A pharmacokinetic evaluation of single and multiple doses of extended-release hydrocodone bitartrate in subjects experiencing surgical or osteoarthritic pain.

OBJECTIVES: To assess the single-dose and steady-state pharmacokinetics of a single-entity hydrocodone extended-release (ER) formulation in patients enrolled in two separate phase 2 clinical studies. SETTING: Both studies were multicenter clinical studies. SUBJECTS AND INTERVENTIONS: In study 1, 115 subjects with postsurgical pain (bunionectomy) received single doses of 10, 20, 30, or 40 mg hydrocodone-ER, 10 mg hydrocodone/325 mg acetaminophen immediate-release (IR), or placebo. In study 2, 37 subjects with osteoarthritic pain received doses of 10, 20, 30, or 40 mg of hydrocodone- ER twice-daily for 7 days. Venous blood samples were taken periodically up to 24 hours postdosing after the single dose (study 1) or after 7 days of dosing (study 2) and were assayed for concentrations of hydrocodone and its major metabolites. MAIN OUTCOME MEASURES: Standard pharmacokinetic parameters were estimated by noncompartmental analysis methods. RESULTS: Following a single dose of hydrocodone-ER, Tmax was prolonged to approximately 6 hours at all dose levels of hydrocodone-ER compared with 2.9 hours for the IR formulation. All doses of hydrocodone-ER formulations provided prolonged and sustained release of hydrocodone throughout the 12-hour dosing interval with reduced peak-to-trough fluctuation at steady state compared with hydrocodone/acetaminophen-IR comparator. Both single-dose and steadystate mean Cmax and AUClast values showed reasonable dose-proportionality. Norhydrocodone and hydromorphone plasma concentrations were 32-38 percent and <2.1 percent, respectively, of hydrocodone concentrations in both studies. CONCLUSIONS: The sustained plasma concentrations of hydrocodone support twice-daily dosing with a 12-hour dosing interval.

Effects of food and alcohol on the pharmacokinetics of an oral, extended-release formulation of hydrocodone in healthy volunteers.

BACKGROUND: The purpose of this study was to evaluate the pharmacokinetics, bioavailability, and safety of oral extended-release hydrocodone (HC-ER) when administered with food or alcohol. METHODS: Two single-center, open-label, randomized, crossover studies were conducted in healthy volunteers. In a two-period food-interaction study, 12 subjects received HC-ER 20 mg after an overnight fast and a high-fat meal. In a three-period alcohol-interaction study, 30 naltrexone-blocked subjects received HC-ER 50 mg with a 0%, 20%, or 40% alcohol/orange juice solution after an overnight fast. Pharmacokinetic parameters were derived from plasma concentrations of hydrocodone and its metabolites. RESULTS: Exposure to hydrocodone after HC-ER 20 mg was similar in the fed and fasted states, as assessed by area under the plasma concentration versus time curve from time of dosing to time of last detectable concentration (AUC0-t; 316.14 versus 311.94 ng · h/mL); relative bioavailability (Frel) was 101.74%. Differences (fed versus fasted) in hydrocodone mean maximum plasma concentration (Cmax; 28.86 versus 22.74 ng/mL) and median time to Cmax (tmax; 6 versus 8 hours) were not clinically significant. Administration of 20% alcohol with HC-ER 50 mg did not increase systemic exposure relative to 0% alcohol (AUC0-t 878 versus 832 ng · h/mL; Frel 105%) or result in clinically meaningful changes in Cmax (51.8 versus 46.3 ng/mL) or tmax (5.44 versus 6.16 hours). Administration with 40% alcohol increased AUC0-t (1,008 ng · h/mL versus 832 ng · h/mL; Frel 120%) and Cmax (109 versus 46.3 ng/mL), and shortened tmax (2.43 versus 6.16 hours). Adverse events occurred in 10.0%, 24.1%, and 66.7% of subjects after 0%, 20%, and 40% alcohol, respectively. CONCLUSION: HC-ER can be administered without regard to meals. While there was no evidence of "dose-dumping" (an unintended, rapid release in a short time period of all or most of the hydrocodone from HC-ER), even with 40% alcohol, as with all opioids, alcohol should not be ingested while using HC-ER.

A long-term, open-label safety study of single-entity hydrocodone bitartrate extended release for the treatment of moderate to severe chronic pain.

