Optimizing Process Parameters for Controlled Drug Delivery: A Quality by Design (QbD) Approach in Naltrexone Microspheres.

The formulation of microspheres involves a complex manufacturing process with multiple steps. Identifying the appropriate process parameters to achieve the desired quality attributes poses a significant challenge. This study aims to optimize the critical process parameters (CPPs) involved in the preparation of naltrexone microspheres using a Quality by Design (QbD) methodology. Additionally, the research aims to assess the drug release profiles of these microspheres under both in vivo and in vitro conditions. Critical process parameters (CPPs) and critical quality attributes (CQAs) were identified, and a Box-Behnken design was utilized to delineate the design space, ensuring alignment with the desired Quality Target Product Profile (QTPP). The investigated CPPs comprised polymer concentration, aqueous phase ratio to organic phase ratio, and quench volume. The microspheres were fabricated using the oil-in-water emulsion solvent extraction technique. Analysis revealed that increased polymer concentration was correlated with decreased particle size, reduced quench volume resulted in decreased burst release, and a heightened aqueous phase ratio to organic phase ratio improved drug entrapment. Upon analyzing the results, an optimal formulation was determined. In conclusion, the study conducted in vivo drug release testing on both the commercially available innovator product and the optimized test product utilizing an animal model. The integration of in vitro dissolution data with in vivo assessments presents a holistic understanding of drug release dynamics. The QbD approach-based optimization of CPPs furnishes informed guidance for the development of generic pharmaceutical formulations.

Impacts of genetic polymorphisms and cancer cachexia on naldemedine pharmacokinetics and bowel movements in patients receiving opioid analgesics.

BACKGROUND/OBJECTIVES: Clinical responses to naldemedine vary between individuals with advanced cancer. This is a prospective, single-center, observational study aimed to evaluate the influence of genetic polymorphisms and cachexia status on plasma naldemedine and clinical responses. METHODS: Forty-eight patients being treated with naldemedine for opioid-induced constipation under treatment of cancer pain were enrolled. Plasma naldemedine concentrations were determined on the fourth day or later after administration of naldemedine, and the associations with genotypes, cachexia status, and clinical responses were assessed. RESULTS: Cancer patients exhibited a large variation in the plasma naldemedine concentrations, and it was correlated with serum total protein level. Patients who were homozygous CYP3A5*3 had a higher plasma concentration of naldemedine than those with the *1 allele. ABCB1 genotypes tested in this study were not associated with plasma naldemedine. A negative correlation was observed between the plasma naldemedine concentration and 4ß-hydroxycholesterol level. The plasma naldemedine concentration was lower in patients with refractory cachexia than in those with precachexia and cachexia. While serum levels of interleukin-6 (IL-6) and acute-phase proteins were higher in patients with refractory cachexia, they were not associated with plasma naldemedine. A higher plasma concentration of naldemedine, CYP3A5*3/*3, and an earlier naldemedine administration after starting opioid analgesics were related to improvement of bowel movements. CONCLUSION: Plasma naldemedine increased under deficient activity of CYP3A5 in cancer patients. Cachectic patients with a higher serum IL-6 had a lower plasma naldemedine. Plasma naldemedine, related to CYP3A5 genotype, and the initiation timing of naldemedine were associated with improved bowel movements.

Effects of genotype and food on naltrexone exposure in adolescents.

Naltrexone (NTX), an opioid antagonist metabolized by aldo-keto reductase 1C4 (AKR1C4), is prescribed for psychiatric conditions like eating disorders with variable response. Systemic exposure is highly variable in adults, yet no data exist in children. The purpose of this study was to evaluate NTX exposure in adolescents with eating disorders. Adolescents aged 12-21 years with eating disorders underwent postdose blood sampling in the fasted and/or fed state. NTX and primary active metabolite, 6-ß-naltrexol, were determined by ultra-high performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. DNA was genotyped for AKR1C4 missense mutations associated with decreased activity (rs3829125 and rs17134592). Linear mixed effects modeling was performed. In 21 participants, aged 16.9 ± 1.9 years (15-21 years), 81% female participants, maximum concentration (Cmax ) was 90.4 ± 129 nM/mg/kg, area under the concentration-time curve from zero to infinity (AUC0-∞ ) was 166 ± 154 nM h/mg/kg, and varied 63-fold and 21-fold, respectively. Compared with wildtype, those with AKR1C4 allelic variations (n = 7) displayed 3.2-fold higher AUC0-∞ , four-fold higher Cmax and delayed time to Tmax . Linear mixed effects modeling demonstrated a large effect of genotype on AUC0-∞ (Cohen's d -2.3) and Cmax (Cohen's d -1.4). Food effect was large for AUC0-∞ (Cohen's d 2.6), but highly variable and failed to reach significance for Cmax. The respective model accounted for 82% of the variance in NTX AUC0-∞ and 46% of the variance in Cmax . NTX systemic exposure is highly variable in adolescents with eating disorders and modulated, in part, by AKR1C4 genotype and food intake. These findings may, in part, explain the large degree of interindividual variability observed response to NTX.

