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Mitigation of Adverse Clinical Events of a Narrow Target Therapeutic Index Compound through Modified Release Formulation Design: An in Vitro, in Vivo, in Silico, and Clinical Pharmacokinetic Analysis David J. Good,*,† Ruiling Hartley,† Neil Mathias,† John Crison,† Giridhar Tirucherai,‡ Peter Timmins,§ Munir Hussain,† Raja Haddadin,† Otilia Koo,† Faranak Nikfar,† and Nga Kit Eliza Fung∥ †

Drug Product Science and Technology, Bristol-Myers Squibb, New Brunswick, New Jersey 08903, United States Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, New Jersey 08543, United States § Drug Product Science and Technology, Bristol-Myers Squibb, Moreton, U.K. ∥ Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, New Jersey 08543, United States ‡

S Supporting Information *

ABSTRACT: BMS-914392 is a tricyclic pyranoquinoline BCS class 2 weak base that demonstrates high solubility in low pH environments. Initial clinical studies indicated that rapid release of high dose BMS-914392 led to transient adverse events associated with peak plasma concentrations. A modified release (MR) formulation strategy was proposed to suppress the peak blood concentration and maintain total exposure to overcome the adverse effects. Three modified release prototype formulations were developed and tested via a USP 3 dissolution method to verify that each formulation can effectively slow the release of BMS-914392. A pharmacokinetic (PK) absorption model was employed to guide the formulation development and selection. Simulations showed good agreement with plasma levels measured after oral dosing in dogs. Identification of key formulation factors to achieve release rates suitable for blunting peak blood levels without diminishing exposure were achieved through combined preclinical data and use of GastroPlus simulations. PK absorption model refinements based on phase 1 data, dog pharmacokinetic results, and in vitro data provided reliable predictions of human absorption profiles and variability in patients. All three prototype formulations demonstrated lower maximum plasma concentrations of BMS-914392 and maintained satisfactory relative bioavailability. Both the PK absorption model and subsequent clinical data indicated that an acidified hydrophilic matrix MR formulation had the greatest potential to reduce the incidence of adverse events and showed the best exposure profile in fasted state healthy subjects with and without famotidine coadministration. The risk based development process achieved successful screening and selection of a suitable modified release formulation to enable clinical efficacy trials. KEYWORDS: modified release formulation, pharmacokinetic absorption model, in vivo site of absorption, in vitro dissolution, BCS 2 weak base, pH effect mitigation, hydrophilic matrix tablets, enteric coating

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INTRODUCTION Modified release drug delivery systems provide an effective way to improve therapeutic outcomes by altering drug release to prolong systemic drug absorption or reduce the spike in drug absorption from immediate-release dosage forms.1−3 Their impact can optimize the efficacy of a drug by achieving a preferred pharmacokinetic−pharmacodynamic balance or reducing the safety/tolerability burden of the drug. A popular application is modulating the pharmacokinetic profile of a drug with a short half-life for the purpose of extending the plasma time course for a convenient dosing regimen. Another important application is maintaining constant blood levels to eliminate adverse events driven by a spike in blood levels. Extended release nifedipine and extended release oxybutynin are typical examples of products with improved safety profiles that use this strategy.4−6 Numerous recent publications have also demonstrated similar successes with managing both safety and efficacy through MR formulation.7−11 This strategy was © XXXX American Chemical Society

highlighted through the design and development of a BMS914392 MR product to eliminate adverse effects and progress the drug in further clinical trials. BMS-914392 is a weak base (pKa 4.3, 6.7; logD 3.6 at pH 6.5), BCS-II, cardiovascular agent used to reduce atrial fibrillation (AF) burden.12−15 Early clinical results showed that high dose immediate release (IR) tablets could result in transient adverse effects, which occurred at the time of maximum plasma concentrations and subsided with decreasing drug levels. The occurrence of these events did not present a hazard to the well-being of patients; however, reducing occasions by controlling peak drug levels was desired to provide an optimal patient profile. Dose fractionation studies Received: August 13, 2015 Revised: October 21, 2015 Accepted: October 26, 2015

A

DOI: 10.1021/acs.molpharmaceut.5b00624 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics

granulation excipients were blended in a bin blender. The blend was dry granulated by roller compaction (Alexanderwerk WP120, Alexanderwerk Inc., Horsham, PA). Granules were mixed with extragranular excipients to generate a final blend that was then compressed on a Korsch press with a single 3/8 in. round concave punch. In the final formulation, the drug to polymer ratio was 1:1.5. Prototype 3 (Acidified Hydrophilic Matrix Tablets). Tablets were prepared similarly to prototype 2 (hydrophilic matrix tablets) using the same drug polymer ratio (1:1.5), but substituting in HPMC K100M grade polymer and 20% citric acid as an intragranular component to sustain the acidic microenvironmental pH of the tablet. Dissolution Studies. Dissolution studies for all modified and immediate release formulations were conducted using a USP-3 apparatus (Varian’s BIO-DIS III Extended Release Testing Station, Varian Inc., Palo Alto, CA). To mimic fasted state dissolution, all formulations were tested in 250 mL of 0.1 N HCl for the first 2 h to simulate gastric environment exposure, and followed by a switch to 250 mL of 25 mM pH 6.8 phosphate buffer to simulate intestinal environment. Phosphate buffer at pH 5.5 was also used to simulate famotidine treated gastric environment. Since the prototype 1 enteric coating dissolves at pH 5.5 or greater, these tablets exhibit a dissolution rate in intestinal media equivalent to the IR formulation. The dissolution temperature was 37 °C, and the agitation rate was 10 dipping cycles per minute. 1.0 mL samples were withdrawn at 0.25, 0.5, 1, 2, 3, 4, and 6 h, and drug release was analyzed by reverse phase HPLC. Reverse Phase HPLC. A Waters Alliance 2695 HPLC system (Milford, MA) equipped with a Waters 2487 UV/vis dual wavelength detector was used to determine the drug concentration from dissolution samples. A Phenomenex Luna C-18 column (50 mm × 4.6 mm i.d., 5 μm, Phenomenex, Torrance, CA) was used at 40 °C. The sample chamber temperature was set as 20 °C. The mobile phase consisted of 55% 10 mM ammonium acetate in water and 45% acetonitrile. The flow rate was 1.0 mL/min, and the elution profile was isocratic. The detection wavelength was 238 nm. Dog Studies. A crossover study in 4 fasted, male, pentagastrin-pretreated Beagle dogs (8−12 kg) was conducted to test the MR dosage forms relative to the IR tablet. Dogs were fasted overnight. Water was withheld for 1 h predose and for 1 h postdose. Pentagastrin (6 μg/kg) was administered by intramuscular injection 30 min before dose administration. The IR tablet and 3 MR prototypes were dosed at the back of the throat, followed by a 50 mL water flush administered via oral gavage. Plasma samples were withdrawn using a 22-gauge butterfly catheter inserted into the cephalic vein on the foreleg at predose, 0.5, 1, 2, 4, 8, 24, and 48 h. Samples were placed in a K3EDTA vaccutainer and then centrifuged at 200g at 4 °C to harvest the plasma. Plasma was stored at −70 °C until LC− MS/MS analysis. LC−MS/MS Analysis. Plasma concentrations of BMS914392 were determined by a validated liquid chromatography tandem mass spectrometry (LC−MS/MS) method. The plasma samples were spiked with an internal standard (BMS91432-03, a stable deuterated analogue) solution. BMS-914392 was then extracted by a liquid−liquid extraction and subjected to LC injection. Briefly, 50 μL of plasma sample was mixed with 50 μL of 100 ng/mL BMS-914392-03 internal standard working solution and 50 μL of 1 M ammonium formate, pH 5 buffer. 650 μL of n-butyl chloride was added and shaken for