OBJECTIVE: To evaluate the long-term safety, tolerability, and effectiveness of single-entity extended-release hydrocodone in opioid-experienced subjects with moderate to severe chronic pain not receiving adequate pain relief or experiencing intolerable side effects from their current opioid. METHODS: This multicenter, open-label study started with a conversion/titration phase (≤6 weeks) where subjects (n=638) were converted to individualized doses (range 20-300 mg) of extended-release hydrocodone dosed every 12 hours, followed by a 48-week maintenance phase (n=424). The primary objective (safety and tolerability) and the secondary objective (long-term efficacy as measured by change in average pain score; 0= no pain, 10= worst imaginable pain) were monitored throughout the study. RESULTS: Subjects were treated for a range of chronic pain etiologies, including osteoarthritis, low back pain, and neuropathic and musculoskeletal conditions. The mean hydrocodone equivalent dose at screening was 68.9±62.2 mg/day and increased to 139.5±81.7 mg/day at the start of the maintenance phase. Unlimited dose adjustments were permitted at the investigator's discretion during the maintenance phase, reflecting typical clinical practice. No unexpected safety issues were reported. Common adverse events during the conversion/titration and maintenance phases, respectively, were constipation (11.3% and 12.5%), nausea (10.7% and 9.9%), vomiting (4.1% and 9.7%), and somnolence (7.7% and 4.2%). Four deaths occurred during the study; all were considered unrelated to treatment. One subject died 13 months after the study ended. From the start to end of the conversion/titration phase, 84% of subjects had a clinically meaningful improvement in average pain score (≥30% improvement), and the mean average pain scores remained stable through the maintenance phase. CONCLUSION: This single-entity, extended-release formulation of hydrocodone was generally safe, well tolerated, and effective in reducing chronic pain for 48 weeks. This formulation provides a new option for patients experiencing chronic pain, especially those who are taking immediate-release hydrocodone and have concerns about liver toxicity due to acetaminophen.

Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic low back pain: a randomized double-blind, placebo-controlled study.

OBJECTIVE: A single-agent, extended-release formulation of hydrocodone (HC) has been developed for treatment of chronic moderate-to-severe pain. This study was designed to examine the safety and efficacy of HC extended release in opioid-experienced adults with moderate-to-severe chronic low back pain (CLBP). METHODS: This multicenter, enriched enrollment, randomized withdrawal study comprised an open-label conversion/titration phase (≤6 weeks) followed by placebo-controlled, double-blind treatment (12 weeks). During the conversion/titration phase, subjects (N = 510) converted from their current opioid and were titrated to a stabilized dose of HC extended release (20-100 mg every 12 hours). During treatment, subjects (N = 151 per group) received HC extended release or placebo; rescue medication was permitted. The primary efficacy end point was mean change in average pain intensity from baseline to day 85. Response rates (30% pain improvement) and satisfaction (Subject Global Assessment of Medication) were assessed. RESULTS: Demographic and baseline characteristics were similar between groups. Mean ± SD change in average pain intensity score from baseline to day 85 was significantly lower in the HC extended-release treatment group vs placebo (0.48 ± 1.56 vs 0.96 ± 1.55; P = 0.008). Significantly more responders were in the treatment group (68% vs 31%; P < 0.001). Mean Subject Global Assessment of Medication scores increased significantly (0.8 ± 1.3 vs 0.0 ± 1.4; P < 0.0001), indicating greater satisfaction with HC extended release. The adverse event profile was consistent with other opioids. CONCLUSIONS: Extended-release HC is well tolerated and effective, without acetaminophen-associated risks of liver toxicity, for treatment of CLBP.

A review of needle-free sumatriptan injection for rapid control of migraine.

The treatment of migraine was transformed in 1992 with the introduction of the first triptan-based therapy, subcutaneous (SC) sumatriptan. SC sumatriptan has high efficacy and a rapid onset of action compared with other available triptans and formulations presumably because of its short Tmax, high Cmax, and avoidance of enteral absorption. Because of these characteristics, SC sumatriptan is still considered the most reliably and rapidly effective self-administered medication available for acute migraine. Even so, it is relatively little used possibly in part because of patient "needle-phobia." The needle-free sumatriptan injection system (Sumavel DosePro) was developed to address this concern. Clinical trials have shown that the needle-free system is bioequivalent to needle-based injection systems, easy to use, and capable of providing rapid and effective symptom relief for many migraine episodes. Sumavel DosePro is an effective treatment for migraine and should be part of the therapeutic armamentarium, particularly in cases where a rapid onset of action is critical or where oral administration is problematic.

Population pharmacokinetic analysis for hydrocodone following the administration of hydrocodone bitartrate extended-release capsules.

