Biochemometric Analysis of Fatty Acid Amide Hydrolase Inhibition by Echinacea Root Extracts.

Recent research demonstrates that Echinacea possesses cannabimimetic activity with potential applications beyond common contemporary uses for relief of cold and flu symptoms. In this study, we investigated the in vitro inhibitory effect of root extracts of Echinacea purpurea and Echinacea angustifolia on fatty acid amide hydrolase, the main enzyme that degrades the endocannabinoid anandamide. The objective was to relate variation in bioactivity between commercial Echinacea genotypes to their phytochemical profiles and to identify determinants of activity using biochemometric analysis. Forty root extracts of each of species were tested for inhibition of fatty acid amide hydrolase and analyzed by HPLC-DAD/MS to identify and quantitate alkylamides and caffeic acid derivatives. Fatty acid amide hydrolase inhibition ranged from 34 - 80% among E. angustifolia genotypes and from 33 - 87% among E. purpurea genotypes. Simple linear regression revealed the caffeic acid derivatives caftaric acid and cichoric acid, and the alkylamide dodeca-2E,4Z-diene-8,10-diynioc acid 2-methylbutylamide, as the strongest determinants of inhibition in E. purpurea (r* = 0.53, 0.45, and 0.20, respectively) while in E. angustifolia, only CADs were significantly associated with activity, most notably echinacoside (r* = 0.26). Regression analysis using compound groups generated by hierarchical clustering similarly indicated that caffeic acid derivatives contributed more than alkylamides to in vitro activity. Testing pure compounds identified as determinants of activity revealed cichoric acid (IC50 = 45 ± 4 µM) and dodeca-2E,4E,8Z,10E-tetraenoic acid isobutylamide (IC50 = 54 ± 2 µM) as the most active. The results suggest that several phytochemicals may contribute to Echinacea's cannabimimetic activity and that ample variation in genotypes exists for selection of high-activity germplasm in breeding programs.

Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat.

BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. METHODS: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS: The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS: Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid α-Glucosidase in Pompe Patients Co-administered with Alglucosidase α.

Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat-related adverse events or drug-related tolerability issues were identified.

Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking. METHODS: The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed. RESULTS: Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m2 (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated. CONCLUSIONS: Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations. TRIAL REGISTRATION NUMBER: NCT00925301; Pre-results.

Evaluation of the safety, pharmacodynamic, and pharmacokinetic effects following oral coadministration of immediate-release morphine with ethanol in healthy male participants.

OBJECTIVE: This paper aimed to evaluate the effects of coadministered immediate-release morphine and ethanol on safety, pharmacokinetic, and pharmacodynamic measures. METHODS: In the first stage of a randomized, double-blind, placebo-controlled, crossover study, 16 healthy men with a history of moderate drinking received morphine 50 mg+ethanol 0.7 g/kg, morphine 50 mg+ethanol placebo, and morphine placebo+ethanol 0.7 g/kg. In the second stage, participants received either a lower (30 mg) or higher (80 mg) morphine dose (alone and in combination with ethanol) depending on their tolerability to treatments in stage 1. Safety, pharmacodynamic (including visual analog scales, pupillometry, capnography, and psychomotor and cognitive measures), and pharmacokinetic assessments were conducted. RESULTS: With the exception of one severe adverse event (AE), all others were mild or moderate in intensity. Morphine resulted in dose-related increases in AEs. When morphine was administered with ethanol, similar AEs were observed (dizziness, headache, somnolence, nausea, and vomiting), but these were sometimes more frequent compared with those observed with either drug alone. No consistent additive or interaction effects were observed on pharmacodynamic measures. Ethanol had no apparent effects on the pharmacokinetics of morphine or its metabolites. CONCLUSIONS: Coadministration of single doses of morphine and ethanol tested in this study did not affect the safety, pharmacodynamics, or pharmacokinetics of morphine or ethanol administered alone. Copyright © 2014 John Wiley & Sons, Ltd.

Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02).

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

Population Pharmacokinetics of Oral Migalastat in Adolescents and Adults With and Without Renal Impairment.

