WO2018013771A1 - Treatment of pain using hydrocodone formulations - Google Patents

Abstract

Extended release, abuse deterrent dosage forms in which the active ingredient consists essentially of hydrocodone are disclosed, wherein administration of the dosage form to a subject in at least one dose per day over multiple days does not produce a therapeutically significant effect on one or more pharmacokinetic parameters following a first dose or at steady state. Methods of treating pain using such dosage forms are also provided.

Description

TREATMENT OF PAIN USING HYDROCODONE FORMULATIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority to U.S. Provisional App. No. 62/362,017, filed July 13, 2017, the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD

[0002] The present disclosure relates to treatment of pain using opioid analgesics.

BACKGROUND

[0003] Hydrocodone is the most commonly prescribed opioid in the United States (IMS Institute for Healthcare Informatics, 2011), where, until recently, it was available only as an immediate-release (IR) formulation in combination with other nonopioid analgesics such as acetaminophen and ibuprofen (The American Society of Health- System Pharmacists, 2011). Key limitations associated with the use of hydrocodone combination products include the toxicity profile of the nonopiod analgesic (acetaminophen-induced liver toxicity and gastrointestinal, renal, and cardiovascular complications associated with ibuprofen) (Barkin, 2001) and restrictions to dose titration due to the dosage ceiling of the nonopiod analgesic (American Pain Society, 2012). Extended-release (ER) opioid formulations, which can be administered once or twice daily, offer several advantages over IR formulations that require administration every 4 to 6 hours, including smaller fluctuations in peak-to-trough plasma concentrations, which may lead to more consistent control of pain (Beaulieu, 2007), and decreased dosing frequency, which potentially can improve adherence (Argoff, 2009; Beaulieu, 2007; McCarberg, 2001). However, opioids have the potential to be abused when the tablets are ingested or when they are manipulated to increase the rate of opioid release (Argoff, 2009; Larochelle, 2015). As a result, newer ER opioid formulations are being developed with properties that potentially make them less attractive to abusers (Larochelle, 2015).

[0004] A single-agent (i.e., acetaminophen- and ibuprofen-free) ER hydrocodone bitartrate formulation (Teva Branded Pharmaceutical Products R & D, Inc., Frazer, PA) was developed to provide sustained pain relief with doses of up to 90 mg twice daily (Darwish, 2015). This hydrocodone ER formulation employs CIMA® Abuse-Deterrence Technology (ADT; CIMA LABS, Inc., Brooklyn Park, MN), a platform that is intended to hinder rapid release of hydrocodone when tablets are comminuted (i.e., broken into small pieces by crushing, milling, grating, or grinding) and to prevent dose dumping if the tablets are taken with alcohol (CIMA LABS Inc., 2012). In a placebo-controlled clinical trial of hydrocodone ER, patients with moderate to severe chronic low back pain identified an analgesic dose (30, 45, 60, or 90 mg every 12 hours) in an open-label titration period and were treated with the identified dose in a 12-week double-blind treatment period. At the end of the 12 weeks, patients receiving hydrocodone ER experienced significantly greater reductions in pain intensity than patients receiving placebo (Hale, 2015).

[0005] Food intake can alter the pharmacokinetics of certain medications and lead to variability in drug bioavailability by altering gastric pH, modifying absorption, delaying gastric emptying, and/or physically or chemically interacting with the formulation/drug substance (Charman, 1997; Singh, 1999).

[0006] Two randomized, open-label studies assessed the pharmacokinetics of single and multiple doses of hydrocodone extended-release (ER) formulated with CFMA^® Abuse- Deterrence Technology. Other dosage forms that may be used in accordance with the presently disclosed methods include those disclosed in U.S. Pat. No. 9,216, 176, the entire contents of which are incorporated herein by reference. Healthy subjects in the fed and fasted states received single 90-mg doses of hydrocodone ER (Study 1 and 2) or multiple doses of hydrocodone ER titrated to 180 mg/day on days 2-5 followed by maintenance at this dose on days 6-11 (Study 2). Naltrexone was administered to minimize opioid-related adverse events. Pharmacokinetic parameters included maximum hydrocodone plasma concentration (C_max) and area under the concentration-vs.-time curve from 0 to infinity (AUC₀._∞) in Study 1 (day 1) and for one dosing interval at steady state (AUC_YSS) in Study 2 (day 11). Results indicated that the single-dose Cma_X was 40% higher under fed vs. fasted conditions (least squares mean ratio [90% CI]: 1.40 [1.31, 1.51]; Study 1), while overall exposure was relatively similar (AUCo-_∞: 1.11 [1.06-1.16]). Prior to conducting the multiple-dose study, fitting of single-dose data with a population pharmacokinetic methodology predicted that the effect of food would be much less at steady state (predicted fed:fasted steady-state C_maxss and AUCn_ss ratio of 1.18 and 1.09, respectively). Results from the multiple-dose study validated these predicted ratios and indicated that the steady-state 90% CIs were within 0.80-1.25 for the fed:fasted C_MXSS (1 14 [1.07-1.21]) and AUCy_ss (1.11 [1.04-1.17]) parameters, indicating that clinically meaningful food effects at steady state are not expected. Hydrocodone ER was generally well tolerated by naltrexone- blocked subjects in the fed and fasted state.