with the same oral dose delivered as 8 divided doses every 30 min confirmed that the incidence of adverse events was eliminated when the peak concentrations were reduced by approximately 50%, without any change in overall exposure (AUC). Therefore, a blunted Cmax was considered a desirable attribute in dose and dosing regimen selection for clinical efficacy studies. While the Cmax could be restricted using a more frequent administration (e.g., TID) of a lower dose in exploratory efficacy studies, a commercial MR dosage form alternative to the IR tablet would ultimately be desirable to facilitate a convenient and safe method of self-administration. The target for the MR dosage form was to reduce Cmax while maintaining similar exposure (AUC) relative to the IR tablet. Several formulation strategies with potential to achieve this goal include enteric or pH-sensitive coating, diffusing or eroding through polymer matrix system, using mixed-release granules in tablets, osmotic pressure controlled system, etc.16 In this study, we explored three MR formulation prototypes of BMS-914392 including a hydrophilic matrix polymer-based formulation with and without microenvironmental pH control as well as entericcoated tablets to reduce dissolution in the low pH stomach compartment where the compound is highly soluble. The prototype tablet formulations were designed, developed, and tested using an integrated in vitro, in vivo, and in silico approach. Prototype tablets were first analyzed by in vitro dissolution to characterize the release rates. Next, animal pharmacokinetic studies were conducted to evaluate the extent of Cmax reduction relative to the IR tablet. A two compartment PK-absorption model was developed to predict the human performance and critical formulation factors as well as to predict sensitivity to gastric pH and food for rational design of clinical studies. Lastly, a formulation screening single dose PK relative bioavailability study was conducted to evaluate the performance of the selected prototypes and identify the most appropriate tablet formulation for further optimization.

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MATERIALS AND EXPERIMENTAL METHODS Materials. BMS-914392 was synthesized by proprietary means to obtain 99+% purity. Hydropropyl methylcellulose K100M and K4M were purchased from Dow Chemical Company (Midland, Michigan), and Acryl-EZE aqueous acrylic enteric coating was obtained from Colorcon Inc. (Harleysville, PA). Other excipients and chemicals were of pharmaceutical grade obtained from established commercial vendors and used as received. Preparation of Prototype Modified Released Tablets. Three prototype formulations were formulated as follows: Prototype 1 (EC-IR Tablets). The IR core tablets included 20% drug and 80% excipients comprising diluents, disintegrants, and lubricants. Core tablets were compressed with 3/8 in. round concave punches on single punch tablet press (Korsch Press PH-106, Korsch AG, Berlin, Germany). Tablet fill weight was 300 mg, and strength was around 20 scu. Acrylic enteric coating (Acryl-EZE with TEC plasticizer, Colorcon, West Point, PA) system was used to coat the core tablets in a pan coater (Vector LDCS, Freund-Vector Company, Marion, IA) until the coating weight reached 10% of core tablet weight. A two weight percent base HPMC film coat was applied prior to the functional enteric coat. Prototype 2 (Hydrophilic Matrix Tablets). Tablets were prepared using several ratios of BMS-914392 and HPMC K4M polymer and included other excipients (MCC, magnesium stearate) to aid with tablet processability. Drug, polymer, and B

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Molecular Pharmaceutics 15 min, followed by centrifugation. Approximately 420 μL of the organic supernatant layer was transferred into a clean 96well round-bottom plate and evaporated to dryness at 40 °C under nitrogen. The dried supernatant was reconstituted in 200 μL of 30% acetonitrile and 70% water. 5 μL of the supernatant was injected to the LC−MS/MS system. The extraction recovery was 40%. Chromatographic separation was achieved by gradient elution on an Agilent Zorbax Eclipse Plus C18 (2.1 mm × 50 mm, 3.5 μm, Agilent, Santa Clara, CA). Mobile phase A contained 10 mM ammonium acetate in water, and mobile phase B contained 90% acetonitrile and 10% 10 mM ammonium acetate in water. The gradient was as follows: 0.01−1.30 min, hold at 30% B, 1.30−1.80 min, 30% B to 60% B; 1.80−3.00 min, 60% B; 3.00−3.30 min, 60% B to 100% B; 3.30−4.70 min, 100% B; 4.70−4.80 min, 100% B to 30% B; 4.80−5.00 min, 30% B. The total run time was 5.0 min. Detection was performed by positive ion electrospray mass spectrometry on an API 4000 mass spectrometer (AB Sciex, Foster City, CA). The standard curve, which ranged from 5 to 1500 ng/mL, was fitted to a 1/x2 weighted quadratic regression model. All study samples were analyzed in a total of seven analytical runs. GastroPlus Model. The pharmacokinetic absorption model of the BCS class II compound BMS-914392 was developed using commercially available software GastroPlus (v8.5, Simulations Plus, Inc., Lancaster, CA). The model was developed and refined through a combination of experimentally determined physicochemical properties and parameters fitted to in vivo data. Simulations of dog pharmacokinetics for the early development of prototype modified release formulations used a model derived from observed dog single dose intravenous and oral solution administration between 1 and 3 mg/kg. The model pharmacokinetic parameters were derived using the PKPlus module and included values for systemic total plasma clearance and volume of distribution of 0.7 L/h/kg and 2.7 L/ kg, respectively. The GastroPlus model employed a mechanistic based gastrointestinal tract for entering formulation information integrated with a compartmental pharmacokinetic model to represent the distribution phase. Human permeability values for specific intestinal segments were determined from a site of absorption study in 15 healthy males using an IntelliCap system (details below). The user defined ACAT permeability values adopted from the site of absorption study are specified in the Supporting Information. Compartmental distribution parameters were fitted to observed clinical data using the PKPlus module, resulting in a two compartment model that was utilized for all simulations of IR and MR dosage forms. Simulations for each prototype MR tablet were conducted using a controlled release dosage form and corresponding release profile. These controlled release profiles were taken from in vitro dissolution testing with a USP apparatus 3 using two consecutive pH conditions (gastric pH 1.2 and intestinal pH 6.8) or a single pH 5.5 condition in the case of famotidine physiology simulations. Sensitivity analysis was conducted for the gastric emptying time, which included simulations for 0.25 and 2.0 h durations of gastric residence. Simulations of two physiologies (fasted and elevated gastric pH/famotidine) were carried out during the formulation development and the design of clinical protocols. Model parameters specific to each of these physiologies are presented in the Supporting Information.