Migalastat is approved for the treatment of Fabry disease (FD) with amenable variants. Objectives were to characterize effects of estimated glomerular filtration rate (eGFR) on oral clearance (CL), predict doses in mild to moderate renal impairment and in pediatric patients with FD, and to improve designs of FD studies. A 2-compartment model was fit to data from 260 subjects with/without FD and iteratively refined with evolving data. FD, eGFR, and weight affected CL, while weight and FD affected volume. Optimal sampling theory was used to choose pharmacokinetic sampling times for pediatric studies. Doses in patients with renal impairment and in pediatrics were determined by targeting exposure in adults receiving migalastat 123 mg every other day. A clinical study was conducted in 20 adolescent patients with FD ≥45 kg. eGFR had the largest effect on CL. Simulations showed that exposures in moderate renal impairment were within phase 2-3 exposures; patients aged 2-17 years require weight-based dosing; and predicted exposures in adolescent patients ≥45 kg receiving migalastat 123 mg every other day were similar to adults (data confirmed in a clinical study). Model-informed drug development optimized dosing and design of clinical studies and supported that no dose adjustments were needed in patients with mild to moderate renal impairment or in adolescent patients ≥45 kg.

The relative bioavailability of morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®) and an extended release morphine sulfate capsule formulation (KADIAN®) in healthy adults under fasting conditions.

Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®, King Pharmaceuticals®, Inc., Bristol, TN), indicated for the management of chronic, moderate to severe pain, contain extended release morphine pellets with a sequestered naltrexone core (MS-sNT). If the product is tampered with by crushing, naltrexone, a µ-opioid antagonist, is intended for release to mitigate morphine-induced subjective effects. The primary end point of this randomized 2-way crossover study in healthy fasted volunteers was evaluation of morphine bioequivalence between MS-sNT (treatment A) and morphine sulfate extended release capsules (KADIAN®, treatment B). Morphine pharmacokinetics were assessed predose to 72 hours postdose of single 100-mg doses of treatment A or B. Analysis of variance of ln-transformed ratios of least squares mean of the area under the concentration time curve (AUC) from time 0 to last measurable concentration (AUC0-t) and AUC from time 0 to infinity (AUCinf) and maximum serum concentration (Cmax) for treatments A versus B were performed. Ratios and 90% confidence intervals for least squares mean for AUC0-t (102.2%; 98.6-105.9%), AUCinf (97.4%; 91.2-104.1%), and Cmax (93.8%; 82.4-106.7%) indicated bioequivalence between the 2 formulations. When subjects who vomited during the 12-hour dosing interval were excluded, the confidence interval for AUC0-t and AUCinf fell within the 80%-125% range, but the lower limit for Cmax was 76.9%.

Migalastat Tissue Distribution: Extrapolation From Mice to Humans Using Pharmacokinetic Modeling and Comparison With Agalsidase Beta Tissue Distribution in Mice.

Approved therapies for Fabry disease (FD) include migalastat, an oral pharmacological chaperone, and agalsidase beta and agalsidase alfa, 2 forms of enzyme replacement therapy. Broad tissue distribution may be beneficial for clinical efficacy in FD, which has severe manifestations in multiple organs. Here, migalastat and agalsidase beta biodistribution were assessed in mice and modeled using physiologically based pharmacokinetic (PBPK) analysis, and migalastat biodistribution was subsequently extrapolated to humans. In mice, migalastat concentration was highest in kidneys and the small intestine, 2 FD-relevant organs. Agalsidase beta was predominantly sequestered in the liver and spleen (organs unaffected in FD). PBPK modeling predicted that migalastat 123 mg every other day resulted in concentrations exceeding the in vitro half-maximal effective concentration in kidneys, small intestine, skin, heart, and liver in human subjects. However, extrapolation of mouse agalsidase beta concentrations to humans was unsuccessful. In conclusion, migalastat may distribute to tissues that are inaccessible to intravenous agalsidase beta in mice, and extrapolation of mouse migalastat concentrations to humans showed adequate tissue penetration, particularly in FD-relevant organs.