SUMMARY

[0007] Provided are extended release, abuse deterrent dosage forms in which the active ingredient consists essentially of hydrocodone, wherein administration of the dosage form to a subject in at least one dose per day over multiple days does not produce a therapeutically significant effect on one or more pharmacokinetic parameters following a first dose or at steady state.

[0008] Also provided are methods of treating pain in a subject comprising

administering to the subject at least one dose per day over multiple days of an extended release, abuse deterrent dosage form in which the active ingredient consists essentially of hydrocodone, wherein the administration does not produce a therapeutically significant effect on one or more pharmacokinetic parameters following a first dose or at steady state.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1. Subject disposition. ER=extended release.

[0010] FIG. 2. Mean (+SD) plasma hydrocodone concentration through 72 hours and 12 hours (inset) after administration of a single dose of hydrocodone ER 90 mg in fed or fasted healthy subjects in Study 1 : pharmacokinetic analysis set.

[0011] FIG. 3. Mean (+SD) plasma hydrocodone concentration (single dose [day 1]; steady state [day 11]) after administration of hydrocodone ER 90 mg bid in fed or fasted healthy subjects in Study 2: pharmacokinetic analysis set. [0012] FIG. 4. Fitted hydrocodone concentrations at single dose (a) and predicted hydrocodone concentrations at steady state (b) under fed and fasted conditions.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0013] In accordance with FDA guidance (US Food and Drug Administration, 2002), the effect of food on the single-dose pharmacokinetics of hydrocodone ER formulated with CIMA^® ADT (Darwish, 2012) was assessed.

[0014] However, given that hydrocodone ER would be administered for chronic pain, the effect of food at steady state was of interest as well because it may better reflect conditions encountered in clinical use where it was hypothesized that observed differences in maximum plasma hydrocodone concentration (C_max) would be smaller. To better predict the reason for the food effect after a single dose and to predict what it might be at steady state, data from the single-dose studies (15 and 90 mg) of hydrocodone ER formulated with CIMA* ADT were fitted using a population pharmacokinetic methodology. The final model that best characterized the data was used to predict the effect of food on the pharmacokinetics of hydrocodone ER at steady state. A multiple-dose study was then conducted to validate these predictions and assess the effect of food on the pharmacokinetics at steady state of hydrocodone ER at the highest dose strength (90 mg).

Materials and Methods

Single- and Multiple-Dose Studies

[0015] Two randomized, single-center, open-label, crossover studies were conducted to assess the effect of food on the pharmacokinetics of single and multiple doses of hydrocodone ER 90 mg in healthy subjects receiving naltrexone to block opioid receptors and minimize opi oid-r elated adverse events (AEs). Both studies were approved by institutional review boards and conducted in full accordance with the Good Clinical Practice: Consolidated Guidelines approved by the International Conference on Harmonisation (International Conference on Harmonisation Working Group, 1996). Written informed consent was obtained from all subjects prior to participation in either study.

Subjects

[0016] Healthy men and women aged 18-45 years with body mass indices of 20-30 kg/m² were eligible for participation. Women were required to be surgically sterile, 2 years postmenopausal, or using a medically acceptable method of contraception during the study and for 30 days thereafter.

[0017] Key exclusion criteria included any clinically significant uncontrolled medical condition; any disorder that would interfere with absorption, distribution, metabolism, or excretion; a history of drug or alcohol abuse or habitual consumption of >21 units of alcohol per week; or clinically significant abnormalities in laboratory, electrocardiogram (ECG), or physical examination findings. Subjects were also excluded if they had used nicotine products within 12 months or topical or oral nicotine cessation products within 3 months of the first dose of hydrocodone ER or were poor metabolizers via CYP2D6.

