A Continuous Intestinal Absorption Model to Predict Drug Enterohepatic Recirculation in Healthy Humans: Nalbuphine as a Model Substrate.

Nalbuphine (NAL) is a κ-agonist/µ-antagonist opioid being developed as an oral extended formulation (ER) for the treatment of chronic cough in idiopathic pulmonary fibrosis and itch in prurigo nodularis. NAL is extensively glucuronidated and likely undergoes enterohepatic recirculation (EHR). The purpose of this work is to develop pharmacokinetic models for NAL absorption and enterohepatic recirculation (EHR). Clinical pharmacokinetic (PK) data sets in healthy subjects from three trials that included IV, oral solution, and ER tablets in fed and fasted state and two published trials were used to parametrize a novel partial differential equation (PDE)-based model, termed "PDE-EHR" model. Experimental inputs included in vitro dissolution and permeability data. The model incorporates a continuous intestinal absorption framework, explicit liver and gall bladder compartments, and compartments for systemic drug disposition. The model was fully PDE-based with well-stirred compartments achieved by rapid diffusion. The PDE-EHR model accurately reproduces NAL concentration-time profiles for all clinical data sets. NAL disposition simulations required inclusion of both parent and glucuronide recirculation. Inclusion of intestinal P-glycoprotein efflux in the simulations suggests that NAL is not expected to be a victim or perpetrator of P-glycoprotein-mediated drug interactions. The PDE-EHR model is a novel tool to predict EHR and food/formulation effects on drug PK. The results strongly suggest that even intravenous dosing studies be conducted in fasted subjects when EHR is suspected. The modeling effort is expected to aid in improved prediction of dosing regimens and drug disposition in patient populations.

A population pharmacokinetic-pharmacodynamic model evaluating efficacy of nalbuphine extended-release in patients with prurigo nodularis.

AIMS: Population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) models were used to describe the exposure-response (E-R) relationship between nalbuphine exposure and two widely used rating scales for itch: the Numerical Rating Scale for the subject's 'average'; itch experience (NRS-AV) and the Worst Itch (WI-NRS), with 24-h recall. Simulations based on the model E-R relationship were used to support dose selection for Phase 3 clinical trials and were evaluated with a target of reducing the 7-day average of the 24-h WI-NRS by at least 30% from baseline in most of the analysis population. METHODS: Data from two clinical trials (NCT02373215: 9 healthy subjects; NCT02174419: 62 subjects with PN), in patients with prurigo nodularis (PN) with moderate to severe itch who received treatment with either of two doses of nalbuphine extended release (ER) or placebo, were used for the analysis. A two-compartment PK model with serial zero and first-order oral absorption was used to describe drug exposure. A maximum effect ( E max ) model with a placebo effect was used to model the itch response endpoints (NRS-AV, WI-NRS). RESULTS: The PK-PD model predicted the exposure-related reduction in both NRS-AV and WI-NRS over time with approximately 63% and 27% of E max , respectively. Exposures associated with 80% of E max were achieved in about 78% of the patients at 162 mg, twice daily (BID), compared to 35% at 81 mg BID. CONCLUSION: Simulated dose response indicated that 108 and 162 mg BID doses result in the highest proportion of patients achieving at least a 30% reduction in NRS-AV and WI-NRS, respectively.

Role of kappa-opioid and mu-opioid receptors in pruritus: Peripheral and central itch circuits.

Modern genetic approaches in animal models have unveiled novel itch-specific neural pathways, emboldening a paradigm in which drugs can be developed to selectively and potently target itch in a variety of chronic pruritic conditions. In recent years, kappa-opioid receptors (KORs) and mu-opioid receptors (MORs) have been implicated in both the suppression and promotion of itch, respectively, by acting on both the peripheral and central nervous systems. The precise mechanisms by which agents that modulate these pathways alleviate itch remains an active area of investigation. Notwithstanding this, a number of agents have demonstrated efficacy in clinical trials that influence both KOR and MOR signalling. Herein, we summarize a number of opioid receptor modulators in development and their promising efficacy across a number of chronic pruritic conditions, such as atopic dermatitis, uremic pruritus and beyond.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Nalbuphine ER Tablets for Uremic Pruritus.

