Pharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended-Release Tablets.

Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended-release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. Spearman ρ2 and Pearson r2 values were calculated for PD (maximum effect [Emax ] for "at the moment" Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration-time curve [AUC], maximum drug concentration [Cmax ], time to Cmax [Tmax ], and abuse quotient [PK AQ; Cmax /Tmax ]) for all treatments. In the oral study, correlations were strongest between Emax of "at the moment" Drug Liking and PK parameters (Cmax [ρ2  = 0.4446], PK AQ [ρ2  = 0.5179], Tmax [ρ2  = 0.5093], and early systemic exposure [ρ2  = 0.4782]). For Overall Drug Liking and Take Drug Again VAS, ρ2 values for correlations with PK parameters ranged from 0.2620 to 0.3637. In the intranasal study, no clear correlations between PK and PD parameters were apparent.

Prescription Opioid Type and the Likelihood of Prolonged Opioid Use After Orthopaedic Surgery.

INTRODUCTION: A common belief is that some narcotic medications have a higher association with prolonged use. We assessed whether the initial opiate type prescribed to postoperative, opiate-naive orthopaedic trauma patients was associated with prolonged opioid use. METHODS: We studied 17,961 adult, opiate-naive patients treated for a surgical musculoskeletal injury. Discharge prescription in morphine milligram equivalents (MMEs, a standardized dosing unit that allows for comparison across opioid types) was calculated. Opioid prescribing beyond 90 days after injury was defined as prolonged use. RESULTS: Initial analysis demonstrated a higher likelihood of prolonged use for patients discharged on hydromorphone or morphine versus hydrocodone. However, when we adjusted for discharge MME, only opioid quantity was predictive of prolonged use (P < 0.001). In addition, discharge MME was associated with opioid type (P < 0.01). DISCUSSION: Persistent opiate use was associated with discharge opioid quantity, not the opioid type. These results highlight the importance of calculating equivalence doses when selecting opioid types and considering amount of narcotics prescribed. LEVEL OF EVIDENCE: Level III.

Time Scaling for In Vitro-In Vivo Correlation: the Inverse Release Function (IRF) Approach.

In vitro-in vivo correlations (IVIVC) are methods used to create a link between biopharmaceutical properties such as dissolution and physiological response such as plasma concentration. Level A IVIVC defines 1:1 relationship between the percent absorbed in vivo and the percent dissolved in vitro. A successful level A IVIVC provides the capacity to predict in vivo behavior based only on in vitro data with application in formulation development and support of biowaivers recognized by regulatory agencies across the world. Level A regression may be complicated due to differences in time scales as well as the lack of coincident times of similar release in vitro and in vivo leading to approximate time-to-time links and subsequent loss of information. Here, a novel method to establish Levy's plot and to provide time scaling for improved IVIVC predictive capacity is presented. The method is mathematically closed and is an inverse release function (IRF) characterizing the single (or more) phases of dissolution/absorption. It uses the complete set of information available from all time points both in vitro and in vivo. An extended-release formulation development situation is presented with three increasing release rate test products compared in a trial versus a reference product. First, the standard level A regression was made. Prediction errors for internal validation were higher than 10% for Cmax. The IRF method was applied to obtain the in vitro times of percentage dissolved equivalent to percentage absorbed. The prediction errors from the IRF level A correlation were nearly negligible.

Pharmacokinetics and Abuse Potential of Benzhydrocodone, a Novel Prodrug of Hydrocodone, After Intranasal Administration in Recreational Drug Users.