Study Design

[0018] In both studies, subjects were administered hydrocodone ER with 240 mL of water approximately 30 minutes after ingesting an FDA-defined standard high-fat and high- calorie meal (fat being approximately 50% of total caloric content of the meal) (US Food and Drug Administration, 2002) and after an overnight fast of approximately 10 hours on the morning of day 1 (single- and multiple-dose studies) and 11 (multiple-dose study only). During the multiple-dose study, subjects were administered hydrocodone ER on an empty stomach on the mornings of days 2-7 and evenings of days 2-6 and after a minimum 4-hour fast on the mornings of days 8-10 and evenings of days 7-10, whereas subjects in the fed state were administered hydrocodone ER approximately 30 minutes after ingesting a meal in the mornings and evenings of days 2-10. In both studies, the fed and fasted sequences were separated by a washout of >14 days.

[0019] In the single-dose study, participants were randomized to three treatment sequences in which a single 90-mg dose of hydrocodone ER was administered as two 45-mg tablets on day 1. In the multiple-dose study, participants were randomized to two 12-day treatment sequences in which hydrocodone ER was administered as a single 90-mg dose on the morning of day 1, followed by 45 mg twice daily on days 2-3, 60 mg twice daily on days 4-5, 90 mg twice daily on days 6-10, and 90 mg once on the morning on day 1 1.

[0020] Throughout each study, subjects were administered naltrexone to block opioid receptors and minimize opioid-related AEs. Subjects were administered naltrexone every 12 hours beginning at 15 hours before the first dose and continuing through 21 hours after each hydrocodone ER dose in the single-dose study and 33 hours after the last dose of hydrocodone ER in each period in the multiple-dose study,

[0021] Venous blood samples (3 mL) were collected for pharmacokinetic analyses within approximately 5 minutes before dosing and at various time points after dosing for 72 hours (single-dose study) or for the intended 12-hour dosing interval on days 1 and 1 1 (multiple- dose study).

Bioanalytical Method

[0022] Blood samples were collected in tubes containing K₂EDTA as an anticoagulant and centrifuged (1500 g, -15 min at 4°C) within 1 hour after collection. For each sample, plasma was transferred to polypropylene tubes and stored in an upright position at approximately -25°C until shipped from the study center to PPD (Richmond, VA, USA) for bioanalysis.

Concentrations of hydrocodone and the active metabolite, hydromorphone, were determined using a validated high-performance liquid chromatography method with tandem mass spectrometric detection. The validated quantifiable range of the assay was 0.100 to 100 ng/mL for hydrocodone and 0.0500 to 50 ng/mL for hydromorphone.

Pharmacokinetic Measures

[0023] Pharmacokinetic parameters for hydrocodone and hydromorphone in plasma were determined by noncompartmental methods using the validated WinNonlin^® software (Enterprise Version 5.1.1, Pharsight Corporation, Mountain View, CA, USA, 2006) and the Pharsight Knowledgebase Server (PKS, version 3.1).

[0024] In the single-dose study, the pharmacokinetic parameters assessed included the Cniax, the time to Cmax (tmax), the apparent terminal half-life (tv₂), and the area under the plasma concentration -time curve (AUC) from time 0 to infinity (AUC₀._∞). The percentage extrapolation was also calculated as (AUC₀._∞ - AUC₀-t)/AUC₀._∞ ^x 100, where AUC₀._t represents AUC from time 0 to the time of the last quantifiabl e concentration. In the mul tiple-dose study, C_inax, t_inax, and AUC from 0 to 12 hours (AUCo-12) for single-dose administration (day 1) and AUC for one dosing interval (AUC_XSS) on day 1 1 for multiple-dose administration at steady state were calculated. Additionally, the observed accumulation ratio (R₀bs) was calculated as AUC_XSS (day

Safety and Tolerability

[0025] Safety and tolerability were assessed by evaluating AEs, clinical laboratory data, 12-lead ECG data, physical examination findings, vital signs (i.e., pulse, blood pressure, and respiratory rate), oxyhemoglobin saturation monitoring (Sp0₂), and concomitant

medications.

Statistical A nalysis

[0026] The safety analysis sets in both studies included all subjects who received >1 dose of hydrocodone ER. In the single-dose study, the pharmacokinetic analysis set included all subjects in the safety analysis set who had sufficient data to calculate pharmacokinetic parameters, and in the multiple-dose study, the pharmacokinetic analysis set included all subjects in the safety analysis set who had sufficient data to calculate Cmaxss and AUC_XSS (day 11) for both administration sequences.