Spontaneous tension pneumothorax and acute pulmonary emboli in a patient with COVID-19 infection.

The COVID-19 pandemic has had a significant impact on the structure and operation of healthcare services worldwide. We highlight a case of a 64-year-old man who presented to the emergency department with acute dyspnoea on a background of a 2-week history of fever, dry cough and shortness of breath. On initial assessment the patient was hypoxic (arterial oxygen saturation (SaO2) of 86% on room air), requiring 10 L/min of oxygen to maintain 98% SaO2 Examination demonstrated left-sided tracheal deviation and absent breath sounds in the right lung field on auscultation. A chest radiograph revealed a large right-sided tension pneumothorax which was treated with needle thoracocentesis and a definitive chest drain. A CT pulmonary angiogram demonstrated segmental left lower lobe acute pulmonary emboli, significant generalised COVID-19 parenchymal features, surgical emphysema and an iatrogenic pneumatocoele. This case emphasises the importance of considering coexisting alternative diagnoses in patients who present with suspected COVID-19.

Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study.

BACKGROUND AND OBJECTIVE: Given the dual public health challenges of undertreated pain and opioid abuse, there is a need to reduce attractiveness of opioid analgesics to drug abusers. ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules, indicated for treatment of chronic, moderate to severe pain, contain polymer-coated pellets of morphine, each with a core of sequestered naltrexone intended for release only upon tampering (crushing). The purpose of this study was to assess the pharmacodynamic effects (including drug-liking and euphoria) of whole and crushed ALO-01 versus morphine sulfate solution (MSS) and placebo. METHODS: This was a randomized, double-blind, placebo-controlled, triple-dummy, four-way crossover study carried out at a clinical research centre. Participants were experienced non-dependent opioid users. Subjects were given either two ALO-01 60 mg capsules, crushed pellets from two ALO-01 60 mg capsules, MSS 120 mg or placebo; there was a 14- to 21-day washout between treatments. The primary endpoints were drug-liking visual analogue scale score, scores on items from the Addiction Research Center Inventory (ARCI) and Cole/ARCI scales characterizing abuse potential and euphoria, and pupil diameter as measured by pupillometry. RESULTS: Morphine plasma concentrations were similar after ALO-01 crushed and MSS, with a median time to reach maximum plasma concentration (t(max)) of 1.1 and 1.2 hours, respectively; the plasma naltrexone median t(max) was 1.1 hours after ALO-01 crushed. By comparison, the median t(max) for morphine with ALO-01 whole was 8.1 hours. The maximum effect (E(max)) of MSS was significantly greater than placebo on pupillometry and the subjective measures (all p < 0.001). ALO-01 whole and crushed produced lower E(max) values and flatter effect-time profiles for subjective measures and caused less pupillary constriction than MSS. CONCLUSION: The results of this study demonstrated that ALO-01, whether taken orally whole as intended or tampered with by crushing and taken orally, had reduced desirability compared with MSS.

Regulatory strategies for rare diseases under current global regulatory statutes: a discussion with stakeholders.