BACKGROUND: Pruritus is a distressing hallmark of the uremic condition, affecting approximately 60% of hemodialysis patients. Abnormal endogenous opioid ligand activity at µ and κ-opioid receptors has been postulated as a mechanism in uremic pruritus. Nalbuphine is a µ-opioid antagonist and κ-opioid agonist. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg (NAL 120), 60 mg (NAL 60), or placebo and treated for 8 weeks. Three hundred seventy-one were analyzed for efficacy. The primary endpoint was the change from baseline to treatment weeks 7 and 8 in itching intensity on a Numerical Rating Scale (NRS, 0 [no itching]; 10 [worst possible itching]) using an intent-to-treat approach. The aim was to evaluate the safety and antipruritic efficacy of NAL. RESULTS: The mean duration of itching was 3.2 years. From a baseline NRS of 6.9 (1.5), the mean NRS declined by 3.5 (2.4) and by 2.8 (2.2) in NAL 120 mg and the placebo groups, respectively (p = 0.017). There was no evidence of tolerance. A trend for less sleep disruption due to itching (p = 0.062, NAL 120 vs. placebo) was also observed. There were no significant differences between NAL 60 vs. placebo. Serious adverse events occurred in 6.7, 12.7, and 15.4% in the NAL 120, NAL 60, and placebo groups respectively. CONCLUSIONS: In this largest-to-date randomized controlled trial in uremic pruritus, NAL 120 durably and significantly reduced the itching intensity among hemodialysis patients.

Pharmacokinetics of nalbuphine hydrochloride extended release tablets in hemodialysis patients with exploratory effect on pruritus.

BACKGROUND: Uremic pruritus is a common and deleterious condition among hemodialysis (HD) patients. Central gating of µ/κ opiate circuitry plays an important role in mediating and countering pruritogenic sensation. The objective of this study was to assess the safety and pharmacokinetics (PK) of the mixed µ-antagonist/κ-agonist nalbuphine, administered orally as nalbuphine HCl extended release (ER) tablets in HD patients, and explore its effect on pruritus. METHODS: In this open-label multiple escalating dose study, 15 HD patients with pruritus and 9 matched healthy subjects were enrolled. Nalbuphine HCl ER dose was escalated from 30 mg QD to 240 mg BID over 15 days. A full PK profile was obtained under dialysis and non-dialysis conditions as a function of dose. Clearance during dialysis was determined by sampling dialysate and arterial/venous blood during dialysis. Pruritus severity was assessed twice daily using a Visual Analog Scale (VAS). Safety monitoring included extensive monitoring of EKG, blood pressure, and pulse oximetry. RESULTS: In HD patients, nalbuphine concentration peaked within 4-9 hours and attained steady state within 2-3 days, with no significant accumulation. Mean half-life was 14.2 hours, mean Cmax and AUCtau ranged between 13 and 83 ng/mL and 118 and 761 ng∙h/mL, respectively, with exposure increasing in a nearly dose-proportional fashion. Exposure in HD patients was about 2-fold higher than in healthy subjects. There was no meaningful difference between exposure on dialysis and non-dialysis days with 1% or less of the dose removed by dialysis. Nalbuphine suppressed itch in a dose-dependent manner, reducing mean VAS score from 4.0 to 1.2 at 180 mg and 0.4 at 240 mg. CONCLUSIONS: Nalbuphine HCl ER tablets can be safely administered to HD patients without dose adjustment up to 240 mg BID and may hold promise in treating uremic pruritus.

Disposition of Oral Nalbuphine and Its Metabolites in Healthy Subjects and Subjects with Hepatic Impairment: Preliminary Modeling Results Using a Continuous Intestinal Absorption Model with Enterohepatic Recirculation.