[0027] The natural log-transformed values of C_max and AUC for the fed and fasted states were compared statistically using a linear mixed-effect model, which included treatment, regimen sequence, and period as fixed effects and subject nested within the sequence as a random effect. The fed:fasted ratio and corresponding 2-sided 90% confidence intervals (CIs) of geometric least squares means (LSM) were calculated. Per industry guidelines, the default bioequivalence criteria were used to determine the effects of food on the pharmacokinetics of hydrocodone ER. If the 90% CIs for the ratio of LSMs of hydrocodone and AUC fell completely within the limits of 0.80 to 1.25 for both parameters, no clinically significant effect of food on the pharmacokinetics of hydrocodone ER was to be concluded (US Food and Drug Administration, 2002).

Fitting of Single-Dose Data and Predictions of Steady-State

[0028] Before the conduct of the actual multiple-dose study, single-dose data were analyzed carefully, first to understand the potential reason(s) for the apparent Cma_x difference after the first dose and then to predict the expected food effect on both Cmaxss and AUC_XSS after multiple-dose administrations. Fed and fasted hydrocodone and hydromorphone data from two single-dose studies of hydrocodone ER (1 study with 15 mg and 1 study with 2 x 45 mg) were fitted using a population pharmacokinetic methodology and the final model was then applied to predict steady-state hydrocodone and hydromorphone concentrations under fed and fasted conditions. [0029] Using ADAPT 5 (Biomedical Simulations Resource, Los Angeles, CA) (D'Argenio, 2009), multiple pharmacokinetic compartmental models were constructed and discriminated between themselves first with standard two-stage analyses and then with the iterative two-stage method. Using the final developed fed and fasted pharmacokinetic model, Monte Carlo simulations were performed where 1 x 1 5 mg or 2 x 45 mg hydrocodone were administered to 1000 subjects at doses of 15 or 90 mg twice daily for a total of 1 1 doses, with the last dose being given on the sixth day (e.g., at steady state). Simulations were conducted under both fed and fasted conditions to allow comparison of expected concentration-time profiles and pharmacokinetic parameters. Concentrations were simulated by the model, the

noncompartmentally derived parameters C_inaxss and AUC_Qss for each simulated subject were determined, and a fed:fasted natural log-transformed ratio was obtained for each

pharmacokinetic parameter of interest. In addition, 40 different studies, each containing 25 subjects, were simulated to estimate the average expected 90% CI for each parameter.

Results

Subjects

[0030] In the single-dose study, 40 subjects were randomized, received study medication and were included in the safety analysis set; 36 subjects were included in the pharmacokinetic analysis set; and 35 completed the study (Figure 1). The majority of subjects were male (75%) and white (65%) with a median age of 28.5 (range, 19-44) years and a median body mass index of 25.8 (range, 21.5-30.0) kg/m². In the multiple-dose study, 43 subjects were randomized, received >1 dose of study medication, and were included in the safety analysis set; 30 (69.8%)) subjects completed the study and were included in the pharmacokinetic analysis set (Figure 1). The majority of subjects were also male (56%) and white (58%) with a median age of 32.0 (range, 19-42) years and a median body mass index of 25.7 (range, 20.3-30.0) kg/m². Pharmacokinetics

[0031] The noncompartmental pharmacokinetic parameters of single-dose hydrocodone ER 90 mg under fed and fasted conditions are summarized in Table 1.

Table 1. Mean (SD) Pharmacokinetic parameters of single- and multiple-dose hydrocodone ER 90 mg in fed and fasted states: pharmacokinetic analysis set

Parameter, Study 1: Study 2: Study 2: Mean (SD) Single Dose Single Dose Multiple Dose

Fed Fasted Fed Fasted Fed Fasted

(n=35) (n=36) (n=30) (n=30) (n=30) (n=30)

Cmax, ng/mL 66.9 49.7 131.2 1 15.2

86, 1 (22,7) 60.6 (14.5)

(16.5) (12.2) (35.9) (31.9) tmax, hours* 9.0 (6.0- 8.0 (5.0- 6.0 (5.0- 9.0 (6.0- 6.0 (0.0- 6.0 (0.5-

12.0) 10.0) 12.0) 12.0) 8.0) 9.0)

AUG^1', 1205

1262 (269) 1 135 (275) 489 (97) 398 (97) 1334 (355)

ng-hr/mL (329)

Extrapolation,

0.5 (0.5) 0.8 (0.7) ND ND ND ND % t_½, hours 9.4 (2,7) 10.0 (3.7) ND ND ND ND

Robs* NA NA NA NA 2.7 (0.5) 3.1 (0.7)

* Median (range).

^TAUCo for study 1, AUCo-12 for study 2 single-dose, and AUC_D for study 2 multiple-dose.