Rare or orphan diseases often are inherited and overwhelmingly affect children. Many of these diseases have no treatments, are incurable, and have a devastating impact on patients and their families. Regulatory standards for drug approval for rare diseases must ensure that patients receive safe and efficacious treatments. However, regulatory bodies have shown flexibility in applying these standards to drug development in rare diseases, given the unique challenges that hinder efficient and effective traditional clinical trials, including low patient numbers, limited understanding of disease pathology and progression, variability in disease presentation, and a lack of established endpoints.To take steps toward improving rare disease clinical development strategies under current global regulatory statutes, Amicus Therapeutics, Inc. and BioNJ convened a 1-day meeting that included representatives from the Food and Drug Administration (FDA), biopharmaceutical industry, and not-for-profit agencies. The meeting focused on orphan diseases in pediatric and adult patients and was intended to identify potential strategies to overcome regulatory hurdles through open collaboration.During this meeting, several strategies were identified to minimize the limitations associated with low patient numbers in rare diseases, including the use of natural history to generate historical control data in comparisons, simulations, and identifying inclusion/exclusion criteria and appropriate endpoints. Novel approaches to clinical trial design were discussed to minimize patient exposure to placebo and to reduce the numbers of patients and clinical trials needed for providing substantial evidence. Novel statistical analysis approaches were also discussed to address the inherent challenges of small patient numbers. Areas of urgent unmet need were identified, including the need to develop registries that protect patient identities, to establish close collaboration and communication between the sponsor and regulatory bodies to address methodological and statistical challenges, to collaborate in pre-competitive opportunities within multiple sponsors and in conjunction with academia and disease-specific patient advocacy groups for optimal data sharing, and to develop harmonized guidelines for data extrapolation from source to target pediatric populations. Ultimately, these innovations will help in solving many regulatory challenges in rare disease drug development and encourage the availability of new treatments for patients with rare diseases.

Effect of concomitant ingestion of alcohol on the in vivo pharmacokinetics of KADIAN (morphine sulfate extended-release) capsules.

UNLABELLED: The recent withdrawal of hydromorphone hydrochloride extended-release capsules (Palladone; Purdue Pharma L.P., Stamford, CT) from the market after pharmacokinetic data revealed a risk of alcohol-induced dose-dumping prompted a re-examination of the risk-benefit profiles of extended-release drugs. Although warnings on concomitant alcohol use are included on opioid product labels, further investigations of extended-release formulations to determine the risk of dose-dumping were recommended by the US Food and Drug Administration. The present study was undertaken to assess the single-dose relative bioavailability of polymer-coated, extended-release morphine sulfate capsules (KADIAN, 100 mg; Alpharma Pharmaceuticals LLC, Piscataway, NJ). This open-label, randomized, 3-way crossover study with an additional index arm, conducted among 32 healthy male volunteers, found no significant evidence of a formulation interaction between KADIAN and alcohol, in vivo. The pharmacokinetics of serum morphine did not differ significantly among subjects taking KADIAN with water (fasted) or with 240 mL 40% alcohol under fasted or fed conditions. Analysis of variance ratios of least-squares means for ln-transformed AUC(infinity) and C(max) satisfied the criteria (90% confidence intervals within 80%-125%) to declare no drug formulation interaction among the KADIAN regimens dosed with alcohol compared with KADIAN taken with water. There were no serious adverse events or deaths reported during the study. PERSPECTIVE: Because of the high rate of alcohol use in the United States, the potential for drug-alcohol interactions is an important clinical concern. Although it is recommended that alcohol not be used while the patient is taking opioids, results of this in vivo study indicate that the risk of alcohol-induced dose-dumping in connection with the use of KADIAN is negligible.

Transcriptome changes in apple peel tissues during CO2 injury symptom development under controlled atmosphere storage regimens.

Apple (Malus × domestica Borkh.) is one of the most widely cultivated tree crops, and fruit storability is vital to the profitability of the apple fruit industry. Fruit of many apple cultivars can be stored for an extended period due to the introduction of advanced storage technologies, such as controlled atmosphere (CA) and 1-methylcyclopropane (1-MCP). However, CA storage can cause external CO2 injury for some apple cultivars. The molecular changes associated with the development of CO2 injury are not well elucidated. In this study, the global transcriptional regulations were investigated under different storage conditions and during development of CO2 injury symptoms on 'Golden Delicious' fruit. Fruit peel tissues under three different storage regimens, regular cold atmosphere, CA and CA storage and 1-MCP application were sampled at four storage durations over a 12-week period. Fruit physiological changes were affected differently under these storage regimens, and CO2 injury symptoms were detectable 2 weeks after CA storage. Identification of the differentially expressed genes and a gene ontology enrichment analysis revealed the specific transcriptome changes associated with each storage regimen. Overall, a profound transcriptome change was associated with CA storage regimen as indicated by the large number of differentially expressed genes. The lighter symptom was accompanied by reduced transcriptome changes under the CA storage and 1-MCP application regimen. Furthermore, the higher enrichment levels in the functional categories of oxidative stress response, glycolysis and protein post-translational modification were only associated with CA storage regime; therefore, these processes potentially contribute to the development of external CO2 injury or its symptom in apple.