Objective: Developing an acetaminophen-free, immediate-release hydrocodone product remains an unmet medical need; however, new opioid analgesics should not introduce new abuse risks. Benzhydrocodone is a prodrug of hydrocodone that must be metabolized into hydrocodone by enzymes in the intestinal tract to optimally deliver its pharmacologic effects. This study evaluated the intranasal pharmacokinetics and abuse potential of benzhydrocodone active pharmaceutical ingredient (API) compared with hydrocodone bitartrate (HB) API. Design: Single-center, randomized, double-blind, crossover study. Setting: Clinical research site. Subjects: Healthy adult, nondependent, recreational opioid users. Methods: Subjects (N = 51 Completers) were randomized to receive 13.34 mg of intranasal benzhydrocodone API and 15.0 mg of intranasal HB API (molar-equivalent doses of hydrocodone). Blood samples were taken, and Drug Liking scores (assessed on a bipolar visual analog scale) were obtained throughout each dosing interval. Nasal irritation and safety were assessed. Results: Peak hydrocodone plasma concentration (Cmax) was 36.0% lower, and total hydrocodone exposures (AUClast and AUCinf) were 20.3% and 19.5% lower, respectively, for benzhydrocodone API compared with HB API (P < 0.0001). All partial AUC values were lower for benzhydrocodone API, with a ≥ 75% reduction in hydrocodone exposure at all time intervals up to one hour postdose (P < 0.0001). Median Tmax of hydrocodone following benzhydrocodone API was delayed by more than one hour compared with HB. Drug Liking score, as assessed by maximal liking (Emax), was significantly lower for benzhydrocodone API vs HB API (P = 0.004), with 45% of subjects showing a ≥ 30% reduction in Drug Liking Emax. Conclusion: Reductions in hydrocodone exposure and associated decreases in Drug Liking relative to HB suggest that the prodrug benzhydrocodone may deter intranasal abuse.

Evaluation of the Relative Intranasal Abuse Potential of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users.

Objective: To assess the intranasal abuse potential of hydrocodone extended-release (ER) tablets developed with CIMA Abuse-Deterrence Technology compared with hydrocodone powder and hydrocodone bitartrate ER capsules (Zohydro ER, original formulation [HYD-OF]). Design: Single-dose, randomized, double-blind, quadruple-dummy, active- and placebo-controlled, crossover study. Setting: One US site. Subjects: Healthy, adult, nondependent, recreational opioid users. Methods: Subjects able to tolerate intranasal hydrocodone and discriminate hydrocodone from placebo were eligible for study enrollment. Eligible participants randomly received intranasal hydrocodone ER, intranasal hydrocodone powder, intranasal HYD-OF, intact oral hydrocodone ER, and placebo. Coprimary pharmacodynamic end points were a maximum effect on "at the moment" Drug Liking visual analog scale and Overall Drug Liking visual analog scale. Pharmacokinetics and safety were assessed. Results: Mean maximum effect for "at the moment" Drug Liking was significantly (P < 0.01) lower for intranasal hydrocodone ER (72.8) compared with hydrocodone powder (80.2) and HYD-OF (83.2). Similar results were observed for Overall Drug Liking maximum effect (68.5 vs 77.1 and 79.8, respectively; P < 0.01). Secondary end points, including balance of effects and positive, sedative, and other effects, were consistent with these results. Intranasal treatments showed significantly greater effects vs placebo, while intact oral hydrocodone ER was similar to placebo. For each treatment, plasma concentration-time profiles paralleled "at the moment" Drug Liking over time. Incidences of adverse events for intranasal treatments were 52% for hydrocodone ER, 53% for hydrocodone powder, and 61% for HYD-OF. Conclusions: The statistically significant differences between hydrocodone ER vs hydrocodone powder and HYD-OF for the primary drug liking end points indicate a lower intranasal abuse potential with hydrocodone ER in healthy, nondependent, recreational opioid users.

Effect of Food on the Pharmacokinetics of Single- and Multiple-Dose Hydrocodone Extended Release in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Food intake can alter the pharmacokinetics of certain medications, including changes in their oral bioavailability, which is of particular concern for extended-release (ER) opioids because of the high drug loads. Two randomized, open-label studies assessed the effect of food on the pharmacokinetics of single and multiple doses of hydrocodone ER formulated with CIMA® Abuse-Deterrence Technology. METHODS: Healthy subjects in fed and fasted states received single 90-mg doses of hydrocodone ER (Studies 1 and 2) or multiple doses of hydrocodone ER (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 in the morning on day 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-versus-time curve from time 0 to infinity (AUC0-∞) in Study 1 (day 1) and for one dosing interval at steady state (AUCτ,ss) in Study 2 (day 11). Before conducting the multiple-dose study, single-dose data were fitted with a population pharmacokinetic methodology. RESULTS: In total, 40 subjects were randomized to Study 1 and 43 subjects were randomized to Study 2. While overall exposure (AUC0-∞) was relatively similar (least squares mean ratio [90% CI]: 1.11 [1.06-1.16]), results indicated that the single-dose C max was 40% higher under fed versus fasted conditions (least squares mean ratio [90% CI]: 1.40 [1.31-1.51]; Study 1). Modeling of single-dose data predicted that the effect of food would be much less at steady state [predicted fed:fasted C max at steady state (C max,ss) and AUCτ,ss ratios of 1.18 and 1.09, respectively]. The multiple-dose study results validated these predicted ratios and indicated that the steady-state 90% CIs were within 0.80-1.25 for the fed:fasted C max,ss (1.14 [1.07-1.21]) and AUCτ,ss (1.11 [1.04-1.17]) parameters, indicating that clinically meaningful food effects at steady state are not expected. CONCLUSION: No evidence of an effect of food was found on the pharmacokinetics of hydrocodone ER after multiple days of twice-daily dosing.

Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone.

This study compared the development of tolerance to two orally bioavailable prescription opioids, oxycodone and hydrocodone, to that of morphine, and the reversal of this tolerance by ethanol. Oxycodone (s.c.) was significantly more potent in the mouse tail-withdrawal assay than either morphine or hydrocodone. Oxycodone was also significantly more potent in this assay than hydrocodone when administered orally. Tolerance was seen following chronic subcutaneous administration of each of the three drugs and by the chronic administration of oral oxycodone, but not following the chronic oral administration of hydrocodone. Ethanol (1 g/kg i.p.) significantly reversed the tolerance to the subcutaneous administration of each of the three opioids that developed when given 30 minutes prior to challenge doses. It took twice as much ethanol, when given orally, to reverse the tolerance to oxycodone. We investigated whether the observed tolerance to oxycodone and its reversal by ethanol were due to biodispositional changes or reflected a true neuronal tolerance. As expected, a relationship between brain oxycodone concentrations and activity in the tail-immersion test existed following administration of acute oral oxycodone. Following chronic treatment, brain oxycodone concentrations were significantly lower than acute concentrations. Oral ethanol (2 g/kg) reversed the tolerance to chronic oxycodone, but did not alter brain concentrations of either acute or chronic oxycodone. These studies show that there is a metabolic component of tolerance to oxycodone; however, the reversal of that tolerance by ethanol is not due to an alteration of the biodisposition of oxycodone, but rather is neuronal in nature.

Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users.

Objective: To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA ® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Design: Randomized, double-blind, placebo-controlled, crossover study. Setting and Patients: One study site in the United States; adult nondependent, recreational opioid users. Methods: After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was "at the moment" drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Results: Mean maximum effect (E max ) for "at the moment" drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P < 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (E max : 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective "at the moment" drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). Conclusions: The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated.

Application of hot-melt extrusion technology in immediate-release abuse-deterrent formulations.

OBJECTIVE: Hot-melt extrusion (HME) technology has been used for manufacturing extended-release abuse-deterrent formulations (ADFs) of opioid-type analgesics with improved tamper-resistant properties. Our objective was to describe application of this technology to immediate-release (IR) ADFs. DESIGN: For development of a sample IR ADF (hydrocodone 10 mg/acetaminophen 325 mg) based on HME, feasibility studies were performed using different excipients. The formulation selected for further development was evaluated via in vitro test battery. Moreover, in vivo performance of IR ADF technologies was investigated in an open-label, randomized, cross-over, phase 1, relative oral bioavailability study with another opioid (model compound). SETTING: Single-center bioavailability trial. PARTICIPANTS: Twenty-four healthy white male subjects. INTERVENTIONS: ADF IR formulation of an opioid and marketed IR formulation. MAIN OUTCOME MEASURE(S): For feasibility and in vitro studies, dissolution profiles, syringeability, particle size distribution after physical manipulation, and extractability were evaluated. For the phase 1 study, pharmacokinetic parameters were evaluated and compared for ADF IR and a marketed IR formulation. RESULTS: After manipulation, the majority of particles from the ADF IR formulation were >500µm and, thus, not considered suitable for intranasal abuse, while the majority of particles for the reference marketed IR formulation were <500µm. The ADF IR formulation was resistant to syringing and preparation for potential intravenous injection. In healthy subjects, pharmacokinetics of an ADF and marketed IR formulation of an opioid were nearly identical. CONCLUSIONS: Application of HME to IR formulations led to development of products with improved mechanical resistance to manipulation for intranasal or intravenous preparation, but similar bioavailability.

Oral Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users.