Calculated as AUC_D (day 11, period 2)/AUCo-i2 (day 1 , period 1).

ER=^:extended release; SD=standard deviation; C,„_3x=^:maximum observed plasma hydrocodone concentration; t_raax=time to maximum observed plasma hydrocodone concentration; AUCo-,»=area under the plasma hydrocodone concentration-vs.-time curve from time O to infinity; AUC_x=area under the plasma hydrocodone concentration-vs.-time curve for 1 dosing interval (day 11) of multiple-dose regimen; extrapolation: (AUCo-∞ - AUCo-t)/AUCo-» ^x 1 0; ND=not determined; ^elimination half-life;

accumulation ratio; NA=not applicable.

[0032] The shape of the concentration-vs.-time profile after a single dose of hydrocodone ER appeared to be relatively similar in the fed and fasted states (Figure 2), but mean plasma concentrations were lower in the fed vs. fasted state during the first 4 hours and were then higher until 24 hours. The 90% CIs of the fed:fasted ratios for hydrocodone C_max did not fall within the 0.80-1.25 range; the ratio was approximately 40% higher under fed conditions than after fasting. The 90% CI for the LSM ratio for day 1 AUCo-_∞ was within the range of 0.80- 1.25 (Table 2), suggesting an absence of a food effect on the overall systemic exposure. Table 2. Comparative bioavailability of single- and multiple-dose hydrocodone ER 90 mg in fed and fasted states: pharmacokinetic analysis set

* Ratio is the geometric means ratio of the fed to fasted states.

ER=extended release; LS =ieast squares; CI=^:confidence interval; C_max=maximum observed plasma hydrocodone concentration; AUC₀-_∞=area under the plasma hydrocodone concentration-vs.-time curve from time 0 to infinity; AUCo-^area under the plasma hydrocodone concentration-vs.-time curve from 0 to 12 hours; AUC_x=area under the plasma hydrocodone concentration-vs.-time curve for 1 dosing interval (day 1 1) of multiple-dose regimen.

[0033] The present single-dose data were carefully evaluated so that the difference in Cmax could be better understood, and the effect of food on hydrocodone ER pharmacokinetics at steady state were then simulated to determine if the C_max difference seen after single-dose administration would likely be observed at steady state. The final model was a two-compartment model for both hydrocodone and hydromorphone with linear absorption, metabolism, and elimination characteristics, but where the absorption was characterized by multiple distinct absorption peaks representing fast, medium, and slow absorption processes. The final model fit of observed vs. predicted concentration is presented in Figure 4. The higher C_max ratio was partially explained by the 11% apparent higher overall bioavailability of hydrocodone under fed conditions (e.g., the fed:fasted ratio for AUCo- ), but the remaining 29% apparent difference was attributed by the model to a differential effect of food on the absorption processes of

hydrocodone ER. Under fed conditions, 10%, 20%, and 70% of the bioavailable doses were absorbed via the fast, medium and slow absorption processes, respectively, while under fasted conditions, 10%, 0%, and 90% of the bioavailable doses were absorbed through them. The slower absorption peak obviously did not influence the Cmax after the single dose but would influence the Cma_X seen after multiple doses. After repeated dosing, the influence of the slower absorption rate constant on any subsequent Cmax becomes more significant because of accumulation (i.e., the slower absorption rate under fasted conditions causes a proportion of the dose to be absorbed at a later time than under fed conditions, thereby contributing to overall concentrations that increase with subsequent doses until steady-state is attained). Therefore, the Cmax under fasted conditions increases more than the C_max under fed conditions with every subsequent dose until steady state, and the difference between C_max values (fed vs. fasted) at steady state becomes less pronounced than after a single dose. This simulation then predicted a reduced food effect with multiple vs. single doses with the expected Cmax at steady state for fed regimen still being higher than for the fasted regimen (simulation at steady state is presented in Figure 4), but only by 18% instead of 40%. The model also predicted that steady-state overall hydrocodone exposure (AUC_XSS) would be similar to what was seen after single dose (AUC₀._∞), a non-clinically significant 9% increase under fed vs. fasted conditions (Table 2).