The Impact of Age and Genetics on Naltrexone Biotransformation.

Naltrexone, an opioid antagonist primarily metabolized by aldo-keto reductase 1C4 (AKR1C4), treats pediatric conditions involving compulsiveness (e.g., autism spectrum, Prader-Willi, eating disorders, non-suicidal self-injury). Pharmacokinetic variability is apparent in adults, yet no data are available for children. This study aimed to examine the impact of age and genetic variation on naltrexone biotransformation. Human liver cytosol (HLC) samples (n = 158) isolated from children and adult organ donors were incubated with therapeutically relevant concentrations of naltrexone (0.1, 1 µM). Naltrexone biotransformation was determined by ultraperformance mass spectrometry quantification of the primary metabolite, 6-beta-naltrexol (6ßN), and 6ßN formation rates (pmol/mg protein/min) were calculated. HLCs from organ donors, age range 0-79 y (mean 16.0 ± 18.2 y), 37% (n = 60) female, 20% (n = 33) heterozygous and 1.2% (n = 2) homozygous for co-occurring AKR1C4 variants (S145C/L311V) showed >200-fold range in 6ßN formation (0.37-76.5 pmol/mg protein/min). Source of donor samples was found to be a substantial contributor to variability. Model estimates for a trimmed data set of source-adjusted pediatric samples (aged 0-18 y) suggested that AKR1C4 genetic variation, age, and sex explained 36% of the variability in 6ßN formation. Although activity increased steadily from birth and peaked in middle childhood (2-5 years), genetic variation (S145C/L311V) demonstrated a greater effect on activity than did age. Naltrexone biotransformation is highly variable in pediatric and adult livers and can be partly accounted for by individual factors feasible to obtain (e.g., genetic variability, age, sex). These data may inform a precision therapeutics approach (e.g., exposure optimization) to further study Naltrexone responsiveness in children and adults. SIGNIFICANCE STATEMENT: Biotransformation of the commonly used opioid antagonist naltrexone is highly variable and may contribute to reduced therapeutic response. Age, sex, and genetic variation in the drug-metabolizing enzyme, AKR1C4, are potential factors contributing to this variability. In pediatric samples, genetic variation (S145C/L311V) demonstrates a greater impact on activity than age. Additionally, the source of donor samples was identified as an important contributor and must be accounted for to confidently elucidate the biological variables most impactful to drug biotransformation.

Naloxone and nalmefene absorption delivered by hollow microneedles compared to intramuscular injection.