Virtual Trial Simulations. Virtual clinical trials were performed using the Virtual Trial function within GastroPlus. The results of these simulations were compared for each prototype dosage form to characterize anticipated exposure and variability for an adult population. These virtual clinical trials were performed using a 60 mg dose of BMS-914392 and included 36 subjects per trial with body weight between 52 and 82 kg and mean weight of 71 kg. All model parameters for the virtual trial simulations were designated to target coefficients of variation at or below ten percent with log-normal distributions except for effective permeability 65%, clearance 40%, and liver blood flow 30%, as well as GI transit times and volume of distribution each with 20%. The prototype formulations were analyzed using the Bioequivalence toolkit of WinNonlin v 5.2 (Pharsight Corp., Cary, NC) software (parallel study with population averages). The prototype formulations were considered bioequivalent if the 90% CI for Cmax and AUC(0−t) fell within the range of 0.80 to 1.25. Summary PK parameters (Cmax, AUC, Tmax, etc.) were obtained from the WinNonlin PK/PD/NCA Analysis wizard using a noncompartmental model to fit the plasma concentration versus time profile for each individual subject. Descriptive statistics for each trial and box plots were also generated through WinNonlin. Human Site of Absorption Studies. Regional human gastrointestinal absorption and permeability assessment used an InteliSite capsule radiofrequency activated, non-disintegrating, remotely controlled, drug delivery device that is noninvasively opened, to release drug in preselected GI tract segments. BMS914392 precipitation-resistant solution and crushed tablets were delivered directly to GI tract segments using the InteliSite capsule, which contained indium 111 (In-111), which was used to monitor capsule movement along the GI tract via gamma scintigraphy. Administration of the InteliSite capsule was immediately followed by 30 mL of water containing diethylenetriaminopentaacetic acid (DTPA) labeled with the metastable nuclear isomer technetium 99 (Tc-99m), which was used to outline the GI tract and delineate the targeted site(s) of BMS-914392 release. Each remote opening released a single BMS-914392 dose at a single GI tract segment such as the proximal small intestine (PSI), the distal small intestine (DSI), and the colon. Separate administrations were used to evaluate the relative bioavailability and solubility of BMS-914392 along the entire GI tract. Human Clinical Study of Prototype Formulations. A randomized four way crossover study of the 60 mg IR and three prototype MR formulations (ER-IR, hydrophilic matrix, and acidified hydrophilic matrix) was conducted in 8−16 fasted healthy subjects. This study (Arm 1) was to demonstrate the capability of each prototype toward reducing the Cmax while maintaining the AUC, relative to the IR reference, and aid in selecting a lead prototype formulation. A second study (Arm 2) was conducted as a randomized crossover study with the three 60 mg prototype MR formulations administered in the fasted state in the presence or absence of a gastric pH modifier, famotidine (40 mg), to determine the impact of gastric pH on the release rate and exposure of BMS-914392. Table 1 is a list of treatments from Arms 1 and 2.

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RESULTS AND DISCUSSION Physicochemical Properties of BMS-914392. BMS914392 is a small molecule (MW < 400 g/mol) weak base compound with two pKa values (4.3, 7.0) and logD of 3.3 at pH C

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Molecular Pharmaceutics Table 1. Treatments Provided in Human Clinical Studies of IR and Prototype MR Formulations treatment

formulation

Arm 1 A IR B MR prototype 1 (EC-IR) C MR prototype 2 (hydrophilic matrix) D MR prototype 3 (acid modified hydrophilic matrix) Arm 2 B MR prototype 1 (EC-IR) C MR prototype 2 (hydrophilic matrix) D MR prototype 3 (acid modified hydrophilic matrix) E MR prototype 1 (EC-IR) F MR prototype 2 (hydrophilic matrix) G MR prototype 3 (acid modified hydrophilic matrix)

physiology

subjects

fasted fasted fasted fasted

16

fasted fasted fasted

8

Figure 1. Observed exposure of BMS-914392 administered in different human intestine segments. (a) 10 mg solution formulation was taken orally (black line with circles). (b) 10 mg solution formulation was targeted to proximal small intestine (red line with inverted triangles). (c) 10 mg solution formulation was targeted to distal small intestine (green line with squares). (d) 10 mg solution formulation was targeted to ascending colon (blue line with diamonds). (e) 10 mg crushed immediate release tablet was targeted to ascending colon (magenta line with triangles).