BACKGROUND AND OBJECTIVE: Hydrocodone is a semi-synthetic narcotic analgesic and antitussive. Although hydrocodone products have been on the market for over 50 years, relatively little is known about its pharmacokinetics. Additionally, there are no published reports of population pharmacokinetic analyses for hydrocodone. Furthermore, current labeling of hydrocodone-containing products provides little guidance in terms of the impact of patient descriptors on the pharmacokinetics of hydrocodone. The objectives of this analysis were to develop a population pharmacokinetic model that characterizes the pharmacokinetics of hydrocodone following single and multiple oral doses of hydrocodone extended-release capsules (hydrocodone bitartrate ER capsules) in healthy subjects and patients, to examine the impact of patient descriptors on pharmacokinetic parameters and to assess the dose-proportionality of hydrocodone pharmacokinetic. METHODS: A total of 4,714 plasma hydrocodone concentrations from 220 subjects were available for this analysis. The data were extracted from seven studies (five phase 1 and two phase 2 studies). A two-compartment open mamillary model with linear elimination and a complex absorption model was used to fit the data, using NONMEM(®) version 7.1.2 software. The absorption model involved two sequential first-order absorption processes with the delay in the first process accomplished by means of multiple transit compartments. Covariate analysis was performed using standard forward selection followed by backward elimination processes. Model evaluation was performed using a prediction-corrected visual predictive check (pcVPC). RESULTS: The population estimates of apparent oral central volume of distribution and apparent oral linear clearance were 714 L and 64.4 L/h, respectively. The first absorption process was rapid. Creatinine clearance and body surface area (BSA) were statistically significant predictors of the apparent oral clearance and apparent oral volume of distribution. The pcVPC indicated that the model provided a robust and unbiased fit to the data. CONCLUSIONS: A linear model for hydrocodone elimination provided an adequate fit to the observed data over the entire dose range, which supports that hydrocodone bitartrate ER capsules exhibit dose-proportional pharmacokinetics. The formulation of hydrocodone bitartrate ER capsules results in absorption profiles that are variable across and within subjects. Despite the variability in absorption profiles, a relatively simple model provided an adequate fit to the data. Creatinine clearance and BSA were statistically significant predictors of the apparent oral clearance and apparent oral volume of distribution. Absorption characteristics of hydrocodone bitartrate ER capsules should still allow effective plasma concentrations of hydrocodone to be reached quickly and for effective concentrations to be maintained for a long period.

Needle-free subcutaneous sumatriptan for triptan users requiring a change in migraine therapy: efficacy and impact on patient-rated functionality, satisfaction, and confidence.

OBJECTIVE: To evaluate efficacy of, satisfaction with, and confidence in SDP (SUMAVEL DosePro *) among triptan users requiring a change in therapy. SDP is a needle-free, subcutaneous sumatriptan product that confers relief as early as 10 minutes postdose. RESEARCH DESIGN AND METHODS: In an open-label study, SDP was administered for ≤4 migraine attacks over ≤60 days by migraineurs currently treated with triptans (any form/dosage). In the 90 patients with baseline Migraine-ACT scores ≤2 (indicating the need for a change in therapy), efficacy data were collected from patient diaries, and satisfaction was measured with the revised Patient Perception of Migraine Questionnaire (PPMQ-R). CLINICAL TRIAL REGISTRATION NUMBER: NCT01016834 on clinicaltrials.gov. RESULTS: Across all attacks, the rates of pain relief were 30.7%, 66.4%, 80.1%, 81.6%, and 77.6% at 0.25, 0.5, 1, 2, and 24 hours postdose, respectively. Corresponding results for pain-free response were 0.7%, 14.8%, 35.0%, 48.0, and 65.7%. Sustained 24-hour pain relief was observed in 61.0% of attacks. PPMQ-R scores (transformed to 0-100 scales, mean ± SD) improved from baseline to end of treatment for Efficacy (52.5 ± 17.8 versus 74.8 ± 23.4, p < 0.0001) and Functionality (46.2 ± 22.3 versus 71.3 ± 25.2, p < 0.0001) with no deterioration in Tolerability (80.6 ± 14.7 versus 83.5 ± 17.7, p = 0.12). PPMQ-R Overall Satisfaction score increased from baseline to end of treatment (55.1 ± 23.2 versus 74.6 ± 27.7, p < 0.0001). The percentage of patients (90% confidence interval) confident or very confident in treating migraine attacks increased from 22.2% (15.2, 30.6) at baseline to 57.8% (48.6, 66.6) at end of treatment. Results should be interpreted in the context of the open-label design of the original study. CONCLUSION: With SDP, triptan users requiring a change in therapy experienced increased efficacy, satisfaction with therapy, and confidence in treatment without deterioration in tolerability.

