Plasma Concentrations Of Naltrexone Research Articles

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.

Effect of food on the pharmacokinetics of oxycodone and naltrexone from ALO-02, an extended release formulation of oxycodone with sequestered naltrexone.

ALO-02 is being developed as an abuse-deterrent formulation of extended-release oxycodone hydrochloride with naltrexone hydrochloride sequestered in the core of pellets contained in capsules. The primary objective of this study was to assess the effects of administration of ALO-02 capsule whole under fed conditions or sprinkling the pellets from ALO-02 capsule on applesauce under fasting conditions on the pharmacokinetics (PK) of oxycodone, naltrexone and 6-ß-naltrexol compared with ALO-02 capsule administered whole under fasting conditions. The plasma naltrexone and 6-ß-naltrexol concentrations were used to assess the sequestration of naltrexone in the ALO-02 formulation. The secondary objective was to evaluate the safety and tolerability of single 40 mg doses of ALO-02 in healthy volunteers. This was an IRB-approved, open-label, single-dose, randomized, 3-period crossover study in 24 healthy adult volunteers, aged 18-55 years. Each subject was assigned to receive single 40 mg doses of ALO-02 administered whole (intact capsule) under fasting conditions, administered whole under fed conditions (high-fat breakfast ∼ 950 calories), or sprinkling the contents of the ALO-02 capsule (pellets) over applesauce and swallowing the dose without chewing under fasting conditions. Each treatment was separated by a 7-day washout interval. Plasma samples were analyzed just before dosing through 48 hours postdose for oxycodone, and through 120 hours postdose for naltrexone and its major metabolite, 6-ß-naltrexol. Pharmacokinetic parameters included maximum plasma concentration [Cmax ], area under the plasma concentration-time profile from time 0 to infinity [AUCinf ] and to the last quantifiable concentration [AUClast ], time to Cmax [Tmax ], and terminal half life [t1/2 ]. Adverse events, vital signs, and laboratory parameters were monitored for safety assessment. The t1/2 and Tmax values for oxycodone were similar for all 3 treatments. There was a lack of effect of food (whole capsule, fed vs. fasted) or of sprinkling on applesauce (pellets vs. whole capsule, fasted) on oxycodone bioavailability. The Test/Reference ratios of adjusted geometric means for oxycodone AUCinf , AUClast , and Cmax were 99.2%, 100%, and 107%, respectively, for the effect of food; and 101%, 101%, and 97.5%, respectively, for the effect of sprinkling on applesauce. The 90% confidence intervals contained entirely within the bioequivalence limits of 80% to 125% for each comparison. Naltrexone remained sequestered during each treatment, based on the sporadic and low measurable plasma concentrations of naltrexone and 6-ß-naltrexol. Single doses of ALO-02 40 mg were well tolerated, and adverse events were mild, with no apparent difference in frequency for all 3 treatments. Results indicate that ALO-02 can be administered without regard to food. Also, the contents of ALO-02 can be sprinkled over applesauce and consumed without chewing as an alternative treatment option by subjects with difficulty swallowing. Naltrexone remained sequestered in the ALO-02 formulation under all 3 treatments.

Assessment of Pharmacodynamic Effects Following Oral Administration of Crushed Morphine Sulfate and Naltrexone Hydrochloride Extended-Release Capsules Compared with Crushed Morphine Sulfate Controlled-Release Tablets and Placebo in Nondependent Recreational Opioid Users

To compare the pharmacodynamic effects, including self-reports of "drug liking" and "high," of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules (MSN), crushed morphine sulfate controlled-release (CR) tablets, and placebo in an abuse potential study. Randomized, double-blind, placebo-controlled, three-way crossover study. Single-center. Nondependent recreational opioid users. Orally administered crushed MSN (120-mg morphine sulfate and 4.8-mg naltrexone hydrochloride), crushed 120-mg morphine sulfate CR, and placebo. Subjective ratings (100-point visual analog scales) of positive drug effects (drug liking, high, good effects, take drug again, and overall drug liking), any effects, and negative effects (bad effects, feel sick, nausea, sleepy, and dizzy), along with pupillometry, pharmacokinetic (PK), and safety assessments. Crushed morphine sulfate CR significantly increased ratings of all positive subjective measures relative to placebo (P < 0.0001). Crushed MSN significantly decreased all positive subjective ratings compared with morphine sulfate CR (P ≤ 0.005), but significantly increased ratings compared with placebo (P < 0.03). Peak pupil diameter was significantly larger for MSN than morphine sulfate (P < 0.0001). PK analysis of morphine plasma concentrations indicated that Cmax was significantly lower and tmax significantly longer for crushed MSN compared with crushed morphine sulfate CR. Plasma concentrations of naltrexone and 6-β-naltrexol were present following crushed MSN. This study demonstrated that when crushed and administered orally to nondependent recreational opioid users, MSN was associated with significantly lower scores on all positive subjective measures including drug liking and high, and significantly less pupil constriction compared with crushed morphine sulfate CR.