Naloxone and nalmefene were administered to seven research beagle dogs (mean weight approximately 12 kg) at doses of 0.04 mg/kg and 0.014 mg/kg for naloxone and nalmefene, respectively. Each dose was administered intramuscularly (IM) with a standard IM injection and with a hollow microneedle device array using needles of 1 mm in length. The IM injection was delivered in the epaxial muscles, and the microneedle injection was delivered in the skin over the shoulder of each dog. Each dog received the same injections in a crossover design. Following the injection, blood samples were collected for plasma analysis of naloxone and nalmefene by high-pressure liquid chromatography with mass spectrometry detection (LCMS). The plasma sample concentrations were plotted for observed patterns of absorption and analyzed with non-compartmental pharmacokinetic methods (NCA). The results showed that the injection of naloxone from the microneedle device produced a higher peak concentration (CMAX) by 2.15 × compared the IM injection of the same dose, and time to peak concentration (TMAX) was similar. For the nalmefene injection, the peak was not as high (lower CMAX) by 0.94 × for the microneedle injection compared to the IM injection of the same dose. The microneedle produced an exposure, measured by area under the curve (AUC), that was 0.85 × and 0.58 × as high for naloxone and nalmefene, respectively, than the injection by the IM route. We also observed that although the dose for naloxone was approximately 3 × higher for naloxone compared to nalmefene, the mean peak concentration achieved from the naloxone injection was more than 12 × higher than that from the nalmefene injection. These studies were designed to test the feasibility of using the hollow microneedle array as an effective method of naloxone and nalmefene delivery for emergency treatment of opioid-induced respiratory depression (OIRD). The results of these studies will form the basis of future studies, using the dog as a model, for development of hollow microneedle microarray devices to deliver opioid antagonists for treatment of OIRD in people.

Involvement of the Peripheral µ-Opioid Receptor in Tramadol-Induced Constipation in Rodents.

Tramadol is a weak opioid that produces analgesic effect via both the µ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3-100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01-10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01-0.3 mg/kg, and complete recovery was observed at 0.3-10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation.

Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent.

BACKGROUND: One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. METHODS: A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. RESULTS: A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01-0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. CONCLUSIONS: Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.

Using physiologically-based pharmacokinetic modeling for predicting the effects of hepatic impairment on the pharmacokinetics of olanzapine and samidorphan given as a combination tablet.

A combination of olanzapine and samidorphan (OLZ/SAM) was recently approved by the US Food and Drug Administration for treatment of patients with schizophrenia or bipolar I disorder. The effects of moderate hepatic impairment on the pharmacokinetics (PKs) of olanzapine and samidorphan after a single dose of OLZ/SAM were characterized in a clinical study. Physiologically-based pharmacokinetic (PBPK) modeling was used to extend the clinical findings to predict the effects of varying degrees of hepatic impairment on the PKs of olanzapine and samidorphan. A previously developed PBPK model for OLZ/SAM was refined to recover the observed pharmacokinetic differences between individuals with moderate hepatic impairment and healthy controls. The optimized model was applied to predict changes in olanzapine and samidorphan PKs after multiple once-daily doses of OLZ/SAM in subjects with mild, moderate, and severe hepatic impairment relative to healthy controls. Modifications to model parameters, including absorption rate constant and fraction unbound to plasma protein, were made to recover the observed change in the PKs of olanzapine and samidorphan in individuals with moderate hepatic impairment. In applying the optimized model, mild, moderate, and severe hepatic impairment were predicted to increase steady-state total systemic exposures by 1.1-, 1.5-, and 1.6-fold, respectively, for olanzapine, and by 1.2-, 1.9-, and 2.3-fold, respectively, for samidorphan. PBPK modeling allowed for prediction of untested clinical scenarios of varying degrees of hepatic impairment in lieu of additional clinical studies.

Population Pharmacokinetics of Olanzapine and Samidorphan When Administered in Combination in Healthy Subjects and Patients With Schizophrenia.

A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5'-diphospho-glucuronosyltransferase-mediated direct glucuronidation and cytochrome P450 [CYP]-mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5'-diphospho-glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure.

Chronic Naltrexone Therapy Is Associated with Improved Cardiac Function in Volume Overloaded Rats.