Relative bioavailability and the effect of meal type and timing on the pharmacokinetics of migalastat in healthy volunteers.

Migalastat HCl is an investigational, pharmacological chaperone for mutant α-galactosidase A, which is responsible for Fabry disease, an X-linked, lysosomal storage disorder. Two Phase I studies evaluated relative bioavailability, effect of meal type and timing on pharmacokinetics, safety, and tolerability of migalastat HCl in healthy volunteers. Study 1 (N = 15, 19-55 years): single 100-mg doses of migalastat HCl capsule and solution formulations were bioequivalent. The ratios of LSM (90% CIs) for Cmax were 97.1% (86.8-109) and AUC0-inf 97.9% (88.8-108) under fasted conditions. Single 100-mg doses of migalastat HCl capsules administered with a high-fat meal decreased Cmax by 40% and AUC0-inf by 37%. A high-fat meal delayed tmax by approximately 1 hour. Study 2 (N = 20, 18-65 years): A high-fat or light meal up to 1 hour before or after administration of single 150 mg doses of migalastat HCl capsules decreased Cmax and AUC0-inf up to 40%, but had no apparent effect on tmax (range of medians with food: 1.5-3 hours, median fasted: 3 hours). A 50-g glucose drink co-administered with migalastat HCL did not result in clinically significant changes in migalastat absorption. No serious safety or tolerability issues were identified.

An open-label study to determine the pharmacokinetics and safety of migalastat HCl in subjects with impaired renal function and healthy subjects with normal renal function.

OBJECTIVES: Renal function may progressively decline in patients with Fabry disease. This study assessed pharmacokinetics, safety, and tolerability of a single oral dose of migalastat HCl 150 mg in subjects with normal or mildly, moderately, or severely impaired renal function. METHODS: Volunteers were enrolled into two cohorts stratified for renal function calculated using the Cockcroft-Gault equation for creatinine clearance. Pharmacokinetic parameters determined were: area under the concentration-time curve (AUC) from time zero to the last measurable concentration postdose (AUC0-t ) and extrapolated to infinity (AUC0-∞ ), maximum observed concentration (Cmax ), time to Cmax (tmax ), concentration at 48 hours postdose (C48h ), terminal elimination half-life (t1/2 ), oral clearance (CL/F), and apparent terminal elimination rate constant (λz) (ClinicalTrials.gov registration: NCT01730469). RESULTS: Thirty-two subjects enrolled and completed the study (Cohort 1: n = 24; Cohort 2: n = 8). Migalastat clearance decreased with increasing renal impairment, resulting in increases in migalastat HCl plasma t1/2 , AUC0-∞ , and C48h compared with subjects with normal renal function. Incidence of adverse events was comparable across all renal function groups. CONCLUSIONS: Plasma migalastat clearance decreased as degree of renal impairment increased. Data from the migalastat HCl clinical program will guide dosing and intervals for patients with Fabry disease with renal impairment.

Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

UNLABELLED: Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified. TRIAL REGISTRATION: ClinicalTrials.gov NCT01196871.

Pharmacokinetics and pharmacodynamics of a novel nizatidine controlled-release formulation in healthy subjects.

