PWIV-004 - IMPACT OF PREGNANCY ON THE PHARMACOKINETICS AND METABOLISM OF NICOTINAMIDE IN HUMANS.

M. Fashe, M. Gower, I. Mulrenin, K. Dorman, K. Boggess, C. Lee; University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Nicotinamide (NAM, vitamin B3-amide) has protective effects in preeclampsia preclinical models and entered clinical trials. NAM is metabolized in the liver by NAM N-methyltransferase to methyl-NAM (MNA), which is then metabolized to methyl-2-pyridone-5-carboxamide (M2PY) by aldehyde oxidase. However, the pharmacokinetics of NAM and its major metabolites has never been studied in pregnant individuals.

Methods: Healthy pregnant (gestational age 24-33 weeks) and female nonpregnant volunteers (n = 6/group) were enrolled. Blood samples were collected before and 1, 2, 4, 8, and 24 hr after single 1 gm oral NAM dose. Pooled urine was collected from 0-8 hr. NAM, MNA and M2PY concentrations were quantified by LC-MS/MS. Concentration-time data were analyzed by noncompartmental analysis (Phoenix WinNonlin 8.3). The amount excreted in urine from 0-8 hr was used to calculate MNA+M2PY metabolite formation CL (CLform) and NAM (CLR,NAM) and total metabolite (CLR,MNA+M2PY) renal CL. Log-transformed data were compared across groups by t-test.

Results: Plasma NAM AUC0-24 did not differ in pregnant (median [25%-75%]: 69 [62-86] µg*hr/mL) and nonpregnant individuals (73 [61-118] µg*hr/mL) (p = 0.49). In contrast, MNA+M2PY plasma AUC0-24 was significantly lower in pregnant vs nonpregnant individuals (50 [45-53] vs 101 [85-113] µg*hr/mL; p < 0.01). CLR,NAM (1.3 [1.0-1.8] vs 1.2 [0.9-1.2] L/hr; p = 0.18) and CLform (10.3 [7.2-11.5] vs 9.8 [5.1-10.8] L/hr; p = 0.43) did not differ across groups. However, CLR,MNA+M2PY was significantly higher in pregnant vs nonpregnant individuals (22 [20-26] vs 12 [11-17] L/hr; p < 0.01).

Conclusion: NAM systemic exposure and metabolism was not altered during pregnancy. However, systemic exposure to NAM’s major metabolites was reduced due to an apparent pregnancy-associated increase in renal elimination.