PURPOSE: Myocardial opioid receptors were demonstrated in animals and humans and seem to colocalize with membranous and sarcolemmal calcium channels of the excitation-contraction coupling in the left ventricle (LV). Therefore, this study investigated whether blockade of the cardiac opioid system by naltrexone would affect cardiac function and neurohumoral parameters in Wistar rats with volume overload-induced heart failure. METHODS: Volume overload in Wistar rats was induced by an aortocaval fistula (ACF). Left ventricular cardiac opioid receptors were identified by immunohistochemistry and their messenger ribonucleic acid (mRNA) as well as their endogenous ligand mRNA quantified by real-time polymerase chain reaction (RT-PCR). Following continuous delivery of either the opioid receptor antagonist naltrexone or vehicle via minipumps (n = 5 rats each), hemodynamic and humoral parameters were assessed 28 days after ACF induction. Sham-operated animals served as controls. RESULTS: In ACF rats mu-, delta-, and kappa-opioid receptors colocalized with voltage-gated L-type Ca2+ channels in left ventricular cardiomyocytes. Chronic naltrexone treatment of ACF rats reduced central venous pressure (CVP) and left ventricular end-diastolic pressure (LVEDP), and improved systolic and diastolic left ventricular functions. Concomitantly, rat brain natriuretic peptide (rBNP-45) and angiotensin-2 plasma concentrations which were elevated during ACF were significantly diminished following naltrexone treatment. In parallel, chronic naltrexone significantly reduced mu-, delta-, and kappa-opioid receptor mRNA, while it increased the endogenous opioid peptide mRNA compared to controls. CONCLUSION: Opioid receptor blockade by naltrexone leads to improved LV function and decreases in rBNP-45 and angiotensin-2 plasma levels. In parallel, naltrexone resulted in opioid receptor mRNA downregulation and an elevated intrinsic tone of endogenous opioid peptides possibly reflecting a potentially cardiodepressant effect of the cardiac opioid system during volume overload.

Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects.

BACKGROUND: Naldemedine is a peripherally acting µ-opioid receptor antagonist that is indicated to treat opioid-induced constipation. OBJECTIVES: To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. METHODS: Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. RESULTS: A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC0-inf 1.78-fold and Cmax 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC0-inf 2.91-fold and 1.90-fold, and Cmax 1.12-fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC0-inf by 83% and Cmax by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. CONCLUSIONS: Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated.

Naldemedine is a targeted medication approved in the USA, Europe, and Japan for the treatment of opioid-induced constipation. Symptoms of constipation may include passing fewer stools than usual, having lumpy or hard stools, and/or straining to have bowel movements. In some cases, these symptoms are side effects of regular opioid use, which is often medically necessary for the management of moderate-to-severe pain. For naldemedine to be prescribed safely, doctors must know what other medications a patient is taking and how these medications may affect one another. This is commonly known as drug-drug interactions. Some drug-drug interactions may decrease how well a medication works, while other drug-drug interactions may increase the side effects experienced by a patient. In this paper, researchers report the results of three Phase 1 studies in healthy subjects examining how naldemedine interacts with other drugs. The drugs chosen for investigation are commonly evaluated in DDI studies and may affect the transport or metabolic pathway of naldemedine, including the P-glycoprotein inhibitor cyclosporine, the CYP3A inhibitors itraconazole and fluconazole, and the CYP3A inducer rifampin. These studies demonstrate that co-administration of naldemedine with each of these drugs impacted the pharmacokinetics of naldemedine. Cyclosporine, itraconazole, or fluconazole all increased naldemedine exposure, while rifampin decreased naldemedine exposure. For all drug combinations, observed side effects were generally mild and well tolerated. Additional testing, including vital signs and heart monitoring, did not reveal any other safety concerns. In conclusion, these findings support the cautious use of naldemedine in combination with cyclosporine, itraconazole or fluconazole. Concomitant use with rifampin should be avoided.

Tissue Residue Levels of the Tranquilizer Combination of Butorphanol, Azaperone, and Medetomidine, and the Antagonists, Naltrexone, Atipamezole, and Tolazoline, in Black Bears (Ursus americanus) Postimmobilization.

The tranquilizer combination of butorphanol, azaperone, and medetomidine (BAM) has shown good efficacy for immobilization of wildlife, including black bears (Ursus americanus). BAM is antagonized with a combination of naltrexone and atipamezole. We immobilized 19 adult captive wild caught black bears and, except for three bears that were euthanized immediately, bears were recovered with naltrexone and atipamezole. Tissue residues (≥0.01 ppm) for the tranquilizers butorphanol, azaperone, and medetomidine were detected in liver and muscle of all three bears euthanized on day 0 postinjection (PI). Azaperone was not detected after 1 d PI. Residue for medetomidine was detected in two bears: in the liver 3 d PI and in the kidney 6 d PI. Butorphanol was reported in three bears: in fat 5 d PI, in kidney 6 d PI, and, surprisingly, in kidney, muscle, and fat 7 d PI. No tissue residues were detected in the three bears euthanized at 8 d PI. Tissue residues for the antagonists, naltrexone and atipamezole, were detected in bears euthanized 2 and 6 d PI, but not in tissues from animals euthanized at 7 or 8 d PI.