[0034] The multiple-dose study confirmed the results of the steady-state predictions. The 90% CIs for the LSM ratios for day 1 1 Cmaxss and AUC_XSS were fully within the 0.80-1 .25 range (Table 2), suggesting no clinically meaningful difference in steady-state maximum and total exposure between the fed and fasted states. The Robs estimates for accumulation of the AUC_X from the single to the multiple-dose arms were comparable between the fed and fasted states, albeit slightly higher for the fasted regimen (3 , 1 vs. 2,7) (Table 1). The shapes of the concentration-vs.-time profiles after multiple doses of hydrocodone ER appeared to be qualitatively similar in the fed and fasted states (Figure 3). [0035] In both the single- and multiple-dose studies, the shapes of the plasma concentration-vs.-time profiles of the active metabolite, hydromorphone, were similar to the corresponding profiles of hydrocodone (data not shown). The concentrations of hydromorphone were approximately 2 orders of magnitude lower than those of the parent compound.

Safety and Tolerability

[0036] All subjects in both studies received naltrexone to minimize opioid-r elated adverse events. No serious AEs or deaths were reported in either study. In the single-dose study, one subject discontinued because of vomiting after receiving hydrocodone ER 90 mg in the fed state. In the multiple-dose study, nine subjects discontinued because of AEs; vomiting was the most common AE leading to discontinuation (fed: n=7; fasted: n=l). According to study protocol, subjects were to be discontinued if vomiting occurred at any time after receiving study medication because of the potential effect on meeting the study's objectives.

[0037] The incidence of AEs was higher in the fed vs. the fasted state in the single-dose study (6 [16%] vs. 3 [8%], respectively) but was relatively similar in the fed vs. fasted state in the multiple-dose study (21 [54%] vs. 19 [51%], respectively). AEs occurring in >10% of patients in the fed or fasted state in either study are presented in Table 3.

Table 3. Adverse events occurring in >10% of subjects in the fed and fasted states in either study: safety analysis set

Study 1: Single Dose Study 2: Multiple Dose

Adverse Event, Fasted Fed Fasted Fed n (%) (n=37) (n=37) (n=37) (n=39)

Subjects with >\ 6 (16) 3 (8) 19 (51 ) 21 (54) adverse event

Infrequent bowel 1 (3) 0 8 (22) 6 (15) movements

Nausea 1 (3) 1 (3) 4 (11) 7 (18)

Vomiting 1 (3) 1 (3) 1 (3) 7 (18)

Constipation 0 0 5 (14) 1 (3) Headache 1 (3) 0 5 (14) 7 (18)

Dizziness 4 (11) 1 (3) 2 (5) 3 (8)

[0038] The most frequent AEs observed in the single-dose study was dizziness (4

[11%]) in the fasted state and nausea, vomiting, and dizziness in the fed state (1 [3%>] each). With multiple doses, infrequent bowel movement (7 [19%>]) and constipation (5 [14%>]) were the most common AEs in the fasted state, and in the fed state infrequent bowel movements (6

[15%o]), vomiting (4 [10%>]), and headache (4 [10%>]) were the most common AEs. All AEs were mild or moderate in severity. AEs considered to be treatment-related by the investigator were reported in 2 (5%>) subjects in the fed state and 4 (11%>) subjects in the fasted state in the single- dose study. Treatment-related AEs were reported in 19 (49%>) subjects in the fed state and 13 (35%) subjects in the fasted state in the multiple-dose study.

[0039] In the single-dose study, no overall clinically meaningful changes in clinical laboratory variables, ECG or physical examination findings, or Sp0₂ measurements were observed. Decreases in systolic (<85 mm Hg and decrease >20 mm Hg) and diastolic (<40 mm Hg and decrease >15 mm Hg) blood pressure and respiratory rate (<10 breaths/minute) were reported, occurring at comparable rates both before and after administration of hydrocodone ER. These changes were not associated with any clinical symptoms and were not likely clinically meaningful. No correlation was detected between these events and plasma hydrocodone concentrations. Respiratory rates were within the range of normal resting respiratory rates for healthy subjects. No decreases in respiratory rate or blood pressure were reported as AEs.

[0040] In the multiple-dose study, approximately three quarters of subjects in both the fed and fasted states had changes in vital signs that were potentially clinically significant based on normal ranges. The most frequent changes in vital signs were respiratory rate <10

