Development of In Vitro – In Vivo Correlation for Extended‐Release Niacin After Administration of Hypromellose‐Based Matrix Formulations to Healthy Volunteers

Kesisoglou, Filippos; Rossenu, Stefaan; Farrell, Christine; Heuvel, Michiel van den; Prohn, Marita; Fitzpatrick, Shaun; Kam, Pieter-Jan de; Vargo, Ryan

doi:10.1002/jps.24179

Cited by 15 publications

(12 citation statements)

References 16 publications

(18 reference statements)

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“…Based on the current results, it seems reasonable to speculate that mealtime dosing might reverse these negative effects on glucose control. The specific exposure profile of NiAc used in our preclinical study markedly differs from exposures achieved after oral niacin dosing in patients (55). Clinical niacin dosing has not been optimized for FFA lowering, and therefore simply giving currently available formulations at mealtime may not reproduce the beneficial effects seen in the present study.…”

Section: A Therapeutically Relevant Niac Exposurementioning

confidence: 89%

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

Kroon

Baccega

Olsen

et al. 2017

Journal of Lipid Research

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Section: A Therapeutically Relevant Niac Exposurementioning

confidence: 89%

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

Kroon

Baccega

Olsen

et al. 2017

Journal of Lipid Research

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“…Several factors probably prevent ER formulations from reducing average FFA levels: 1 ) Dosing has not been designed to lower FFA; rather, the goal has been to ameliorate dyslipidemia via effects now understood to be independent of the FFA-lowering mechanism ( 46 ). 2 ) Although the ER formulation prolongs plasma NiAc exposure, maximum plasma NiAc levels are reduced compared with equivalent crystalline formulation doses ( 47 ), likely resulting in poor FFA suppression over a large fraction of the day [based on the relationship between circulating NiAc levels and FFA suppression ( 23 )]. 3 ) In addition, clinical dosing is also associated with signifi cant FFA rebound [e.g., ( 42 )].…”

Section: Discussionmentioning

confidence: 99%

Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats

Kroon

Kjellstedt

Thalén

et al. 2015

Journal of Lipid Research

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explored and provide evidence supporting this concept. This includes inactivation of hormone sensitive lipase (HSL) ( 5, 6 ) and A 1 -adenosine receptor agonists ( 7 ). In addition, several other G protein-coupled receptors (GPRs) are involved in controlling adipocyte FFA release, including GPR43, GPR81, and GPR109A ( 8-10 ).The GPR109A agonist nicotinic acid (NiAc) has been used clinically ever since its antidyslipidemic effects (HDL elevation and reductions of total cholesterol, LDL-cholesterol, and TG) were discovered more than 50 years ago ( 11-15 ). Although NiAc potently lowers FFA acutely, large-scale clinical studies, with repeated oral NiAc administration, often report increased levels of fasting glycemia ( 16-19 ). NiAc has not been optimized to achieve durable and therapeutically meaningful FFA lowering. By this, we specifi cally mean reducing around-the-clock FFA area under the curve (AUC). In theory, this might be achieved by sustained NiAc exposure; however, the FFA-lowering effect seen initially appears to be lost over time despite maintained NiAc exposure (tolerance development) ( 20 ). Time-dependent loss of both FFA lowering and glucose control improvement also occur in patients with type 2 diabetes, treated with the NiAc analog acipimox ( 21,22 ). To avoid tolerance development, drug holidays are needed. However, at the end of each NiAc exposure period, there is the risk of FFA rebound (here referring to the situation where FFA overshoots pretreatment levels in connection with NiAc decline) due to the short NiAc plasma half-life ( 23 ). FFA rebound is associated with impaired glucose control ( 24, 25 ). The question of whether there might be an optimal balance between periods of continuous exposure (which would minimize rebound) and drug holidays (which would minimize tolerance) in order to achieve maximal FFA lowering has not been addressed. Lipid overload in nonadipose tissues has been linked to the pathogenesis of insulin resistance and atherogenesis ( 1-4 ). A potential means for reversing peripheral lipid overload is to restrict the release of FFAs from adipose tissues. A number of independent mechanisms have been N.D. Oakes, P. Thalén, and A. Kjellstedt Abbreviations: ATGL, adipocyte triglyceride lipase; AUC, area under the curve; ER, extended release; GIR, glucose infusion rate; GPR, G protein-coupled receptor; HOMA-IR, homeostasis model assessment for insulin resistance; HSL, hormone sensitive lipase; NiAc, nicotinic acid; PDE-3B, phosphodiesterase-3B .

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“…N-methylnicotinamide is an intermediate involving in nicotinic acid pathway [42], and it had a significant (p=0.0107) elevation comparing the six period with the first period (Figure 3i), suggesting a cognitive dysfunction after the 520 days' isolation. 3-Hydroxymandelate is a metabolite of catecholamine [43] and it has a notable elevation in the last three periods comparing with the second period (p<0.01).…”

Section: Metabolic Responses To 520 Days' Isolationmentioning

confidence: 99%

Urinary Metabolic Profiling of ‘MARS-500 Project’ with Nuclear Magnetic Resonance Spectroscopy

Chen¹,

Yu²,

Dong³

2015

Metabolomics

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# These authors contributed equally to this work. metabolic profiles through analyzing complex biofluids (e.g., urine and plasm) can provide important diagnostic and prognostic information [8]. Among the biofluids most commonly analyzed in metabolomic studies, urine appears to be particularly useful, because it is abundant, readily available, easily stored and can be collected by simple, noninvasive techniques [9]. Although, persistent alterations induced by dietary or chronic interventions may also be detected from plasma, but it just provides a description of the metabolic system at the time of sampling, and yet some biochemical or pathological changes may not be specific to external stimuli or genetic modification. By contrast, information from urine is time-averaged because of its collection and storage in the bladder [8]. Therefore, urine was selected to conduct metabolic mapping in many publications [10][11][12]. Among analytical techniques used in metabonomics, nuclear magnetic resonance (NMR) [13] and mass spectroscopy (MS) [14] possessed the dominant status. As known, NMR has the advantage of being rapid, high reproducibility, nondestructive to samples, applicable to intact biomaterials and rich in chemical structural information. In addition, unlike GC-MS and certain liquid chromatography-mass spectrometry (LC-MS) methods,

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Development of In Vitro – In Vivo Correlation for Extended‐Release Niacin After Administration of Hypromellose‐Based Matrix Formulations to Healthy Volunteers

Cited by 15 publications

References 16 publications

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats

Urinary Metabolic Profiling of ‘MARS-500 Project’ with Nuclear Magnetic Resonance Spectroscopy

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