Physiologically-Based Pharmacokinetic Modeling for Predicting Drug Interactions of a Combination of Olanzapine and Samidorphan.

A combination of the antipsychotic olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. As cytochrome P450 (CYP) 1A2 and CYP3A4 are the major enzymes involved in metabolism of olanzapine and samidorphan, respectively, physiologically-based pharmacokinetic (PBPK) modeling was applied to predict any drug-drug interaction (DDI) potential between olanzapine and samidorphan or between OLZ/SAM and CYP3A4/CYP1A2 inhibitors/inducers. A PBPK model for OLZ/SAM was developed and validated by comparing model-simulated data with observed clinical study data. Based on model-based simulations, no DDI between olanzapine and samidorphan is expected when administered as OLZ/SAM. CYP3A4 inhibition is predicted to have a weak effect on samidorphan exposure and negligible effect on olanzapine exposure. CYP3A4 induction is predicted to reduce both samidorphan and olanzapine exposure. CYP1A2 inhibition or induction is predicted to increase or decrease, respectively, olanzapine exposure only.

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine.

Naldemedine is a peripherally acting µ-opioid-receptor antagonist for the treatment of opioid-induced constipation. Two phase 1 single-dose studies investigated the pharmacokinetics and safety of a 0.2-mg oral dose of naldemedine in subjects with renal impairment (mild, n = 9; moderate, n = 9; severe, n = 6; and end-stage renal disease, n = 8) or hepatic impairment (mild or moderate, n = 8 each) and demographically matched healthy subjects with normal renal and hepatic function (n = 8, both studies). Pharmacokinetic assessments indicate that dose adjustments for naldemedine are not necessary for subjects with any degree of renal impairment or for subjects with mild or moderate hepatic impairment. In subjects with renal impairment compared with healthy subjects with normal renal function, the geometric mean ratios of naldemedine area under the concentration-time curve (AUC0-inf ) ranged from 82.8% (90%CI 69.5% to 98.6%) to 137.8% (90%CI 114.0% to 166.5%). Renal clearance decreased with reduced renal function (normal function 1.3 L/h; mild impairment 1.1 L/h; moderate impairment 1.0 L/h; severe impairment 0.5 L/h), and only 2.7% of naldemedine was removed by hemodialysis. In subjects with hepatic impairment compared with healthy subjects with normal hepatic function, the geometric mean ratio of AUC0-inf ranged from 82.8% (90%CI 65.7% to 104.5%) to 105.2% (90%CI 83.4% to 132.6%). Naldemedine was well tolerated in both healthy subjects and subjects with renal or hepatic impairment, and reported adverse events were generally consistent with the known safety profile.

OREX-1019: A Novel Treatment of Opioid Use Disorder and Relapse Prevention.

There is an urgent need for new pharmacological treatments for substance use disorders, including opioid use disorder, particularly for use in relapse prevention. A combination of buprenorphine with naltrexone has shown particular promise, with clinical studies indicating a substantial improvement over treatment with naltrexone alone. OREX-1019 (formerly BU10119) is a compound that mimics the pharmacology of the buprenorphine/naltrexone combination. This study evaluated, in rhesus monkeys, the therapeutic potential of OREX-1019 for treating opioid use disorder. Pretreatment with OREX-1019 (0.01-0.3 mg/kg s.c.) dose-dependently decreased responding for the µ opioid receptor agonist remifentanil in rhesus monkeys but did not maintain levels of responding above vehicle when it was available for self-administration. OREX-1019 (0.01-1.0 mg/kg s.c.) also decreased cue- plus heroin-primed reinstatement of extinguished responding in monkeys that self-administered remifentanil but did not alter cue- plus cocaine-primed reinstatement of responding in monkeys that self-administered cocaine. OREX-1019 (0.3 mg/kg s.c.), like naltrexone (0.1 mg/kg s.c.), increased heart rate and blood pressure, produced overt observable signs, and eliminated food-maintained responding in monkeys treated chronically with morphine. These results confirm that OREX-1019 has little or no efficacy at µ opioid receptorsand has low abuse potential, and, combined with promising safety (clean profile vs. other off-target proteins including the hERG (human ether-a-go-go-related gene) K+ channel) and pharmacokinetic data (supporting administration by subcutaneous or sublingual routes, but with low oral bioavailability), suggest it could be a safe and effective alternative to current treatments for opioid use disorders particularly as applied to relapse prevention. SIGNIFICANCE STATEMENT: The novel opioid OREX-1019 potentially provides an improved relapse prevention agent for use in opioid use disorder. The current study demonstrates that in monkeys OREX-1019 is able to inhibit the self-administration of, and cue- plus heroin-primed reinstatement of, responding previously maintained by remifentanil.