OBJECTIVES: A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the oral abuse potential and pharmacokinetics (PK) of HYD intact, chewed, or milled to fine particles in comparison with hydrocodone solution or placebo. DESIGN: Single-center, double-blind, randomized, five-period, five-treatment crossover study. SUBJECTS: Healthy adult, nondependent, recreational opioid users. METHODS: Forty subjects received orally administered treatments of hydrocodone 60 mg solution, HYD 60 mg intact, HYD 60 mg chewed, HYD 60 mg milled to fine particles, or placebo, separated by a five- to seven-day washout. Assessments over 36 hours postdose included subjective measures of drug liking and willingness to take drug again (assessed using visual analog scales [VAS]), pupillometry, PK, and safety measures. RESULTS: Following oral administration, HYD intact, HYD chewed, and HYD fine particles led to significantly lower "at this moment" drug liking compared with hydrocodone solution. HYD intact and chewed were significantly different from hydrocodone solution on overall drug liking, take drug again, and good effects. Pupil constriction, as measured by pupillometry, occurred later with HYD intact and HYD chewed than with hydrocodone solution. Across treatments (hydrocodone solution, HYD fine particles, HYD chewed, and HYD intact, respectively), mean C max and rate of absorption (C max /T max ) values decreased, respectively, and median T max values increased, respectively. Safety was consistent with the known effects of opioid agonists. CONCLUSION: HYD demonstrated reduced oral abuse potential compared with hydrocodone solution in healthy adult, nondependent, recreational opioid users.

Pharmacokinetics of guaifenesin, pseudoephedrine and hydrocodone in a combination oral liquid formulation, administered as single and multiple doses in healthy Chinese volunteers, and comparison with data for individual compounds formulated as Antuss®.

1. A new oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone is effective in improving the symptoms of common cold. The pharmacokinetic properties of the individual components were evaluated in a randomized, open-label, four-period study in 12 healthy Chinese volunteers following single and multiple doses. The data were compared with data for the individual ingredients in Antuss®. 2. In the single-dose period, exposure levels (AUC and Cmax) for guaifenesin, pseudoephedrine and hydrocodone increased directly as the dose of the oral liquid formulation increased from 5 to 15 mL. Only minor amounts of guaifenesin and hydrocodone were excreted in urine (∼0.10% and 4.66%, respectively). Pseudoephedrine was mainly excreted unchanged, with 44.95% of the dose excreted in urine within 24 h. After multiple dosing, there was no obvious accumulation of any drug, as assessed by AUC. When considering Cmax, there was a trend toward accumulation of hydrocodone and pseudoephedrine. The pharmacokinetic profiles of guaifenesin and pseudoephedrine in the oral liquid formulation were similar to those in the branded preparation, Antuss®. 3. The newly developed oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone was safe and well tolerated and might provide a reliable alternative to the branded formulation for patients with common colds.

Effects of Renal Impairment and Hepatic Impairment on the Pharmacokinetics of Hydrocodone After Administration of a Hydrocodone Extended-Release Tablet Formulated With Abuse-Deterrence Technology.

Two open-label, single-dose, parallel-group studies assessed effects of renal and hepatic impairment on the pharmacokinetics of a hydrocodone extended-release (ER) formulation developed with the CIMA Abuse-Deterrence Technology platform. Forty-eight subjects with normal renal function or varying degrees of renal impairment received hydrocodone ER 45 mg (study 1); 16 subjects with normal hepatic function or moderate hepatic impairment received hydrocodone ER 15 mg (study 2). Blood samples were obtained predose and through 144 hours postdose. Mean maximum observed plasma hydrocodone concentration (Cmax ) in subjects with normal renal function, mild, moderate, and severe impairment, and end-stage renal disease was 28.6, 33.4, 42.4, 36.5, and 31.6 ng/mL, and mean area under the plasma hydrocodone concentration-versus-time curve from time 0 to infinity (AUC0-∞ ) was 565, 660, 973, 983, and 638 ng·h/mL, respectively. Incidence of adverse events was 57%, 38%, 44%, 33%, and 56%, respectively. Mean Cmax with normal hepatic function and moderate impairment was 10.1 and 13.0 ng/mL, and mean AUC0-∞ was 155 and 269 ng·h/mL, respectively. Incidence of adverse events was 38% in both groups. Altered systemic exposure in renally or hepatically impaired populations (up to ∼70% higher) should be considered when titrating to an effective dose of hydrocodone ER.

Gender difference in prescription opioid abuse: A focus on oxycodone and hydrocodone.