famotidine famotidine famotidine

6.5. The compound has pH-dependent solubility with values of 22 mg/mL, 4.3 mg/mL, 0.05 mg/mL, and 0.02 mg/mL at pH of 1.2, 4.0, 6.5, and 8.0, respectively. The equilibrium solubility in water is 0.023 mg/mL. BMS-914392 has a high permeability, estimated at 29.8 × 10−6 cm/s (from Caco-2 model), consistent with classification as a BCS class 2 compound. Clinical Dose Fractionation and Site of Absorption Studies. Clinical results for BMS-914392 showed that subjects administered high doses of IR tablets (120 mg) had a greater potential to show adverse effects. The incidence of adverse events appeared to correlate with high levels of Cmax. Therefore, attenuation of the Cmax was considered crucial to improving the safety profile of BMS-914392. One strategy to explore this hypothesis was to fractionate the same dose as 8 divided doses (15 mg each capsule) every half hour. The Cmax was reduced by about 50% and the Tmax delayed to 3.5 h from 1 h for the IR tablet. The overall exposure was maintained, and there was no incidence of side effects with the fractionated approach (data not shown). This suggested that slowing the release of drug over a prolonged duration can achieve the desired target PK and safety profile. One key question remaining was whether BMS-914392 was permeable in the distal regions of the GI tract, i.e., would it be absorbed if a MR dosage form was developed? To address the determination of regional GI permeability, a site of absorption study was conducted as an open-label randomized crossover study with 15 healthy males using an InteliSite capsule (ScintiPharma, Lexington, KY) technology. Figure 1 shows the pharmacokinetic profile of BMS-914392 from each of the sites of drug release. The relative bioavailability of a solution dose of BMS-914392 was high (estimated as >92% in every segment) in the proximal small intestine, distal small intestine, and ileocecal/ascending colon (either as a solution or as a crushed tablet) as compared to the reference oral solution exposure listed in Table 2. Rapid absorption was noted for BMS-914392 solution administered orally and in the proximal and distal small intestine with Tmax of 0.5 h. By contrast, BMS-914392 solution released in the colon was gradually absorbed and exhibited a sustained absorption profile. Additionally, the exposure was found to be equivalent when delivered as a crushed tablet or solution to the colon region. The results indicated that dissolution occurs in the low fluid volume of the colonic region and BMS-914392 is effectively

Table 2. Summary Exposure (AUC) from Solution Administration of BMS-914392a treatment (region of administration) oral proximal small intestine distal small intestine ileocecal/ascending colon a

AUC(0−t) (ng·h/mL) 702.0 664.7 797.5 1004.1

(43.0) (38.6) (37.3) (38.7)

Values provided are geometric means and % CV.

absorbed. Taken together, the data from this study confirmed the inherent property of BMS-914392 to be reasonably well absorbed across all intestinal regions. This provided strong rationale to pursue a modified release formulation for once daily dosing, the target profile of such a dosage form being to significantly reduce the Cmax relative to the IR tablet, maintain exposure similar to that of the IR tablet, and maintain a minimum plasma concentration (Cmin) within the efficacious range. Design of MR Dosage Forms. Since BMS-914392 shows rapid dissolution under acidic conditions, the formulation strategy focused on limiting the extent of release in the stomach. Additionally, since the site of absorption studies suggested a large window of absorption with the preferred area for drug release being the colonic region, slow release rates were necessary to sustain drug absorption. Prototype 1 was an enteric-coated immediate release (EC-IR) tablet to protect the core tablet from dissolution in gastric fluid. The pH-sensitive polymer used in the enteric coating dissolves in an environment of pH 5.5 and higher, which targets release of drug in the duodenal−jejunal region of the small intestine. Since BMS914392 has low solubility at high pH, dissolution will be limited by its low solubility in intestinal fluid. One caveat with this approach is that release in humans will be determined by gastric emptying time and the variability of pH in the GI tract for individuals. A second approach considered was a hydrophilic matrix (HPMC) tablet with slow drug release (prototype 2) and a similar HPMC matrix tablet formulated with acid buffers (prototype 3) to ensure dissolution of BMS-914392 in the local microenvironment as drug releases from the polymer matrix. For the latter two prototypes the drug release rate is dependent D

DOI: 10.1021/acs.molpharmaceut.5b00624 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics on the rate of drug diffusion out of the hydrophilic polymer. Consequently, polymer characteristics in the GI environment and drug:polymer ratio will determine drug release. The dynamic nature of GI pH and intestinal transit is one of the major constraints in modified release dosage form design. The GI fluids can affect the dynamics of HPMC hydrophilic matrix system hydration and the gel layer formation. For ionizable drugs both the solubility and release from the HPMC layer are pH dependent since HPMC is generally stable over a wide pH rage of 3−11.17 BMS-914392 is a weak base and has high solubility in low pH fluid. Since the drug release rate would have a more profound effect on Cmax than AUC, it is important to maintain a relatively stable release rate through the GI tract to manage the Cmax and reduce the variability in bioavailability. One strategy to mitigate pH-dependent dissolution associated with GI pH variability is to add tablet buffering agents to control the microenvironmental pH at a level that favors consistent drug dissolution. For the prototype 3 formulation citric acid was incorporated to maintain an acidified local pH and influence a pH-independent release profile of BMS-914392 in intestinal fluid.3,17−23 Dissolution of MR Prototypes. An in vitro dissolution method was developed using a USP-3 apparatus to study drug release rates from the prototype formulations. Figures 2a and 2b show the dissolution rate of BMS-914392 for simulated fasted state with different stomach emptying time. Tablets were first exposed to 0.1 N HCl simulated gastric fluid (SGF) for 2 h or 15 min to simulate different stomach emptying time, followed by intestinal buffer for an additional 6 h. The IR tablet was used as the control and released 100% BMS-914392 in less than 15 min (Figure 2a). The enteric coating for prototype 1 effectively protected the core tablets from dissolving in SGF with no measurable release for 2 h. Once transferred into pH 6.8 buffer, the coating began to dissolve in a few minutes to gradually release BMS-914392, reaching ∼15% drug release by 6 h. For the prototype 2 and 3 tablets, the dosage forms hydrated and swelled slowly in the presence of dissolution media, resulting in a significant increase in tablet volume over time (NMR image data not shown). The entrapped BMS914392 was slowly released by combined erosion and diffusion through the viscous HPMC gel layer. Both matrix tablet prototypes showed almost linear release rate in SGF, reaching about 40−50% over 2 h. On transfer to intestinal buffer BMS914392 release slowed down over the next 22 h, reaching a maximum of 70−80%. When gastric emptying time is estimated to be 15 min (Figure 2b), the release rates for IR and prototype 1 tablets were essentially the same with those tablets in SGF for 2 h. Prototype 2 and 3 tablet release rates were much slower in 24 h, 32% and 48% respectively. The lower release rate from the hydrophilic matrix is predominantly from lesser exposure to gastric pH where BMS-914392 is highly soluble and exhibits a greater driving force for diffusion. To represent the famotidine treated gastric environment a pH 5.5 phosphate buffer was used in dissolution experiments for each formulation (Figure 2c). The release of BMS-914392 from prototype 1 and IR tablets is the same in pH 5.5 dissolution media because the enteric coat rapidly dissolves at pH 5.5. BMS-914392 released about 40% and 55% in prototype 2 and 3 tablets. The linear release rate for hydrophilic matrix system suggests a diffusion controlled release mechanism.1,2 Slightly higher release rate in prototype 3 showed that inclusion of citric acid in the tablet can decrease microenvironmental pH and increase BMS-914392 solubility, therefore accelerating the