Effect of hepatic and renal impairment on the pharmacokinetics of olanzapine and samidorphan given in combination as a bilayer tablet.

BACKGROUND: A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain. METHODS: Two multicenter, open-label, parallel-cohort studies were performed to evaluate the effect of moderate hepatic impairment (Child-Pugh score 7-9 [class B]; study 1) and severe renal impairment (estimated glomerular filtration rate: 15-29 mL/min/1.73 m2; study 2) on the pharmacokinetics, safety, and tolerability of a single dose of OLZ/SAM 5/10 mg. RESULTS: There was a 1.67-fold increase in area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) and a 2.17-fold increase in maximum plasma concentration (Cmax) of olanzapine, and a 1.52-fold increase in AUC0-∞ and a 1.63-fold increase in Cmax of samidorphan, in subjects with moderate hepatic impairment compared with healthy control subjects. Compared with healthy control subjects, subjects with severe renal impairment had a 33% and 56% reduction in clearance, a 1.51- and 2.31-fold increase in AUC0-∞, and a 1.32- and 1.37-fold increase in Cmax of olanzapine and samidorphan, respectively. CONCLUSION: OLZ/SAM 5/10 mg was generally well tolerated under the conditions of the studies, with a safety profile consistent with that observed in other clinical studies of OLZ/SAM.

Hydrogels for diabetic eyes: Naltrexone loading, release profiles and cornea penetration.

Naltrexone (NTX) is a potent opioid growth factor receptor (OGFR) antagonist proved to be useful for treatment of ocular surface complications. The aim of this work was to explore the feasibility of designing NTX-imprinted 2-hydroxyethyl methacrylate-based hydrogels for sustained drug release on the ocular surface. Acrylic acid (AAc) and benzyl methacrylate (BzMA) were chosen as functional monomers able to form binding cavities mimicking OGFR binding sites for NTX. Imprinted hydrogels containing functional monomers loaded higher amounts of NTX compared to non-imprinted ones by simple soaking in drug aqueous solution. In addition, possibility of carrying out the loading and sterilization processes in one step was investigated. NTX release was evaluated both under agitated sink conditions and in a microfluidic flow chamber mimicking the hydrodynamic conditions of the eye, namely the small volume of lachrymal fluid and its renovation rate. Sustained release profiles together with adequate swelling degree (46 to 57% w/w), light transparency (over 85%) and oxygen permeability may make these hydrogels suitable candidates to NTX-eluting contact lenses. NTX-loaded and non-loaded discs successfully passed the chorioallantoic membrane test for potential ocular irritation and were cytocompatible with human mesenchymal stem cells. Finally, NTX-imprinted hydrogels tested in the bovine corneal permeability assay provided therapeutically relevant amounts of NTX inside the cornea, reaching drug levels similar to those attained with a concentrated aqueous solution in spite the discs showed sustained release.

Characterization of the Pharmacokinetics of Samidorphan in Healthy Volunteers: Absolute Bioavailability and the Effect of Food and Age.