Several data gathered in the last decade indicate an increase of abuse of prescription opioid drugs oxycodone (OXY) and hydrocodone (HYDRO) in women. However, to date there are no conclusive evidences investigating the gender-dependent abuse liability of prescription opioids. This study aims to supply a specific focus on women's data through a selective summary of the literature analyzing gender differences in the pharmacokinetic and pharmacodynamic dimension of OXY and HYDRO. Findings from this study suggest that the majority of OXY and HYDRO pharmacokinetic and pharmacodynamic effects do not differ according to gender, though confirming a significant difference in the incidence of adverse effects as demonstrated by the increased gastrointestinal adverse reactions in female subjects. Although the majority of recent clinical studies include an equal number of female and male subjects, the main outcome parameters do not relate specifically to gender differences. Due to the gender influence in activity of CYP3A4 and its crucial role in metabolism of both OXY than HYDRO, we suggest that assessing pharmacokinetic and pharmacodynamic interactions in clinical studies may be useful to clarify the effect of the higher CYP3A4 activity in female in relation to CYP2D6 genotype. Overall, considering the paucity of data regarding gender differences in European Union, this work highlights that impact of new abuse deterrent formulations should be assessed with a special focus on data concerning female subjects.

Intranasal Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users.

OBJECTIVES: A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER® [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the intranasal abuse potential and pharmacokinetics of HYD coarse and fine particles vs hydrocodone powder or placebo. DESIGN: Single-center, double-blind, positive- and placebo-controlled, randomized, four-treatment crossover study. SUBJECTS: Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. METHODS: During four treatment periods, subjects (N = 31) received hydrocodone powder 60 mg, HYD coarse particles 60 mg, HYD fine particles 60 mg, or placebo, with five-to-seven-day washouts between treatments. Measures over 36 hours postdose included drug-liking and willingness to take drug again, assessed using visual analog scales (VASs), pupillometry, intranasal irritation, and pharmacokinetics. RESULTS: Insufflation of both HYD coarse and fine particles led to lower "At this Moment" Drug Liking VAS peak values compared with hydrocodone powder, but higher values compared with placebo (P < 0.001 for all comparisons). Similar results were observed for Overall Drug Liking VAS, Take Drug Again VAS, and Subjective Drug Value. Compared with hydrocodone, insufflation of HYD particles led to reduced miosis and increased nasal irritation. Mean hydrocodone Cmax following insufflation of HYD coarse particles, HYD fine particles, and hydrocodone powder was 27.5, 36.5, and 105.8 ng/mL, respectively; median Tmax was ≥2-fold longer with either HYD particle size than hydrocodone powder; and (Cmax/Tmax) was 9.5, 13.4, and 82.0 ng/mL/h, respectively. Safety was consistent with that of opioid agonists. CONCLUSIONS: HYD demonstrated reduced intranasal abuse potential compared with hydrocodone powder.

Pharmacokinetic Profile and Sustained 24-hour Analgesia of a Once-daily Hydrocodone Bitartrate Extended-release Tablet with Abuse-deterrent Properties.

PURPOSE: The purpose of this study was to evaluate the pharmacokinetics (PK) and 24-hour analgesic effectiveness of once-daily, single-entity, extended-release hydrocodone (HYD) with abuse-deterrent properties. METHODS: Four studies were included. Three open-label PK studies had the following designs: single-dose, 5-treatment, 4-period, crossover, dose-proportionality study; HYD 120 mg for 5 days (steady-state study 1); 2-treatment, 2-period, multiple-dose crossover study assessing the relative bioavailability of HYD 30 mg and hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours (steady-state study 2). A long-term, open-label study assessed the safety and effectiveness of HYD 20 to 120 mg in patients during a 52-week maintenance period. FINDINGS: Thirty-one, 25, and 22 healthy subjects completed the dose-proportionality study, steady-state study 1, and steady-state study 2, respectively, while 410 patients with moderate to severe chronic nonmalignant and non-neuropathic pain completed the long-term effectiveness study. Mean systemic exposure and peak plasma concentration were dose proportional after administration of single doses of HYD 20 to 120 mg. Pharmacokinetic profiles were comparable at day 1 and day 5 after administration of HYD 120 mg once daily. Once-daily HYD 30 mg was associated with lower-fluctuating plasma hydrocodone concentrations compared with immediate-release hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours. In the long-term study, pain control was consistent over the 24-hour dosing interval. IMPLICATIONS: Once-daily HYD exhibits linear, dose-proportional PK properties and is associated with a lower variability in plasma hydrocodone concentrations when compared with an immediate-release hydrocodone combination product. Notably, analgesia provided by HYD is sustained during the 24-hour dosing interval. ClinicalTrials.gov identifier: NCT01400139 (Study 4).