The pharmacokinetics and intragastric pH effects of a novel nizatidine controlled-release (CR) formulation were compared to a currently marketed immediate-release (IR) nizatidine formulation (Axid). The bimodal pulsatile release characteristics of nizatidine CR decreased its Cmax by approximately 42% compared to nizatidine IR while maintaining 90% relative bioavailability; tmax was approximately 1.6 times longer with the CR formulation. These characteristics enabled controlled-release nizatidine to sustain effective plasma drug concentrations for a greater duration than immediate-release nizatidine over the dosing intervals. In multiple doses, the 24-hour AUC ratio for all comparisons of nizatidine CR 150 mg bid, nizatidine CR 300 mg daily, and nizatidine IR 150 mg bid was between 97% and 99%. Mean pH AUC values for nizatidine CR 150 mg bid and nizatidine IR 150 mg bid were similar overall during the 0- to 14-hour and 14- to 24-hour dosing intervals. For the 14- to 24-hour dosing interval, nizatidine CR 150 mg maintained gastric pH over 3.0 and 4.0 for 42% and 27% of the time compared to 39% and 23% for nizatidine IR, respectively. Nizatidine CR 300 mg, compared to the 150-mg CR and IR regimens, had a greater effect on increasing evening intragastric pH, thus providing support for the potential utility of nizatidine CR 300 mg dosed at night in alleviating nocturnal symptoms of gastroesophageal reflux disease.

The bioequivalence of nizatidine (Axid) in two extemporaneously and one commercially prepared oral liquid formulations compared with capsule.

Nizatidine (Axid) is an H2-receptor antagonist used for the treatment of acid-related gastrointestinal disorders. Given the frequency of these conditions in children and the potential for pediatric use of nizatidine, an oral liquid dosage formulation would provide an alternative treatment option for patients unable to swallow solid oral dosage forms. This study was designed as an open-label, single-dose, four-way crossover trial to investigate the bioequivalence of 150 mg nizatidine administered in three oral liquid formulations (a commercially prepared oral syrup, an extemporaneous solution in apple juice, and an extemporaneous suspension in infant formula) relative to the marketed capsule formulation. Twenty-four adult subjects (ages 31.2 +/- 7.5 years; weight 71.1 +/- 11.8 kg) were enrolled, and blood samples for determination of plasma nizatidine concentrations were collected prior to drug administration and at 19 discrete intervals over a 24-hour postdose interval. Nizatidine was quantitated from plasma using a validated HPLC-MS assay, and a noncompartmental approach was used to describe nizatidine biodisposition in all subjects. Significant treatment effects were observed for log-normalized Cmax, AUC0-n, and AUC0-infinity (p < 0.001). Further evaluation revealed that nizatidine prepared in apple juice was markedly less bioavailable than the reference capsule, with 90% confidence intervals (CIs) of 0.518-0.626, 0.682-0.751, and 0.696-0.763 for Cmax, AUC0-n, and AUC0-infinity, respectively. The remaining two oral formulations demonstrated 90% CI within the guidelines established by the Food and Drug Administration (e.g., 0.80-1.25). Thus, nizatidine in infant formula and the commercially prepared oral syrup can be considered bioequivalent to the reference capsule.

Single-dose pharmacokinetics of nizatidine (Axid) in children.

The pharmacokinetics of nizatidine following a single 5.0 mg/kg oral dose given as an extemporaneous liquid formulation in apple juice was examined in 12 healthy children (8.0 +/- 2.4 years, 30.7 +/- 8.4 kg). Nizatidine and N-desmethylnizatidine were quantitated by HPLC/MS from five post dose blood samples taken over a 12-hour period. The apparent terminal elimination rate constant for nizatidine in the pediatric subjects (0.58 +/- 0.8h(-1)) was virtually identical to that (0.54 +/- 0.13 h(-1)) previously reported from adult studies. When corrected for an estimated 30% reduction in nizatidine oral bioavailability observed in adults upon coingestion of the drug with other fruit/vegetable juices, nizatidine pharmacokinetic parameter estimates (e.g., Cmax, CL/F, Vss/F) in our pediatric subjects were similar to those previously reported in adults who were administered dimensionally similar (e.g., approximately 4 mg/kg) solid oral doses of the drug. Examination of the mean area under the curve (i.e., AUC0-infinity for nizatidine and N-desmethylnizatidine suggested an approximate 15% metabolic conversion of the parent drug. Finally, nizatidine plasma concentrations in pediatric patients following a single 5.0 mg/kg oral dose exceeded the EC50 value of the drug for gastric acid suppression determined from adult studies for approximately 6 hours.