Satisfaction with and confidence in needle-free subcutaneous sumatriptan in patients currently treated with triptans.

OBJECTIVE: To evaluate patient satisfaction with and confidence in Sumavel® DosePro® (needle-free subcutaneous sumatriptan) among current triptan users administering Sumavel DosePro for up to 4 migraine attacks. BACKGROUND: Sumavel DosePro is a needle-free, single-use device that facilitates subcutaneous injection of sumatriptan 6 mg and confers relief as early as 10 minutes after dosing. DESIGN/METHODS: In this open-label, multicenter study, Sumavel DosePro was self-administered for ≤4 migraine attacks (over a ≤60-day period) involving moderate or severe baseline pain by adult migraineurs who currently were using triptans (any form, any dosage) and reported being less than very satisfied with their current therapy (i.e., baseline satisfaction ranging from satisfied to very dissatisfied). Treatment satisfaction was measured via the Patient Perception of Migraine Questionnaire, revised (PPMQ-R). RESULTS: Among the 212 patients using Sumavel DosePro to treat ≥1 migraine attack, PPMQ-R Overall Satisfaction (primary endpoint) increased significantly from baseline to the end of treatment (mean ± SD 65.7 ± 19.8 vs. 73.7 ± 29.1, P = .0007), an improvement that met the criterion for clinical significance. From baseline to the end of treatment, PPMQ-R scores also improved significantly for Efficacy (62.2 ± 17.6 vs. 76.2 ± 23.7, P < .0001), Functionality (59.0 ± 22.3 vs. 73.8 ± 25.3, P < .0001), and Tolerability (83.9 ± 13.1 vs. 86.4 ± 15.0, P = .02), but declined for Ease of Use (82.6 ± 15.3 vs 67.8 ± 27.6, P < .0001). For all global satisfaction domains, the percentage of patients satisfied or very satisfied increased from baseline to the end of treatment (Overall Satisfaction 36.3% vs. 64.0%, Satisfaction with Medication Effectiveness 40.1% vs. 68.2%, Satisfaction with Side Effects 48.6% vs. 67.3%). The percentage of patients who were confident or very confident in treating repeated migraine attacks also increased (baseline: 41.0%, 90% confidence interval [CI] 35.4, 46.9 vs. end of treatment: 66.5%, 90% CI 58.9, 70.1). The efficacy results (pain relief, pain-free response, sustained 24-hour pain relief and pain-free response) were consistent with those previously observed with needle-based sumatriptan. CONCLUSIONS: Patients currently treated with triptans and less than very satisfied with their acute migraine therapy experienced a statistically significant and clinically relevant increase in satisfaction with therapy and enhanced confidence in treatment after use of Sumavel DosePro for up to 4 migraine attacks.

Needle-free subcutaneous sumatriptan (Sumavel DosePro): bioequivalence and ease of use.

BACKGROUND: Subcutaneous (s.c.) injection of sumatriptan is currently associated with needle aversion in some patients, and sharps disposal issues. OBJECTIVES: To investigate whether a needle-free system can deliver s.c. sumatriptan. If so, to examine whether needle-free administration is bioequivalent to a 26-gauge needle-based auto-injector. Lastly, to assess the needle-free system for clinical acceptability and ease of use during migraine attacks. METHODS: Two clinical trials. Study A: Pharmacokinetics and bioequivalence was studied in normal adult volunteers (n = 57 total), directly comparing needle-free (Sumavel DosePro) with needle-based (Imitrex STATdose System) administration of 6 mg s.c. sumatriptan. An incomplete, randomized, partial factorial, crossover design was used. Each subject received 2 administrations of each product, at 2 of the 3 anatomical sites (abdomen, thigh or arm). There were appropriate "washout" periods between each. Pharmacokinetic sampling was at standard time points, and tests for bioequivalence then followed. Study B: The term "ease of use" was used for clinical acceptability and utility of the needle-free system when it was assessed among 52 outpatients treating migraine attacks. Instructional materials were used as would be provided after ordinary prescription. The primary endpoint was successful use of the needle-free system to administer sumatriptan at the first attempt, including appropriate injection site selection. Second and subsequent uses of the needle-free system were also documented. RESULTS: For administration sites in the thigh and the abdomen, but not the arm, the needle-free and needle-based systems were bioequivalent (for all pharmacokinetic endpoints the mean ratios between the 2 devices were always between 90.1% and 115%). Among outpatients treating a migraine attack with the needle-free system, 51 of 52 on first attempt used the needle-free system successfully when treating a migraine attack. CONCLUSIONS: Sumavel DosePro needle-free delivery system is a new presentation of s.c. sumatriptan that delivers drug effectively, is bioequivalent to the existing needle auto-injector when used at the thigh or abdomen, and is easy to use.

