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Purpose: To characterize PK of niacin (Nia) and one of its metabolite nicotinuric acid (Nua) in subjects receiving 1 gram of niacin in relationship to variation in both of its major pharmacodynamics effects: flushing and the anti-lipolytic response.
Methods: A prospective, single-dose healthy volunteer study. Serial plasma samples were collected for non-esterified fatty acids (NEFA) and Nia/Nua determination. Flushing was assessed objectively by laser Doppler flowmetry. Nia/NUA concentrations were analyzed by HPLC/MS/MS. PK analysis was done using non-compartmental analysis using WinNonLin.
Results: PK profiles of Nia/Nua were assessed in 59 subjects (51% male, 51% African-American (AA)). AA had a significantly higher Nia Cmax, AUC, and lower clearance (CL) than Caucasian (Cau) subjects. AA had a lower Nua Cmax and AUC, but higher CL. Nia/Nua PK was not significantly different by sex, once adjusting for race and body weight. Nia/Nua PK was not different in subjects experiencing extreme flushing vs. those experiencing mild flushing. PK was also not different in subjects having a greater NEFA suppression vs. those with lesser NEFA suppression. However, Nia AUC was greater in subjects with a larger NEFA rebound.
Pharmacokinetics of Niacin and NUA Stratified by Race | |||
| Cau | AA | p-value |
Nia Cmax (ng/ml) | 17,915 ± 6782 | 23,411± 8158 | 0.008 |
Nia AUC 0-inf (ng*hr/ml) | 28,980 ± 11033 | 37,970 ± 12134 | 0.005 |
Nia CL_F (ml/hr) | 39,954 ± 15967 | 29,941 ± 12166 | 0.005 |
Nua Cmax (ng/ml) | 3388± 657 | 2703± 763 | 0.001 |
Nua AUC 0-inf (ng*hr/ml) | 8777± 2147 | 7615± 2259 | 0.04 |
Nua Cl_F (ml/hr) | 121,207 ± 31472 | 143,834 ± 45177 | 0.04 |
Conclusions: Race differences exist in Nia/Nua PK. Nia/Nua PK was not correlated with flushing response to Nia or degree of NEFA suppression. Subjects with a greater NEFA rebound had significantly greater Nia exposure, suggesting a complex mechanism of action of the rebound effect seen with Nia therapy.