Relative oral bioavailability of morphine and naltrexone derived from crushed morphine sulfate and naltrexone hydrochloride extended-release capsules versus intact product and versus naltrexone solution: A single-dose, randomized-sequence, open-label, three-way crossover trial in healthy volunteers

Background: Morphine sulfate/sequestered naltrexone hydrochloride (HCl) (MS-sNT) extended-release fixed-dose combination capsules, approved by the US Food and Drug Administration (FDA) in August 2009 for chronic moderate to severe pain, contain extended-release morphine pellets with a sequestered core of the opioid antagonist naltrexone. MS-sNT was designed so that if the product is tampered with by crushing, the naltrexone becomes bioavailable to mitigate morphine-induced subjective effects, rendering the product less attractive for tampering. Objectives: The primary aim of this study was to compare the oral bioavailability of naltrexone and its metabolite 6-β-naltrexol, derived from crushed pellets from MS-sNT capsules, to naltrexone solution. This study also assessed the relative bioavailability of morphine from crushed pellets from MS-sNT capsules and that from the whole, intact product. Methods: This single-dose, randomized-sequence, open-label, 3-period, 3-treatment crossover trial was conducted in healthy volunteers. Adults admitted to the study center underwent a 10-hour overnight fast before study drug administration. Each subject received all 3 of the following treatments, 1 per session, separated by a 14-day washout: tampered pellets (crushed for ≥2 minutes with a mortar and pestle) from a 60-mg MS-sNT capsule (60 mg morphine/2.4 mg naltrexone); 60-mg whole, intact MS-sNT capsule; and oral naltrexone HCl (2.4 mg) solution. Plasma concentrations of naltrexone and 6-β-naltrexol were measured 0 to 168 hours after administration. Morphine pharmaco-kinetics of crushed and whole pellets were determined 0 to 72 hours after administration. The analysis of relative bioavailability was based on conventional FDA criteria for assuming bioequivalence; that is, 90% CIs for ratios of geometric means (natural logarithm [In]-transformed C max and AUC) fell within the range of 80% to 125%. Subjects underwent physical examinations, clinical laboratory tests, and ECG at screening and study discharge and were monitored for adverse events (AEs) throughout the study. Results: Of the 24 subjects enrolled in the study, 23 completed it. Most subjects were white (79%) and male (63%); the mean (SD) age was 39.3 (11.2) years and the mean weight was 77.6 (13.5) kg (range, 55.0102.5 kg). Plasma C max and AUC 0-t of naltrexone after the administration of crushed pellets of MS-sNT (579 pg/mL and 1811 h · pg/mL, respectively) and naltrexone solution (584 pg/mL and 1954 h · pg/mL) were not significantly different; 90% CIs were 83.8% to 116% and 83.3% to 102%, meeting the regulatory requirements for assuming bioequivalence in this study population. Plasma naltrexone concentration was below the lower limit of quantitation (4.0 pg/mL) in 23 of 24 subjects (96%) after whole MS-sNT administration. Morphine AUC 0-t was not significantly different whether MS-sNT was crushed (163 h · ng/mL) or administered whole (174 h · ng/mL), but C max was numerically higher (24.5 vs 7.7 ng/mL) and T max was numerically shorter (2.00 vs 7.03 hours) with MS-sNT crushed versus whole. The most commonly reported AEs were nausea (8/23 [35%], 10/24 [42%], and 3/23 [13%] subjects in the crushed, whole, and naltrexone groups, respectively) and emesis (6 [26%], 7 [29%], and 2 [9%]). Conclusions: In this single-dose study, when pellets from MS-sNT were crushed, naltrexone appeared to be completely released and available to mitigate morphine-induced effects. When MS-sNT was administered whole, morphine was released in an extended-release fashion while naltrexone remained sequestered.

Therapeutic drug monitoring of naltrexone in alcohol dependent patients

Rationale: The µ-opiate receptor antagonist naltrexone is a new option for the treatment of alcohol dependence. It has been shown to reduce craving for alcohol and alcohol intake. Objective: The aim of this study was to relate plasma concentrations of naltrexone and its major active metabolite 6β-naltrexol in patients during treatment with naltrexone with clinical effects. Methods: A high performance liquid chromatographic method with column switching and spectrophotometric detection was established and validated and used for determination of naltrexone and 6β-naltrexol in plasma samples collected under steady state conditions. Results: Plasma concentrations exhibited high interindividual variabilities. The sum of concentrations naltrexone plus 6β-naltrexol correlated significantly with the reduction of alcohol intake. Receiver operating characteristics (ROC) analyses revealed significantly (p=0.043) higher rates of reduced alcohol drinking when plasma concentrations of naltrexone and 6β-naltrexol were above 16ng/ml. Conclusions: These data give evidence that monitoring of drug concentrations may be a useful option to improve the outcome of naltrexone treatment aiming to reduce alcohol consumption.

