Results of a randomized, double-blind, placebo-controlled trial of lorcaserin in cocaine use disorder.

BACKGROUND: Cocaine use disorder (CUD) is a major public health problem for which there is no approved pharmacotherapy. The primary purpose of this study was to evaluate the ability of lorcaserin, a 5-hydroxytryptamine2 C (5-HT2 C) receptor agonist, to facilitate abstinence in individuals seeking treatment for CUD. METHODS: This was a 12-site, randomized, parallel arm study with a 13-week Treatment Phase that included a 1-week, single-blind run-in period when all participants received twice daily 15mg acetazolamide capsules (a medication adherence marker), followed by randomization to either twice daily 10mg lorcaserin or placebo capsules for the remaining 12 weeks. Pre-randomization data were utilized in an enrichment strategy aimed at achieving high levels of medication adherence and low placebo response rates in a subgroup of participants that qualified for the "efficacy population." For lorcaserin vs. placebo, the primary efficacy endpoint was the proportion of participants in the efficacy population achieving abstinence during the last three weeks of treatment, as evidenced by self-report of no cocaine use, confirmed by urine testing. RESULTS: Within the efficacy population, 1.1% of 91 participants receiving lorcaserin and 4.3% of 92 receiving placebo achieved abstinence during the last 3 weeks of treatment. Among all randomized participants, 2.5% of 118 receiving lorcaserin and 5.6% of 124 receiving placebo achieved similar abstinence. Study participants receiving lorcaserin exhibited significantly greater reductions in body weight and BMI, indicating that medication adherence was sufficient to produce a pharmacological effect. CONCLUSIONS: Twice daily 10mg lorcaserin failed to demonstrate efficacy in the treatment of CUD.

Fighting Fire with Fire: Development of Intranasal Nalmefene to Treat Synthetic Opioid Overdose.

The dramatic rise in overdose deaths linked to synthetic opioids (e.g., fentanyl, carfentanil) may require more potent, longer-duration opiate antagonists than naloxone. Both the high affinity of nalmefene at µ opiate receptors and its long half-life led us to examine the feasibility of developing an intranasal (IN) formulation as a rescue medication that could be especially useful in treating synthetic opioid overdose. In this study, the pharmacokinetic properties of IN nalmefene were compared with an intramuscular (i.m.) injection in a cohort of healthy volunteers. Nalmefene was absorbed slowly following IN administration, with a median time to reach Cmax (Tmax) of 2 hours. Addition of the absorption enhancer dodecyl maltoside (Intravail, Neurelis, Inc., Encinitas, CA) reduced Tmax to 0.25 hour and increased Cmax by ∼2.2-fold. The pharmacokinetic properties of IN nalmefene (3 mg) formulated with dodecyl maltoside has characteristics consistent with an effective rescue medication: its onset of action is comparable to an i.m. injection of nalmefene (1.5 mg) previously approved to treat opioid overdose. Furthermore, the Cmax following IN administration was ∼3-fold higher than following i.m. dosing, comparable to previously reported plasma concentrations of nalmefene observed 5 minutes following a 1-mg i.v. dose. The high affinity, very rapid onset, and long half-life (>7 hours) of IN nalmefene present distinct advantages as a rescue medication, particularly against longer-lived synthetic opioids.

Pharmacokinetic Interaction between Naloxone and Naltrexone Following Intranasal Administration to Healthy Subjects.

Naloxone (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one HCl), a µ-opioid receptor antagonist, is administered intranasally to reverse an opioid overdose but its short half-life may necessitate subsequent doses. The addition of naltrexone [17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one], another µ-receptor antagonist, which has a reported half-life of 3 1/2 hours, may extend the available time to receive medical treatment. In a phase 1 pharmacokinetic study, healthy adults were administered naloxone and naltrexone intranasally, separately and in combination. When administered with naloxone, the C max value of naltrexone decreased 62% and the area under the concentration-time curve from time zero to infinity (AUC0-inf) decreased 38% compared with when it was given separately; lower concentrations of naltrexone were observed as early as 5 minutes postdose. In contrast, the C max and AUC0-inf values of naloxone decreased only 18% and 16%, respectively, when given with naltrexone. This apparent interaction was investigated further to determine if naloxone and naltrexone shared a transporter. Neither compound was a substrate for organic cation transporter (OCT) 1, OCT2, OCT3, OCTN1, or OCTN2. There was no evidence of the involvement of a transmembrane transporter when they were tested separately or in combination at concentrations of 10 and 500 µM using Madin-Darby canine kidney II cell monolayers at pH 7.4. The efflux ratios of naloxone and naltrexone increased to six or greater when the apical solution was pH 5.5, the approximate pH of the nasal cavity; there was no apparent interaction when the two were coincubated. The importance of understanding how opioid antagonists are absorbed by the nasal epithelium is magnified by the rise in overdose deaths attributed to long-lived synthetic opioids and the realization that better strategies are needed to treat opioid overdoses.

Comparison of the Pharmacokinetic Properties of Naloxone Following the Use of FDA-Approved Intranasal and Intramuscular Devices Versus a Common Improvised Nasal Naloxone Device.