Figure 2. USP3 dissolution for three different MR prototype tablets and IR tablet in (a) pH 1.2 media for 2 h and then switch to pH 6.8 phosphate buffer; (b) pH 1.2 media for 15 min and then switch to pH 6.8 buffer; (c) pH 5.5 phosphate buffer. In vitro kinetic release data was used as input for controlled release in GastroPlus simulations.

dissolution rate. The addition of citric acid to control microenvironmental pH appears to influence the diffusion rate of BMS-914392 through the matrix HPMC gel layer. In summary, in vitro dissolution confirmed that all three prototypes were capable of slowing drug release and were subsequently tested in dogs for pharmacokinetic performance as well as used to generate GastroPlus simulations of exposure for multiple human physiologies (e.g., fasted, famotidine, fed, etc.). GastroPlus Modeling: Role of Gastric Emptying and Drug Release. For MR formulations, a major challenge is the variability in gastric emptying time, pH, and intestinal transit between individual subjects. Enteric-coated polymers being sensitive to intestinal pH would likely release drug sooner for E

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Figure 3. (a) GastroPlus 3D simulations based on different gastric emptying time: relationship of Cmax and time to release 100% at given gastric emptying time. (b) Relationship of AUC vs time to release 100% drug at given gastric emptying time.

patients with fast gastric emptying or be delayed for those patients with very slow gastric emptying. Therefore, entericcoating strategy as such is likely to exhibit variable PK that hinges on the variability of gastric emptying between patients. To better understand this impact on MR dosage form design, GastroPlus modeling was conducted with a range of gastric emptying time and drug release rates to gauge their impact on Cmax and AUC. A range of release profiles were simulated by assuming that the release of BMS-914392 was directly proportional to the square root of time as per the Higuchi model or faster.24,25 Importing the simulated release profiles into the GastroPlus model demonstrated that drug release times of 4 h are likely to significantly reduce the Cmax. Additionally factoring in gastric emptying provides a surface response plot for simulated exposure shown in Figure 3a. A high Cmax was predicted when gastric emptying time is fast (4 h coupled with slow gastric emptying >1 h offers the best chance of achieving a reduction in Cmax that is >50%. It is also anticipated that the longer release times will reduce the potential variability in the Cmax since the slope of the surface response curve becomes less steep when gastric emptying is longer than 1.5 h. Since BMS914392 exhibits good permeability throughout the GI tract, the AUC∞ was not significantly affected by changes in release time up to 10 h or gastric emptying time up to 2 h. In summary, the model demonstrated that delaying the release of BMS-914392 from the formulation to >4 h can reduce the maximum blood concentration of BMS-914392 to safer levels without compromising overall exposure. Dog Pharmacokinetic Results. Dog PK data was obtained with oral dosing of all three prototype formulations relative to the immediate release formulation in fasted, pentagastrin treated dogs to assess their potential for a MR profile in vivo. Additionally, a GastroPlus model was used to predict the in vivo dog PK results for the four formulations. The measured and simulated PK profiles are shown in Figure 4. The absorption of immediate release tablets was fast with a Tmax of 1 h, and a high Cmax of 1287 ng/mL. The time for absorption more than doubled for all three modified release formulations with Tmax of 2−3 h, and the Cmax significantly lowered (406− 548 ng/mL). The relative bioavailability for prototypes 1, 2,

Figure 4. GastroPlus simulated dog PK results vs actual dog study data for modified release and IR formulations: IR formulation (black solid line vs black circles), prototype 1 EC-IR formulation (black long dashed line vs black squares), prototype 2 hydrophilic matrix formulation (black short dashed line vs blue circles), and prototype 3 acidic hydrophilic matrix formulation (red dashed dotted line vs red diamonds). All formulations were dosed as 60 mg tablets.

and 3 compared to the IR tablet was 67%, 82%, and 35% respectively. To establish the GastroPlus model for dog PK data, several input parameters including physicochemical properties and pharmacokinetic parameters are provided in the Supporting Information. The dissolution profiles from Figure 2a were also used in comparing the 4 formulations. The predicted relative bioavailability was in good agreement with the actual dog pharmacokinetics results for all three MR formulations. All MR prototype formulations effectively lowered Cmax, delayed the time to reach Cmax (Tmax) to 3−4 h, and maintained satisfactory relative bioavailability. Taken together, this exercise showed that the GastroPlus model gives us sufficiently reliable prediction of in vivo performance and can be an effective tool to further optimize release kinetics that can achieve a given target MR product PK profile. The combined use of modeling and simulation as well as in vitro dissolution kinetics leveraged a small set of pharmacokinetic dog data for validation and F

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Figure 5. Human clinical data as mean plasma concentration time profile for each treatment. (a) Arm 1 (fasted): immediate release tablets (red/ circles), prototype 1 (turquoise/triangles), prototype 2 (blue/squares), and prototype 3 (black/diamonds). (b−d) Arm 2 famotidine (red/circles) and untreated fasted (blue/squares) for dosage forms: (b) EC-IR tablets (prototype 1); (c) hydrophilic matrix tablets (prototype 2); (d) acidified hydrophilic matrix tablets (prototype 3).