The effects of system parameters on in vivo injection performance of a needle-free injector in human volunteers.

PURPOSE: For a novel needle-free injection (NFI) system, the relationship between frequency of wet or incomplete injections and device-related factors and subject physiological variables was examined. MATERIALS AND METHODS: A total of 26 device configurations of a single-use pre-filled NFI system (Intraject) were used to deliver a total of 3,211 subcutaneous injections into the abdomen of 302 healthy volunteers. Two validated methods were used to determine completeness of each injection (defined as >or=90% dose delivery). Skin-fold thickness, body mass index (BMI), Fitzpatrick skin type, sex, age, and injection site were noted for each volunteer. RESULTS: The proportion of complete injections ranged from 59-98% among the various combinations of device configurations. Two device parameters and two subject-related variables showed strong association with injection performance; Device gas mass (chamber pressure) and orifice size demonstrated statistically significant, independent effects, with increasing gas mass and larger orifice size associated with improved injection performance. BMI and site of injection on the abdomen also demonstrated statistically significant effects with increasing BMI and lateral rather than medial injection sites associated with better injections. CONCLUSION: Both device-related factors and subject variables interact to mediate in vivo performance of a needle-free injector.

Pulmonary delivery of opioids as pain therapeutics.

Pulmonary opioid delivery, on the basis of the fact that small molecular entities can be rapidly and completely absorbed from the peripheral lung, poses a unique opportunity for the treatment of severe (breakthrough) pain, which currently is treated with intravenous therapy. Early clinical studies involving inhaled opioids were focused on treatment of dyspnoea and not pain management, but they showed that inhalation of various opioid compounds is safe, even in severely ill patients. The advent of specialized and efficient pulmonary drug delivery systems has facilitated the evaluation of inhaled opioids, such as morphine and fentanyl, for management of severe pain associated with surgery or malignant disease. This review will summarize recent literature on the pharmacokinetics and pharmacodynamics of inhaled opioids and will discuss safety and efficacy in comparison to injection and other opioid dosage forms available for pain therapy. Finally, regulatory considerations will be discussed towards the approval of this new delivery paradigm for opioid drugs.

Evaluation of the AERx pulmonary delivery system for systemic delivery of a poorly soluble selective D-1 agonist, ABT-431.

PURPOSE: ABT-431 is a chemically stable, poorly soluble prodrug that rapidly converts in vivo to A-86929, a selective dopamine D-1 receptor agonist. This study was designed to evaluate the ability of the AERx pulmonary delivery system to deliver ABT-431 to the systemic circulation via the lung. METHODS: A 60% ethanol formulation of 50 mg/mL ABT-431 was used to prepare unit dosage forms containing 40 microL of formulation. The AERx system was used to generate a fine aerosol bolus from each unit dose that was collected either onto a filter assembly to chemically assay for the emitted dose or in an Andersen cascade impactor for particle size analysis. Plasma samples were obtained for pharmacokinetic analysis after pulmonary delivery and IV dosing of ABT-431 to nine healthy male volunteers. Doses from the AERx system were delivered as a bolus inhalation(s) (1, 2, 4, and 8 mg) and intravenous infusions were given over 1 hr (5 mg). Pharmacokinetic parameters of A-86929 were estimated using noncompartmental analysis. RESULTS: The emitted dose was 1.02 mg (%RSD = 11.0, n = 48). The mass median aerodynamic diameter of the aerosol was 2.9 +/- 0.1 microm with a geometric standard deviation of 1.3 +/- 0.1 (n = 15). Tmax (mean +/- SD) after inhalation ranged from 0.9 +/- 0.6 to 11.5 +/- 2.5. The mean absolute pulmonary bioavailibility (as A-86929) based on emitted dose ranged from 81.9% to 107.4%. CONCLUSIONS: This study demonstrated that the AERx pulmonary delivery system is capable of reproducibly generating fine nearly monodisperse aerosols of a small organic molecule. Aerosol inhalation utilizing the AERx pulmonary delivery system may be an efficient means for systemic delivery of small organic molecules such as ABT-431.