breaths/minute (fed: 22 [56%>]; fasted: 22 [60%>]) and systolic blood pressure <85 mm Hg and decrease >20 mm Hg (fed: 10 [26%>]; fasted: 12 [32%>]). No clinically meaningful trends in vital signs were detected between the fed and fasted states. The observed changes in clinical laboratory variables, ECG or physical examination findings, vital signs, and Sp0₂ measurements were not thought to be clinically relevant. [0041] As noted above, food intake can affect the bioavailability of drugs through a number of mechanisms, including physical or chemical interactions that promote or interfere with the disintegration of the drug formulation (Fleisher, 1999), Therefore, the FDA requires food-effect studies be conducted. The potential impact of food is particularly important for ER formulations, which are designed to provide controlled dmg release over time and thus have a higher drug content than JR formulations. Dose dumping, which can produce high systemic drug concentrations and possible toxicity, is a potential concern for any ER formulation (Fleisher, 1999) and is particularly critical for opioids. Although the FDA generally requires that the food effect assessment be performed after single-dose administration only, it may be meaningful clinically to determine the effects of food on steady-state pharmacokinetics with ER opioid formulations as they are administered chronically. The high-fat, high-calorie meal used in typical food-effect studies is also an extreme-case scenario relative to the fasted condition and it is understood that it does not necessarily represent a typical meal consumed by actual patients; so the results observed in these food-effect studies may exaggerate those that would be observed during real-world patient use.

[0042] The findings reported herein demonstrate that the C_G!ax was increased by approximately 40% after single-dose administration of hydrocodone ER 90 mg with food, no clinically relevant effect (~+10%) was seen on the overall exposure between fed and fasted conditions. Despite the higher

the mean plasma concentrations were lower in the fed vs. fasted state for a short period of time (4 hours) after single-dose administration and the shapes of the plasma concentration-vs.-time curves and taiax were comparable between the fed and fasted states, indicating that the ER characteristics of hydrocodone ER were maintained and that dose dumping did not occur when the medication was administered with food.

[0043] Steady-state simulations of hydrocodone concentrations under fed and fasted multiple-dose conditions predicted that food would have a much less pronounced effect on Cmax at steady state than after single-dose administration. Careful fitting and characterization of the single-dose data under fed and fasted conditions suggested that the high observed single-dose fed:fasted hydrocodone C_inax ratio was due mostly to a greater proportion of the bioavailable dose (approximately 20%) being absorbed with a faster absorption rate constant under the fed regimen, while under fasted conditions, this 20% of the bioavailable dose was absorbed very slowly. This difference between fed and fasted conditions after the single dose was then predicted by the model to decrease with every subsequent administration of hydrocodone ER and disappear at steady state, as the 20% late absorption under fasted conditions would lead to a slightly greater accumulation on the Cma_x than under fed conditions. This slower absorption can be observed in the single-dose profile presented in Figure 2, where higher concentrations for the fasted profile are observed after 24 hours. This hypothesis is also consistent with the observation that the overall exposure of hydrocodone ER is clinically similar (AUC₀._∞ ratio of 1.11) between fed and fasted conditions after single-dose administration. Thus, the overall dose that reaches the systemic circulation from the fed regimen was observed to be only 11% higher than that seen with the single-dose regimen under fasted conditions. This 11% difference in bioavailability will also be present at steady state owing to the linear characteristics of the drug (i.e., AUC₀._∞ ratio after a single-dose will be similar to the AUC₀._[C ratio at steady state).

[0044] The multiple-dose study indicated that the fed:fasted overall exposure ratio was the same as what was seen after single-dose administration (mean fed:fasted ratios for AUC₀._∞ and AUCQ_SS were both 1.1 1), confirming the linear pharmacokinetic characteristics of this drug product. The multiple-dose study also confirmed the simulations and hypotheses that food would have a non-clinically relevant, much less pronounced effect on hydrocodone maximum exposure (Cma_x) at steady state, with the 90% CIs for the LSM ratios for both hydrocodone Cma_xss and AUC_yss being completely within the pre-established range of 0.80 to 1.25 and enabling the conclusion of an absence of a food effect on the pharmacokinetics of hydrocodone ER at steady state.

[0045] Single and multiple doses of hydrocodone ER were generally well tolerated in these studies conducted with healthy fed and fasted "naltrexone-blocked" subjects. The observed AEs were generally consistent with those that are expected with the use of prescription opioids, including those involving the gastrointestinal and nervous systems.

[0046] The effect of food on hydrocodone exposure at steady state was found to be less pronounced than that observed after single-dose administration, with the 90% CIs for the LSM ratios of both Cmaxss and AUC_yss indicative of an absence of a food effect at steady state. It can be concluded that there is no evidence of a clinically significant effect of food on the

pharmacokinetics of hydrocodone ER after multiple days of twice-daily dosing. Single (90 mg) and multiple doses (90 mg twice daily) of hydrocodone ER were generally well tolerated under fed and fasted conditions in healthy naltrexone-blocked subjects. RREEFFEERREENNCCEESS

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File/XHXX_uuUseQfMed j^~eport.pdf. Parsippany, NJ: FMS Institute for Healthcare Informatics. Accessed: March 15, 2016

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Claims

What is Claimed:

1. A method of treating pain in a subject comprising administering to the subject at least one dose per day over multiple days of an extended release, abuse deterrent dosage form in which the active ingredient consists essentially of hydrocodone, wherein the administration does not produce a therapeutically significant effect on one or more pharmacokinetic parameters following a first dose or at steady state.