The clinical PK results of Arm 2 fasted untreated vs famotidine treated patients for the three modified release formulations are shown in Figures 5b−5d. Tables 3 and 4 list

enabled efficient formulation development with limited reliance on routine in vivo animal studies. Human MR Dosage Form Performance. A clinical relative bioavailability study was conducted with the three MR prototypes and compared with the IR tablet. Figure 5a shows the mean PK clinical data for fasted patients (Arm 1). The clinical results demonstrated that all three modified release formulations effectively reduced the plasma Cmax (55−75% reduction) in patients and maintained comparable exposures (Table 3). Prototype 1 (EC-IR) formulation had behavior that

Table 4. Arm 2 Human Clinical PK Summary Data for the Three Prototype Formulations Listed in Table 1 (Materials and Experimental Methods)a treatment prototype 1 (B) prototype 1 + famotidine (E) prototype 2 (C) prototype 2 + famotidine (F) prototype 3 (D) prototype 3 + famotidine (G)

Table 3. Summary Statistics of Key PK Parameters for the Various Arm 1 Prototype Formulationsa treatment IR (A) prototype 1 (B) prototype 2 (C) prototype 3 (D)

Cmax (ng/ mL) 976 445 240 235

(18) (45) (44) (36)

Tmax (h) 1.00 2.00 2.00 1.50

(0.50−1.50) (1.00−12.00) (1.00−24.00) (1.00−3.00)

AUC(0−∞) (ng·h/ mL) 7260 6981 6750 5563

(28) (30) (48) (46)

Cmax (ng/ mL)

Tmax (h)

AUC(0−∞) (ng· h/mL)

555 (64) 774 (30)

4.50 (1.00−5.00) 1.00 (1.00−2.00)

8860 (34) 7368 (25)

180 (32) 134 (29)

1.50 (1.00−24.00) 16.00 (2.00−24.00)

4897 (42) 6825 (41)

292 (44) 219 (31)

1.50 (1.00−24.00) 1.50 (1.00−16.00)

6237 (55) 5841 (32)

a

Estimates provided are geometric means and % CV. Tmax is presented as median (min−max).

a

Estimates provided are geometric means and % CV. Tmax is presented as median (min−max).

the corresponding clinical summary data comparing modified release formulations in the fasted and famotidine physiologies. Prototype 1 (EC-IR) tablets dissolved immediately for the higher stomach pH in famotidine treated patients (E) and provided Cmax and Tmax values similar to fasted patients that received IR tablets. The PK results for enteric-coated tablets (prototype 1) exhibited higher peak concentrations in the presence of famotidine indicating no blunting relative to reference IR Cmax under elevated gastric pH. Therefore, given the pH variability of gastric fluid in patients and sensitivity to comedication with gastric pH-modifying agents, enteric coating may cause faster and more extensive release of BMS-914392.

was not optimal due to variable Tmax (1−12 h) and a high Cmax in some subjects (>1100 ng/mL), presumably due to variable erosion of the enteric coat based on the gastric residence time and pH values of individual subjects. The PK profile of prototype 2 (hydrophilic matrix tablet) appears biphasic with a second absorption phase occurring from approximately 8 to 24 h consistent with good permeability in the lower GI tract. The PK profiles of prototype 3 (acid hydrophilic matrix tablet) provided consistent absorption demonstrated by sustained concentrations from 8 to 24 hours and had lesser variability in Tmax. G

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Molecular Pharmaceutics The risk of adverse events in enteric-coated formulation may be much higher due to patient gastric pH variability and potential dose dumping in subjects with higher resting pH. For prototype 2 hydrophilic matrix tablets, Cmax was slightly lower (∼26% decrease) in famotidine treated subjects (Arm 2) than fasted subjects (Arm 1), but the overall exposure was higher by approximately 50%. A notable delay in Tmax from 1.5 to 16 h was observed with famotidine administration, indicating a shift of absorption to the colon. The acid hydrophilic matrix prototype 3 formulation exhibited the smallest difference in peak and overall exposure in the presence of famotidine. A small (∼15%) decrease in Cmax was observed, but no changes in Tmax or AUC(0−∞) were observed in the presence of famotidine. The consistent Tmax is facilitated by the local pH of the dosage form provided by the citric acid component, which enables a consistent release in the upper GI independent of the gastric pH condition. Overall both hydrophilic matrix tablets provided only slight changes to Cmax and AUC, relative to the EC-IR, in subjects with elevated gastric pH. Therefore, prototypes 2 and 3, based on the hydrophilic matrix technology, were identified as the preferred strategy in formulation development due to observed lower exposure variability and magnitude of pH effect. Since prototype 3 had citric acid as buffer agent in the tablets, it maintains relatively stable pH within the tablet for consistent release of BMS-914392 in different gastrointestinal fluid pH values. Therefore, prototype 3 showed similar Cmax with prototype 2 tablets, but with a consistent upper GI exposure (Cmax and Tmax) and lesser shift to colonic absorption for subjects with high gastric pH. In order to maintain the PK requirement of modified release formulation with consistent release and minimal risk of Cmax related adverse events, prototype 3 was considered the optimal candidate to progress in clinical development. A PK-absorption model (GastroPlus) was also employed to simulate the clinical results. The predicted exposures include all aspects of the pharmacokinetics, absorption distribution, and elimination, as specified by the input model parameters listed in the Supporting Information. Figure 6 shows the simulated exposure of the hydrophilic matrix formulation (prototype 2) in different gastric pH conditions (pH 1.3 and 5.5) with 15 min gastric emptying time. Simulated PK results showed that Tmax