Nalbuphine (NAL) is a mixed κ-agonist/µ-antagonist opioid with extensive first-pass metabolism. A phase 1 open-label study was conducted to characterize the pharmacokinetics (PKs) of NAL and select metabolites following single oral doses of NAL extended-release tablets in subjects with mild, moderate, and severe hepatic impairment (Child-Pugh A, B, and C, respectively) compared to healthy matched subjects. NAL exposures were similar for subjects with mild hepatic impairment as compared to healthy subjects and nearly three-fold and eight-fold higher in subjects with moderate and severe hepatic impairment, respectively. Datasets obtained for healthy, moderate, and severe hepatic impaired groups were modeled with a mechanistic model that incorporated NAL hepatic metabolism and enterohepatic recycling of NAL and its glucuronidated metabolites. The mechanistic model includes a continuous intestinal absorption model linked to semi-physiological liver-gallbladder-compartmental PK models based on partial differential equations (termed the PDE-EHR model). In vitro studies indicated that cytochromes P450 CYP2C9 and CYP2C19 are the major CYPs involved in NAL oxidation, with glucuronidation mainly catalyzed by UGT1A8 and UGT2B7 isozymes. Complex formation and elimination kinetics of NAL and four main metabolites was well predicted by PDE-EHR. The model is expected to improve predictions of drug interactions and complex drug disposition.

Nalbuphine Tablets for Cough in Patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND: There are no approved therapies for cough in patients with idiopathic pulmonary fibrosis (IPF). In this small crossover trial we administered nalbuphine extended-release tablets (NAL ER) as a potential cough therapy for such patients. METHODS: This randomized, double-blind, placebo-controlled, crossover trial involved two 22-day treatment periods (NAL ER→placebo and placebo→NAL ER) separated by a 2-week washout period. NAL ER was started at a dose of 27 mg once daily and was titrated up to 162 mg twice daily at day 16. The primary end point was percent change from baseline in hourly daytime objective cough frequency as measured by an electronic cough monitor. The daytime period was defined as the patient-reported time of awakening and bedtime. Secondary end points included change in objective 24-hour cough frequency, changes in cough frequency, cough severity, and breathlessness, per patient-reported outcomes. RESULTS: A total of 41 patients were randomly assigned and received one or more doses of study medication. There was a 75.1% reduction in daytime objective cough frequency during the NAL ER treatment period versus the placebo treatment period of 22.6%, a 52.5 percentage point placebo-adjusted decrease from baseline (P<0.001) at day 21. There was a 76.1% (95% confidence interval, 83.1 to 69.1) decrease in the 24-hour objective cough frequency with NAL ER, versus a 25.3% (43.9 to 6.7) decrease with placebo, a 50.8 percentage point placebo-adjusted change. Nausea, fatigue, constipation, and dizziness were more common with NAL ER than with placebo. CONCLUSIONS: In this short-term crossover trial, NAL ER reduced cough in individuals with IPF. Larger and longer trials are needed to assess the impact on cough versus drug adverse effects. (Funded by Trevi Therapeutics; ClinicalTrials.gov number, NCT04030026.)

A0001 in Friedreich ataxia: biochemical characterization and effects in a clinical trial.

This study tested the ability of A0001 (α-tocopheryl quinone; EPI-A0001), a potent antioxidant, to improve in vitro measures, glucose metabolism, and neurological function in Friedreich ataxia. We used an in vitro study of protection from cell toxicity followed by a double-blind, randomized, placebo-controlled trial of 2 doses of A0001 in 31 adults with Friedreich ataxia. The primary clinical trial outcome was the Disposition Index, a measure of diabetic tendency, from a frequently sampled intravenous glucose tolerance test, evaluated 4 weeks into therapy. Secondary neurologic measures included the Friedreich Ataxia Rating Scale. A0001 potently inhibited cell death in Friedreich ataxia models in vitro. For the clinical trial, mean guanine-adenine-adenine repeat length was 699, and mean age was 31 years. Four weeks after treatment initiation, differences in changes in the Disposition Index between subjects treated with A0001 and placebo were not statistically significant. In contrast, a dose-dependent improvement in the Friedreich Ataxia Rating Scale score was observed. Patients on placebo improved 2.0 rating scale points, whereas patients on low-dose A0001 improved by 4.9 points (P = .04) and patients on a high dose improved by 6.1 points (P < .01). Although A0001 did not alter the Disposition Index, it caused a dose-dependent improvement in neurologic function, as measured by the Friedreich Ataxia Rating Scale. Longer studies will assess the reproducibility and persistence of neurologic benefit.