For more than a decade, first responders and the general public have been able to treat suspected opioid overdoses using an improvised nasal naloxone device (INND) constructed from a prefilled syringe containing 2 mg of naloxone (1 mg/mL) attached to a mucosal atomization device. In recent years, the U.S. Food and Drug Administration (FDA)-approved Ezvio, an autoinjector that delivers 2 mg by intramuscular injection and Narcan nasal spray (2- and 4-mg strengths; 0.1 mL/dose) for the emergency treatment of a known or suspected opioid overdose. The present study was conducted to compare the pharmacokinetics of naloxone using the FDA-approved devices (each administered once) and either 1 or 2 administrations using the INND. When naloxone was administered twice using the improvised device, the doses were separated by 2 minutes. The highest maximum plasma concentration was achieved using the 4-mg FDA-approved spray. The highest exposures at 5 minutes postdose, based on AUC values, were after administration with the autoinjector and the 4-mg FDA-approved spray; at 10, 15, and 20 minutes postdose, the latter yielded the greatest exposure. Even after 2 administrations, the INND failed to achieve naloxone plasma levels comparable to the FDA-approved devices at any time. The ease of use and higher plasma concentrations achieved using the 4-mg FDA-approved spray, compared with the INND, should be considered when deciding which naloxone device to use.

Enhanced Intranasal Absorption of Naltrexone by Dodecyl Maltopyranoside: Implications for the Treatment of Opioid Overdose.

Based on its high affinity for µ opiate receptors and reported half-life after oral administration, the pharmacokinetic properties of intranasal naltrexone were examined to evaluate its potential to treat opioid overdose. This study was prompted by the marked rise in overdose deaths linked to synthetic opioids like fentanyl, which may require more potent, longer-lived opiate antagonists than naloxone. Both the maximum plasma concentration (Cmax ) and the time (Tmax ) to reach Cmax for intranasal naltrexone (4 mg) were comparable to values reported for a Food and Drug Administration-approved 4-mg dose of intranasal naloxone. The addition of the absorption enhancer dodecyl maltoside (Intravail) increased Cmax by ∼3-fold and reduced the Tmax from 0.5 to 0.17 hours. Despite these very rapid increases in plasma concentrations of naltrexone, its short half-life following intranasal administration (∼2.2 hours) could limit its usefulness as a rescue medication, particularly against longer-lived synthetic opioids. Nonetheless, the ability to rapidly attain high plasma concentrations of naltrexone may be useful in other indications, including an as-needed dosing strategy to treat alcohol use disorder.

Placebo-controlled evaluation of a bioengineered, cocaine-metabolizing fusion protein, TV-1380 (AlbuBChE), in the treatment of cocaine dependence.

BACKGROUND: TV-1380 (AlbuChE) is a novel recombinant fusion protein of mutated butyrylcholinesterase (BChE) that has increased catalytic efficiency for cocaine metabolism compared to wild-type BChE. METHODS: Intra-muscular injections of TV-1380 (150mg or 300mg) or placebo were administered once weekly to participants (n=66-69 per group) in a randomized, double-blind study to evaluate the ability of TV-1380 to facilitate abstinence in treatment-seeking, cocaine-dependent individuals. The primary endpoint was the proportion of participants achieving abstinence from cocaine during the last three weeks of the 12 week treatment phase, based on daily self-report of "no use" confirmed by urine testing. RESULTS: Although there were no significant differences between the TV-1380 treatment groups and placebo for the primary endpoint, 6% of participants in the 150mg and 300mg TV-1380 groups and no participants in the placebo group achieved abstinence. For the only declared secondary endpoint, there was a dose-dependent increase in the group mean percentage of urine samples testing negative for cocaine metabolites during weeks 5-12 (8.1% and 14.6% for the 150mg and 300mg TV-1380 groups, respectively, compared to 4.7% for the placebo group; p=0.0056 for 300mg vs. placebo). No meaningful differences in adverse events were seen between treatment groups. CONCLUSIONS: While the apparent reduction in cocaine use may be of insufficient magnitude to justify further trials of TV-1380 in cocaine dependence, the results argue for development of improved enzymes with greater catalytic activity.

Pharmacokinetic Properties and Human Use Characteristics of an FDA-Approved Intranasal Naloxone Product for the Treatment of Opioid Overdose.

Parenteral naloxone has been approved to treat opiate overdose for over 4 decades. Intranasal naloxone, administered "off label" using improvised devices, has been widely used by both first responders and the lay public to treat overdose. However, these improvised devices require training for effective use, and the recommended volumes (2 to 4 mL) exceed those considered optimum for intranasal administration. The present study compared the pharmacokinetic properties of intranasal naloxone (2 to 8 mg) delivered in low volumes (0.1 to 0.2 mL) using an Aptar Unit-Dose device to an approved (0.4 mg) intramuscular dose. A parallel study assessed the ease of use of this device in a simulated overdose situation. All doses of intranasal naloxone resulted in plasma concentrations and areas under the curve greater than those observed following the intramuscular dose; the time to reach maximum plasma concentrations was not different following intranasal and intramuscular administration. Plasma concentrations of naloxone were dose proportional between 2 and 8 mg and independent of whether drug was administered to 1 or both nostrils. In a study using individuals representative of the general population, >90% were able to perform both critical tasks (inserting nozzle into a nostril and pressing plunger) needed to deliver a simulated dose of naloxone without prior training. Based on both pharmacokinetic and human use studies, a 4-mg dose delivered in a single device (0.1 mL) was selected as the final product. This product can be used by first responders and the lay public, providing an important and potentially life-saving intervention for victims of an opioid overdose.