shifted to 12−24 h, indicating that colonic absorption was more significant in patients with elevated gastric pH. Additionally, a slight decrease in Cmax was projected for the hydrophilic matrix tablet for a high gastric pH condition. These simulated PK results (Figure 6) correlated well with actual clinically observed data in Figure 5c. This simulation demonstrated the likely effect of pH, which justified the need to conduct a clinical famotidine study and also steer formulation design toward the incorporation of citric acid excipient in prototype 3 to mitigate this sensitivity to gastric pH. Figure 7 represents simulated PK results for different gastric retention time vs actual clinical data for prototype 2 and 3 formulations. Simulated Cmax and overall exposure were increased for cases of prolonged gastric retention of the tablet (i.e., 2 h). Longer exposure to low pH gastric environment, where BMS-914392 (weak base) is most soluble, increases the drug release and subsequent absorption. The prototype 2 simulations demonstrate a good fit for the observed upper GI absorption phase (∼1−12 h) as well as the elimination phase. However, the biphasic absorption from the colon is slightly underpredicted in the case of gastric retention between 0.25 and 2 h. The colonic absorption phase of the simulation is highly sensitive to amount released at 24 hours in the in vitro USP3 input data (Figure 2a,b) because of the high colonic permeability demonstrated in the SOA study (Figure 1). Slight differences between in vitro and in vivo factors such as motility and hydrodynamics could account for changes to the amount of colonic release and therefore the positive deviation for observed in vivo exposure at ∼24 h. Prototype 3 exhibited faster in vitro release (Figure 2) due to the solubility impact of the acidifying component, and the corresponding simulated PK profile demonstrates good fit to the observed clinical data in Figure 7b. Virtual trial simulations (36 subjects per trial) were conducted under fasted and famotidine conditions to identify performance attributes of the prototype formulations, which could aid in the clinical study design as well as formulation selection. These simulations of virtual populations demonstrated a potential difference in the exposure and variability of the two hydrophilic release prototypes. The prototype 2 hydrophilic matrix had a noticeable decrease in Cmax as well as a large increase in Tmax values for elevated gastric pH conditions as shown in Figure 8. The prototype 2 geometric mean Tmax values in the fasted and famotidine physiologies (treatments C and F) were 1.4 and 9.6 h, respectively. This large Tmax increase reflects a delayed release rate consistent with the decreased Cmax and lesser absorption from the upper GI tract. The acidified prototype 3 formulation had much less exposure sensitivity for equivalent population sets representing fasted and famotidine conditions (treatments D and G). These simulations conveyed the need to evaluate an acidified hydrophilic formulation and the need for a clinical famotidine leg to benchmark in vivo pH sensitivity. The observed results of the clinical trial presented in Tables 3−5 closely agree with shifts in Tmax simulated for prototype 2 (Figure 8). The agreement between the virtual trial simulations (GastroPlus software) and the clinical study results provided additional confidence in the selection of the acidified hydrophilic matrix. The acidified matrix tablet provided a suitable reduction of Cmax over the IR tablet, a consistent early absorption phase, and sustained release that maintained total exposure (AUC(0−∞)).

Figure 6. Simulation of the impact elevated gastric pH has on the exposure for the prototype 2 tablet (hydrophilic matrix tablet, 0.25 h gastric retention). pH conditions for normal fasted (pH = 1.2) and elevated (pH = 5.5) gastric physiologies are represented in dark gray and red, respectively. H

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Molecular Pharmaceutics

Figure 7. Observed plasma concentration−time profiles for Arm 1 shown as open symbols with dashed line for prototype 2 (left plot, blue symbols) and prototype 3 tablet (right plot, blue symbols). Solid lines represent simulated plasma concentration profiles for 0.25 and 2.0 h gastric emptying in black and red, respectively.

Figure 8. Box plot of virtual trial simulations under fasted or famotidine conditions for hydrophilic matrix tablets with and without acidifying component. Values for virtual patients (n = 36) simulated are shown for Cmax and Tmax on left and right, respectively. Box represents the median, 10, 25, 75, 90th % percentile with all outliers shown. Patient populations that receive treatment with hydrophilic matrix (C and F) exhibit a lower Cmax and extended Tmax for the famotidine physiology (F). The acid modulated MR tablet demonstrates greater consistency for fasted and famotidine conditions (D and G) with only minor changes to Cmax and Tmax values.

Table 5. Human PK Cmax and AUC Clinical Data Shown in Ratios of Adjusted Geometric Meansa Arm 1

Arm 2

(ratio of adjusted geometric means)

(ratio of adjusted geometric means)

treatment

Cmax

AUC(0−∞)

treatment

Cmax

AUC(0−∞)

B/A C/A D/A

0.454 (0.362, 0.570) 0.247 (0.202, 0.302) 0.240 (0.197, 0.293)

1.040 (0.902, 1.200) 1.032 (0.888, 1.198) 0.863 (0.729, 1.023)

E/B F/C G/D

1.460 (1.058, 2.014) 0.712 (0.502, 1.010) 0.756 (0.557, 1.025)

0.894 (0.650, 1.229) 1.478 (1.047, 2.087) 0.952 (0.705, 1.286)

a

A−D stand for fasted patients taking IR tablet and prototype 1, 2, and 3 tablets; E−G stand for famotidine treated patients taking prototype 1, 2, and 3 tablets.

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CONCLUSION This study illustrates the utility of a modified-release dosageform approach to circumvent adverse effects associated with an immediate-release dosage form. The case study with BMS914392 highlights a stepwise risk-based development process to understand compound performance attributes in vivo and use this knowledge to design modified-release dosage forms with reduced Cmax, but acceptable bioavailability. An integrated in vitro, in vivo, and in silico strategy was adopted to understand BMS-914392 release from the oral tablet and absorption in the

GI tract. In vitro dissolution was used to identify lead prototypes with different release characteristics. GastroPlus modeling provided guidance on the desired time for complete drug release from the dosage form as well as the implications of gastric emptying and pH on PK performance. Next, animal PK studies were conducted to confirm that the PK parameters were achieving expected outcomes. Finally, clinical PK results along with GastroPlus modeling revealed the success of the strategy and provided useful insight into the mechanism behind MR I