Single‐ and Multiple‐Dose Pharmacokinetics of Long‐acting Injectable Naltrexone

Oral naltrexone is effective in the treatment of alcohol dependence; however, a major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. A biodegradable, long-acting naltrexone microsphere formulation was developed to achieve continuous naltrexone exposure for 1 month in the treatment of alcohol dependence. The single- and multiple-dose safety and pharmacokinetics of a long-acting naltrexone microsphere preparation were evaluated in healthy subjects. One group of subjects (n = 28) received a single dose of oral naltrexone 50 mg followed by a single gluteal intramuscular (IM) injection of long-acting naltrexone 190 or 380 mg or placebo. A different group of subjects (n = 14) received oral naltrexone 50 mg daily for 5 days, followed by IM long-acting naltrexone 380 mg or placebo every 28 days for a total of 4 doses. A 7-day washout period separated oral and IM administrations. Blood samples were collected to determine plasma concentrations of naltrexone and the primary metabolite, 6beta-naltrexol. After a single IM injection of long-acting naltrexone 380 mg, naltrexone plasma concentrations were measurable in all subjects for at least 31 days postdose. The pharmacokinetics were proportional to the dose and multiple dose observations were consistent with single dose observations. Mean apparent elimination half-lives for naltrexone and 6beta-naltrexol ranged from 5 to 7 days. Exposure to 6beta-naltrexol was reduced with IM injection compared with that oral administration. No serious adverse events occurred. This study demonstrated that the long-acting naltrexone formulation was well tolerated, displayed predictable pharmacokinetics, and resulted in no meaningful drug accumulation upon multiple dosing. Intramuscular administration avoids first-pass metabolism and changes the exposure ratio of 6beta-naltrexol to naltrexone compared with oral administration. By providing continuous exposure to naltrexone for several weeks following IM injection, this long-acting naltrexone formulation may offer therapeutic benefit to those patients who experience difficulty adhering to the daily administration schedule necessitated by oral naltrexone therapy.

The preclinical development of Medisorb® Naltrexone, a once a month long-acting injection, for the treatment of alcohol dependence

Oral naltrexone, a nonselective opioid antagonist, is approved for the treatment of alcohol and opioid dependence. However, the efficacy of oral naltrexone is limited by poor patient compliance. To overcome this limitation, attempts have been made to develop an injectable extended-release formulation of naltrexone, including encapsulation into biodegradable polymer microspheres (e.g. Medisorb Naltrexone, Vivitrex (naltrexone long acting injection)). In 1980, NIDA established development goals that they considered optimal for an extended-release formulation. At Alkermes, different formulations were tested with in vitro assays and in vivo models to select a lead formulation. Pharmacokinetic studies in rats confirmed that the principle formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately one month following a single injection. The pharmacodynamic effects (antagonism of morphine analgesia) of extended-release naltrexone corresponded well with the pharmacokinetic profile from the same animals. While brain mu-opioid receptor density was found to increase over time in these rats, it did not appear to affect the ability of naltrexone to suppress morphine analgesia. Finally the pharmacokinetic profile of extended-release naltrexone in monkeys confirmed long duration of elevated plasma concentrations of naltrexone. Both naltrexone and the PLG polymer matrix in which it is encapsulated are well tolerated. Clinical trials of Vivitrex are currently ongoing in alcohol dependent patients.

Determination of naltrexone and its major metabolite, 6-β-naltrexol, in human plasma using liquid chromatography with electrochemical detection

A sensitive and specific high-performance liquid chromatographic method with electrochemical detection was developed for the simultaneous determination of naltrexone and its major metabolite, 6-β-naltrexol, in human plasma. After alkalinizing 2 ml plasma samples with pH 9 sodium carbonate buffer, naltrexone and 6-β-naltrexol were extracted into dichloromethane and then back-extracted into 0.017 M phosphoric acid. A portion of the acid extract was chromatographed on a YMC phenyl column using a mobile phase of methanol-phosphoric acid (50 mM) (20:80, v/v) (pH∗ 3.2) at a flow-rate of 1.2 ml min −1. Quantification was performed using an ESA Coulometric electrochemical detector. Acceptable intra-day and inter-day assay precision (RSD < 10%) and accuracy (< 16%) for both compounds were observed over concentration ranges of 0.25–50.0 ng ml −1 for naltrexone and 0.5–100 ng ml −1 for 6-β-naltrexol. No degradation of either naltrexone or 6-β-naltrexol was observed in frozen human plasma stored at − 20°C over an 8 month period. The method is sufficiently sensitive and selective to quantify plasma concentrations of naltrexone and 6-β-naltrexol after oral doses of 50 mg of naltrexone to healthy subjects or alcoholic patients.

Plasma concentrations of naltrexone and 6β-naltrexol in patients with liver cirrhosis and drug addicts in chronic treatment with naltrexone

Plasma concentrations of naltrexone and 6β-naltrexol in patients with liver cirrhosis and drug addicts in chronic treatment with naltrexone