Modulation of the kappa and mu opioid axis for the treatment of chronic pruritus: A review of basic science and clinical implications.

Introduction: Treating chronic pruritus is challenging for dermatologists due to the lack of therapeutic options. We review the effects of κ-opioid receptor (KOR) and µ-opioid receptor (MOR) in the modulation of itch, summarize evidence supporting the efficacy and safety of opioid receptor-targeting agents in chronic pruritus, and address clinical considerations. Results: Preclinical studies have found neural pathways underlying detection, transmission, and modulation of itch signaling and spotlighted the importance of neuronal KOR and MOR in itch perception. Clinical reports suggest that opioid axis modulation may be the basis for the successful treatment of chronic itch. Several agents (MOR antagonist naltrexone; KOR agonists nalfurafine and difelikefalin; dual-acting KOR agonists/MOR antagonists butorphanol and nalbuphine) have been evaluated for treating chronic pruritus in case series, small studies, and clinical trials; nalbuphine has progressed through preliminary (phase II/III) studies in uremic pruritus and prurigo nodularis. The antipruritic efficacy of these agents has been observed across multiple disorders with disparate etiologies, suggesting the potential utility of this class to provide a unified approach to chronic pruritus treatment. Conclusions: The relative safety of these agents, including a reduced potential for dependence versus MOR-agonist analgesics, should help overcome resistance to the use of opioid receptor-targeting agents in chronic pruritus treatment.

Elevation of serum cardiac troponin I in a cross-sectional cohort of asymptomatic subjects with Friedreich ataxia.

BACKGROUND: Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia of all four limbs, dysarthria, areflexia, and cardiomyopathy. At present, baseline values of cardiac troponin I are unknown among Friedreich ataxia subjects. METHODS: In this study, we evaluated baseline plasma cardiac troponin I levels among a cross-sectional cohort of 49 pediatric and adult Friedreich ataxia subjects without active arrhythmia, chest pain or features of acute coronary syndrome at the time of sampling. We also reviewed baseline electrocardiograms from 45 of these subjects. RESULTS: Troponin I values were elevated above the 99th percentile population cutoff in 46.9% of all subjects, with 16.3% of asymptomatic subjects having levels typically seen during an acute myocardial infarction. In logistic regression models, younger age and an earlier disease onset predicted higher serum cardiac troponin I values. Only weak correlations were seen between cardiac troponin I values and echocardiogram parameters, including ejection fraction. Additionally, 82.2% of subjects also had abnormal baseline electrocardiograms. CONCLUSION: The present study demonstrates that both abnormal electrocardiograms and elevated serum cardiac troponin I values may be common baseline characteristics seen in Friedreich ataxia subjects. Further longitudinal studies will allow for a better understanding of the cause and prognostic implications of elevated levels, as well as the clinical utility of serum cardiac troponin I testing in Friedreich ataxia.

Use of an adaptive study design in single ascending-dose pharmacokinetics of A0001 (α-tocopherylquinone) in healthy male subjects.

A0001 (α-tocopherylquinone) is a potent antioxidant currently in development for the treatment of symptoms associated with inherited mitochondrial disorders. A0001 pharmacokinetics were studied in a single-blind, adaptive design study following a single daily oral dose of placebo (n = 2) or ascending doses of A0001 (n = 8) at 0.25 and 0.5 g under a fasted state or a 0.5- to 6-g dose with a high-fat meal. Dose escalation was based on safety assessment, and proceeding dose levels were selected based on interim pharmacokinetic analyses. A0001 plasma concentration-time profiles were similar across doses, reaching peak concentration within 4 to 6 hours, with concentrations returning to baseline within 24 hours. Exposure was highly dependent on food and dosing frequency. Exposure was nearly 60-fold higher with food but increased subproportionally above 1-g dose; however, the nonproportionality was offset by administering A0001 in divided doses (0.735 g, 3 times per day). The potential for an A0001:vitamin E interaction was also explored, as vitamin E use is prevalent in this patient population, and suggested that a clinically significant pharmacokinetic interaction is not likely. A0001 was well tolerated with no serious adverse events or dose-limiting toxicities. These findings suggest that A0001 has a favorable pharmacokinetic profile when administered orally with food.