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(4) Arisco, A. M.; Brantly, E. K.; Kraus, S. R. Oxybutynin extended release for the management of overactive bladder: a clinical review. Drug Des., Dev. Ther. 2009, 3, 151−61. (5) Cainazzo, M. M.; Pinetti, D.; Savino, G.; Bartiromo, M.; Forgione, A.; Bertolini, A. Pharmacokinetics of a new extended-release nifedipine formulation following a single oral dose, in human volunteers. Drugs Exp. Clin. Res. 2005, 31 (3), 115−21. (6) Goldenberg, M. M. An extended-release formulation of oxybutynin chloride for the treatment of overactive urinary bladder. Clin. Ther. 1999, 21 (4), 634−42. (7) Brown, J.; Chien, C.; Timmins, P.; Dennis, A.; Doll, W.; Sandefer, E.; Page, R.; Nettles, R. E.; Zhu, L.; Grasela, D. Compartmental absorption modeling and site of absorption studies to determine feasibility of an extended-release formulation of an HIV-1 attachment inhibitor phosphate ester prodrug. J. Pharm. Sci. 2013, 102 (6), 1742− 51. (8) Gupta, E. K.; Ito, M. K. Lovastatin and extended-release niacin combination product: the first drug combination for the management of hyperlipidemia. Heart Dis. 2002, 4 (2), 124−37. (9) Nicholson, S. J.; Timmins, P.; Dockens, R. C.; Connor, A.; Croop, R.; Ferrie, P.; Zeng, J.; Dennis, A. B.; Wilding, I. Development of oral extended release formulations of 6-hydroxybuspirone. Biopharm. Biopharm. Drug Dispos. 2012, 33 (9), 522−35. (10) Silver, N.; Sandage, B.; Sabounjian, L.; Schwiderski, U.; Shipley, J.; Harnett, M. Pharmacokinetics of once-daily trospium chloride 60 mg extended release and twice-daily trospium chloride 20 mg in healthy adults. J. Clin. Pharmacol. 2010, 50 (2), 143−50. (11) Timmins, P.; Brown, J.; Meanwell, N. A.; Hanna, G. J.; Zhu, L.; Kadow, J. F. Enabled clinical use of an HIV-1 attachment inhibitor through drug delivery. Drug Discovery Today 2014, 19, 1288−1293. (12) Dobrev, D.; Carlsson, L.; Nattel, S. Novel molecular targets for atrial fibrillation therapy. Nat. Rev. Drug Discovery 2012, 11 (4), 275− 91. (13) Machida, T.; Hashimoto, N.; Kuwahara, I.; Ogino, Y.; Matsuura, J.; Yamamoto, W.; Itano, Y.; Zamma, A.; Matsumoto, R.; Kamon, J.; Kobayashi, T.; Ishiwata, N.; Yamashita, T.; Ogura, T.; Nakaya, H. Effects of a highly selective acetylcholine-activated K+ channel blocker on experimental atrial fibrillation. Circ. Circ.: Arrhythmia Electrophysiol. 2011, 4 (1), 94−102. (14) Podd, S.; N, F.; Large, J.; Nyland, K.; D, O. C.; E, A.; Firniss, S.; Sulke, N. M. In The first clinical trial of a specific IKACh blocker (BMS914392) in patients with paroxysmal AF using continuous permanent pacemaker holters to assess efficacy; European Cardiac Arrhythmia Society ECAS: Munich, Germany, 2014; pp 20−11. (15) Sulke, N. M. In The first in patient trial of a specific I,KACh blocker: A Pacemaker Holter Study of BMS914392 in paced patients with paroxysmal AF; Heart Rhythm On Demand, May 8, 2014; p 6495. (16) Nokhodchi, A.; Raja, S.; Patel, P.; Asare-Addo, K. The role of oral controlled release matrix tablets in drug delivery systems. BioImpacts 2012, 2 (4), 175−87. (17) Bettini, R.; Colombo, P.; Peppas, N. A. Solubility effects on drug transport through pH-sensitive, swelling-controlled release systems: Transport of theophylline and metoclopramide monohydrochloride. J. Controlled Release 1995, 37 (1−2), 105−111. (18) Majid Khan, G.; Zhu, J. B. Studies on drug release kinetics from ibuprofen-carbomer hydrophilic matrix tablets: Influence of coexcipients on release rate of the drug. J. Controlled Release 1999, 57 (2), 197−203. (19) Cameron, C. G.; McGinity, J. W. Controlled-release theophylline tablet formulations containing acrylic resins, III. Influence of filler excipient. Drug Dev. Ind. Pharm. 1987, 13 (2), 303−318. (20) Gabr, K. E. Effect of organic acids on the release patterns of weakly basic drugs from inert sustained release matrix tablets. Eur. J. Pharm. Biopharm. 1992, 38 (6), 199−202. (21) Hodsdon, A. C.; Mitchell, J. R.; Davies, M. C.; Melia, C. D. Structure and behaviour in hydrophilic matrix sustained release dosage forms: 3. The influence of pH on the sustained-release performance and internal gel structure of sodium alginate matrices. J. Controlled Release 1995, 33 (1), 143−152.

BMS-914392 performance and impact of gastric pH and patient variability on the overall pharmacokinetic profile. As BMS-914392 was well absorbed throughout the GI tract, both the hydrophilic matrix tablet and enteric-coated tablet strategy are viable options to blunt Cmax. However, hydrophilic matrix tablets may be a preferred approach to steer clear of high variability of Cmax and Tmax afforded by the enteric-coating strategy that can be compromised by gastric pH-elevating medication. Controlling the microenvironment pH in hydrophilic matrix tablets offered a clear advantage for BMS-914392. A consistent PK profile was observed for the acidified matrix tablet administered in fasted and famotidine treated conditions. Taken together, the design of a MR dosage form was successfully demonstrated with BMS-914392. Learnings from each of the in vitro, in vivo, in silico, and clinical studies were effectively used to optimize development of a commercially viable dosage form.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.5b00624.

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Parameters for the PK absorption model (PDF)

AUTHOR INFORMATION

Corresponding Author

*1 Squibb Drive, 109-2C-56, New Brunswick, NJ 08903. Tel: 732-227-6284. Fax: 732-227-5150. E-mail: david.good2@bms. com. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was fully financed by Bristol-Myers Squibb. The developments presented in this manuscript directly resulted from collaborations with Nissan Chemical Industries, Ltd. (Tokyo, Japan) and Teijin Pharmaceutical (Tokyo, Japan) for the drug substance and drug product, respectively. The site of absorption study was directed and financed by Bristol-Myers Squibb and executed by Scintipharma Inc. as a contract research organization. The authors gratefully acknowledge the research contributions made by Scintipharma Inc. including specific discussions and analysis provided by Erik Sandefer and Water Doll. This work also benefited from the many contributions of Bristol-Myers Squibb colleagues and leaders from Drug Product Science and Technology, Exploratory Clinical and Translational Research, and Analytical and Bioanalytical Development. The authors specifically recognized the advancements made possible by Thomas Raglione, Feng Qian, Thomas Hooker, Fraz Ismat, and Paul Levesque.

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REFERENCES

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K

DOI: 10.1021/acs.molpharmaceut.5b00624 Mol. Pharmaceutics XXXX, XXX, XXX−XXX