three liquid oral preoperative metabolic preconditioning regimens measured by magnetic resonance


26

Page 27 of 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


imaging in healthy adult volunteers: a randomised double-blind, crossover study. Clin Nutr 2009, 28, (6), 636-41. 40.

Ploutz-Snyder, L.; Foley, J.; Ploutz-Snyder, R.; Kanaley, J.; Sagendorf, K.; Meyer, R. Gastric gas and fluid emptying assessed by magnetic resonance imaging. Eur J Appl Physiol O 1999, 79, (3), 212-220.

41.

Willems, L.; van der Geest, R.; de Beule, K. Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics. Journal of Clinical Pharmacy and Therapeutics 2001, 26, (3), 159-169.

42.

Bae, S. K.; Park, S. J.; Shim, E. J.; Mun, J. H.; Kim, E. Y.; Shin, J. G.; Shon, J. H. Increased oral bioavailability of itraconazole and its active metabolite, 7hydroxyitraconazole, when coadministered with a vitamin C beverage in healthy participants. J Clin Pharmacol 2011, 51, (3), 444-51.

43.

Calbet, J. A. L.; MacLean, D. A. Role of caloric content on gastric emptying in humans. Journal of Physiology-London 1997, 498, (2), 553-559.

44.

Hunt, J. N. A possible relation between the regulation of gastric emptying and food intake. Am J Physiol 1980, 239, (1), G1-4.

45.

Brener, W.; Hendrix, T. R.; McHugh, P. R. Regulation of the gastric emptying of glucose. Gastroenterology 1983, 85, (1), 76-82.


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474x191mm (72 x 72 DPI)


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Mechanistic Understanding of the Effect of PPIs ... - ACS Publications

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