Formulation optimization of a drug in adhesive transdermal analgesic patch.

CONTEXT: Conventional pain management approaches have limitations such as gastrointestinal side effects, frequent dosing, and difficulties in swallowing medications. Hence, to overcome these limitations, we developed a transdermal analgesic patch. OBJECTIVE: This study was designed to formulate a drug in adhesive transdermal patch with codeine (CDB) and acetaminophen (APAP) that may potentially treat moderate pain in children. MATERIALS AND METHODS: Three analgesic drugs hydrocodone bitartrate, CDB and APAP were screened by a slide crystallization study using polarized light microscope and their permeation profiles were studied using vertical Franz diffusion cells across porcine ear skin, dermatomed human skin and epidermis for 24 h, and the samples were quantified by high performance liquid chromatography. Patches used for permeation studies were prepared by dissolving sub-saturation concentration of the drug(s) in adhesive (with/without 5% w/w oleic acid [OA]), cast with a film casting knife. RESULTS AND DISCUSSION: Among the three drugs screened, CDB demonstrated the best permeation profile (660.21 µg/cm2), and shortest lag time (4.35 ± 0.01 h), and hence was chosen for patch studies. The highest concentration of CDB in the patch at which drug does not crystallize was determined as 40% of its saturation solubility (Cs) and that of APAP was determined as 200% of its Cs. CDB standalone patch delivered 105.48 µg/cm2 of CDB, while the CDB-APAP combination patch with 5% w/w OA delivered 151.40 µg/cm2 CDB and 58.12 µg/cm2 APAP in 24 h. CONCLUSION: Drug-in-adhesive patches using CDB and APAP were developed for infants and children. Addition of OA enhanced solubility and permeation of drugs.

Single-dose pharmacokinetics of 2 or 3 tablets of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) under fed and fasted conditions: two randomized open-label trials.

BACKGROUND: Biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) 7.5/325-mg tablets are formulated with gastroretentive ER drug delivery technology that has been associated with clinically meaningful food effects in other approved products. Two phase 1 studies evaluated potential effects of food on single-dose pharmacokinetics of IR/ER HB/APAP tablets. METHODS: These were single-center, open-label, randomized, single-dose, 3-period crossover studies in healthy volunteers (aged 18-55 years). IR/ER HB/APAP was administered as a single 2-tablet dose (study 1) or 3-tablet dose (study 2) under fed (high- and low-fat) and fasted conditions. Area under the plasma concentration-time curve from 0 h to time t (AUC0-t) and from time 0 extrapolated to infinity (AUC0-inf) and maximum observed plasma concentration (Cmax) of hydrocodone and APAP under fed versus fasted conditions were compared using analysis of variance. A 90% confidence interval of the geometric least squares mean ratio fully contained within 80 to 125 % indicated no treatment difference. Safety and tolerability were assessed. RESULTS: Forty of 48 participants in study 1 and 21 of 30 in study 2 completed all treatments. In both studies, under fed (high- or low-fat meal) versus fasted conditions, 90% CIs for AUC0-t and AUC0-inf for both hydrocodone and APAP were entirely contained within the bioequivalent range (80-125%), indicating that high- and low-fat meals did not affect the extent of exposure. In both studies, a high-fat meal did not affect the Cmax for hydrocodone. Hydrocodone Cmax was not affected by a low-fat meal in study 1 but increased by approximately 19% in study 2. A high-fat meal decreased APAP Cmax by approximately 20 % (study 1) and 13 % (study 2); a low-fat meal decreased APAP Cmax by 22% (study 1) and 21% (study 2). Approximately 50% of participants in both studies reported ≥1 treatment-emergent adverse event (TEAE), with no notable difference based on food intake. There were no serious or severe AEs. The most common TEAEs were nausea, vomiting, and dizziness. CONCLUSIONS: Pharmacokinetic and safety findings were similar regardless of food intake. TEAEs were consistent with those reported with low-dose combination opioids. IR/ER HB/APAP can be administered without regard to food. TRIAL REGISTRATION: ClinicalTrials.gov NCT02561650 and NCT02561741 .