BACKGROUND AND OBJECTIVES: Samidorphan (SAM) is a novel µ-opioid receptor antagonist. We report clinical pharmacokinetic (PK) properties of SAM following different routes of administration, and the effects of food and age on the PK of SAM following oral administration in healthy volunteers. METHODS: An open-label, fixed-sequence study (study 1, N = 10) examined the PK parameters following intravenous, sublingual, and oral exposure to SAM to determine absolute bioavailability. A double-blind, placebo-controlled study (study 2, N = 45) compared the PK in participants aged 18-40 years (cohort 1, n = 30) and ≥ 65 years (cohort 2, n = 15) who received a single oral dose of SAM 10 mg under fed (cohort 1 only) or fasted conditions. RESULTS: In study 1, intravenous SAM had a plasma clearance of 33.7 L/h, volume of distribution of 341 L, and elimination half-life of 7-8 h. SAM was well-absorbed following sublingual or oral administration and reached peak concentrations (Cmax) within 2 h, with absolute bioavailability of 71% (sublingual) and 69% (oral). In study 2, concentration-time profiles were similar under fed and fasted conditions (cohort 1) and for young and elderly participants from both cohorts; 90% confidence intervals for the geometric least squares mean ratios for Cmax and area under the concentration-time curve from time zero extrapolated to infinity indicated equivalence. CONCLUSIONS: SAM has high bioavailability that is comparable following sublingual and oral administration and is not subject to extensive first-pass metabolism. The PK of orally administered SAM are not affected by food or age.

A Randomized, Crossover Study on the Effect of Food on the Pharmacokinetic Characteristics of Morphine ARER (MorphaBond™ ER), an Abuse-Deterrent Formulation of Extended-Release Morphine.

INTRODUCTION: Food can alter the pharmacokinetics of certain abuse-deterrent formulations. Morphine ARER is an oral abuse-deterrent formulation of ER morphine sulfate tablets formulated with physical and chemical properties that contribute to the abuse-deterrent aspects of the drug. This study compared the relative bioavailability of Morphine ARER in the presence and absence of food. METHODS: This was a randomized, single-dose, two-treatment, crossover study in which healthy adults received Morphine ARER 100 mg under fasting and fed conditions. Subjects were given naltrexone 50 mg to limit opioid effects. Plasma concentrations of morphine and its active metabolite morphine-6-glucuronide (M6G) were obtained up to 48 h post-dose; area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUC0-∞), maximum observed plasma concentration (Cmax) and time to Cmax (Tmax) were calculated. Safety was evaluated by observation or report of adverse events, which were monitored during the treatment periods. RESULTS: Of 28 enrolled subjects, 27 completed all treatments; 1 subject in the fasted group withdrew voluntarily. Under fed conditions, the Cmax for morphine was 33% higher (44.78 vs. 33.30 ng/ml for fed and fasted conditions, respectively) and the median Tmax was 30 min longer than under fasted conditions. The overall morphine exposure (AUC0-∞) was similar for fed (440.6 ng · h/ml) vs. fasted conditions (395.1 ng · h/ml). For M6G, the Cmax and AUC0-∞ were similar under both conditions, and the median Tmax for M6G was 60 min longer under fed conditions. Common adverse events were somnolence and nausea. CONCLUSION: Morphine ARER can be administered without regard to food. Plain language summary available for this article. FUNDING: Inspirion Delivery Sciences, LLC.

Food alters how the body processes some currently available opioids. How the opioid is formulated in the final commercial product can impact this effect. Morphine ARER is a new oral abuse-deterrent formulation of extended-release morphine created with properties to make it more difficult to abuse via the intranasal and intravenous routes. To better understand how food affects Morphine ARER bioavailability, we compared the amount of morphine in the blood when 100 mg of Morphine ARER was given with or without food, in random order, to 27 healthy volunteers. Plasma samples were collected up to 48 h after dosing to measure the concentrations of morphine and its active metabolite morphine-6-glucuronide. We measured the amount of drug absorbed by using the area under the plasma concentration-time curve (AUC) and the rate of drug absorption by looking at the highest amount of drug observed in the blood using the maximum observed plasma concentration (C_max) and time to C_max (T_max). When subjects were fed, the C_max for morphine was 33% higher (44.78 ng/ml) than when they fasted (33.30 ng/ml). The median T_max was 30 min longer when subjects were fed. Total morphine exposure (AUC_0­∞) was similar when subjects were fed (440.6 ng · h/ml) or when they fasted (395.1 ng · h/ml). Safety was evaluated throughout the treatment periods by adverse events, either observed by the clinician or reported by subjects. The most common adverse events noted were somnolence (e.g., sleepiness) and nausea. Our findings show that Morphine ARER has similar bioavailability when taken with or without food.

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.