2. The method according to claim 1, wherein the pharmacokinetic parameter is AUC, Cma_x, or both.

3. The method according to claim 1 or claim 2, wherein the active ingredient in the dosage form consists of hydrocodone.

4. The method according to any one of claims 1-3, wherein the active ingredient in the dosage form consists of hydrocodone bitartrate.

5. The method according to any one of claims 1-4, wherein a first dose of the dosage form is administered to the subject while the subject is in the fasted state.

6. The method according to any one of claims 1-5, wherein the dosage form comprises hydrocodone bitartrate granules.

7. The method according to any one of claims 1-6, wherein the dosage form comprises 15 mg, 30 mg, 45 mg, 60 mg, or 90 mg of hydrocodone.

8. The method according to any one of claims 1-7 wherein the dosage form comprises granules comprising hydrocodone bitartrate, hydroxypropyl methyl cellulose, and ethyl cellulose.

9. The method according to claim 8 wherein the granules comprise 27 wt% hydrocodone bitartrate, 30 wt% hydroxypropyl methyl cellulose, and 43 wt% ethyl cellulose.

10. The method according to any one of claims 1-7, wherein the dosage form comprises coated hydrocodone bitartrate granules.

11. The method according to claim 10, wherein the coating comprises ethyl cellulose and a lipid excipient.

12. The method according to claim 10, wherein the coated granules comprise 60 wt% hydrocodone bitartrate, 26.7 wt% ethyl cellulose, and 13.3 wt% of said liquid excipient.

13. The method according to claim 11 or claim 12, wherein the lipid excipient comprises glyceryl behenate or a blend of esters of behenic acid with glycerol.

14. The method according to any one of claims 1-13 wherein the dosage form is selected from any of the following 15 mg, 30 mg, 45 mg, 60 mg, and 90 mg tablet formulations:

Magnesium 0.5 2.9 0.5 2.9 0.5 2.9 0.5 5.8 0.5 5.8 Stearate

Total 100 575 100 575 100 575 100 1150 100 1150

15. An extended release, abuse deterrent dosage form in which the active ingredient consists essentially of hydrocodone, wherein administration of the dosage form to a subject in at least one dose per day over multiple days does not produce a therapeutically significant effect on one or more pharmacokinetic parameters following a first dose or at steady state.

16. The dosage form according to claim 15, wherein the pharmacokinetic parameter is AUC, Cmax, or both.

17. The dosage form according to claim 15 or claim 16, wherein the active ingredient in the dosage form consists of hydrocodone.

18. The dosage form according to any one of claims 15-17, wherein the active ingredient in the dosage form consists of hydrocodone bitartrate.

19. The dosage form according to any one of claims 15-18, wherein the dosage form comprises hydrocodone bitartrate granules.

20. The dosage form according to any one of claims 15-19, wherein the dosage form comprises 15 mg, 30 mg, 45 mg, 60 mg, or 90 mg of hydrocodone.

21. The dosage form according to any one of claims 15-20 wherein the dosage form comprises granules comprising hydrocodone bitartrate, hydroxypropyl methyl cellulose, and ethyl cellulose.

22. The dosage form according to claim 21 wherein the granules comprise 27 wt% hydrocodone bitartrate, 30 wt% hydroxypropyl methyl cellulose, and 43 wt% ethyl cellulose.

23. The dosage form according to any one of claims 15-20, wherein the dosag comprises coated hydrocodone bitartrate granules.

24. The dosage form according to claim 23, wherein the coating comprises ethyl cellulose and a lipid excipient.

25. The dosage form according to claim 23, wherein the coated granules comprise 60 wt% hydrocodone bitartrate, 26.7 wt% ethyl cellulose, and 13.3 wt% of said liquid excipient.

26. The dosage form according to claim 24 or claim 25, wherein the lipid excipient comprises glyceryl behenate or a blend of esters of behenic acid with glycerol.

27. The dosage form according to any one of claims 15-26 wherein the dosage form is selected from any of the following 15 mg, 30 mg, 45 mg, 60 mg, and 90 mg tablet formulations:

Magnesium 0.5 2.9 0.5 2.9 0.5 2.9 0.5 5.8 0.5 5.8 Stearate

Total 100 575 100 575 100 575 100 1150 100 1150