TY - JOUR
T1 - A pharmacokinetic assessment of optimal dosing, preparation and chronotherapy of aspirin in pregnancy
AU - Shanmugalingam, Renuka
AU - Wang, XiaoSuo
AU - Munch, Gerald
AU - Fulcher, Ian
AU - Lee, Gaksoo
AU - Chau, Katrina
AU - Xu, Bei
AU - Kumar, Roshika
AU - Hennessy, Annemarie
AU - Makris, Angela
PY - 2019
Y1 - 2019
N2 - Background: The benefit of aspirin in preventing preeclampsia is well established, however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing and preparation of aspirin Objective(s): We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid (SA), in pregnant women to non-pregnant women and examine the effect of dose (100mg vs 150mg), preparation (enteric coated (EC) vs non-EC) and chronotherapy of aspirin (morning vs night) between both groups. Study design: Twelve high-risk pregnant women and three non-pregnant women were enrolled into this study. Pregnant women were in one of four groups (100mg EC, 100mg non-EC, 150mg non-EC morning dosing and 150mg non-EC night dosing) whilst non-pregnant women undertook each of the four dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (pre-ingestion), 1, 2, 4, 6, 12 and 24-hours post-ingestion of aspirin. Plasma obtained was analysed for SA levels through liquid chromatography mass spectrometry (LCMS). Pharmacokinetic values of area under the curve (AUC(t-24)), point of maximum concentration (Cmax), time of maximum concentration (Tmax), volume of distribution (Vd), clearance (CL) and elimination half-life (t½) were analysed for statistical significance with SPSSv25 Results: Pregnant women had a 40% ± 4% reduction in AUC(t-24) (p <0.01) and 29% ± 3% reduction in Cmax (p<0.01) with a 44% ± 8% increase in CL (p<0.01) in comparison to non-pregnant women when 100 mg of aspirin was administered. The reduction in AUC(t-24), however, was minimized with the use of 150mg of aspirin in pregnant women, with which, the AUC(t-24) was closer to that achieved with the use of 100mg aspirin in non-pregnant women. There was a 4-hour delay (p<0.01) in the Tmax, 47% ± 3% reduction in Cmax (p<0.01) and a 48% ± 1% increase in Vd (p<0.01) with the use of 100mg EC aspirin compared to non-EC aspirin with no difference in the overall AUC. There was no difference in the pharmacokinetics of aspirin between morning and night dosing. Conclusion(s): There is a reduction in the total drug metabolite concentration of aspirin in pregnancy and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric coated and non-enteric coated aspirin and between morning and night dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings.
AB - Background: The benefit of aspirin in preventing preeclampsia is well established, however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing and preparation of aspirin Objective(s): We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid (SA), in pregnant women to non-pregnant women and examine the effect of dose (100mg vs 150mg), preparation (enteric coated (EC) vs non-EC) and chronotherapy of aspirin (morning vs night) between both groups. Study design: Twelve high-risk pregnant women and three non-pregnant women were enrolled into this study. Pregnant women were in one of four groups (100mg EC, 100mg non-EC, 150mg non-EC morning dosing and 150mg non-EC night dosing) whilst non-pregnant women undertook each of the four dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (pre-ingestion), 1, 2, 4, 6, 12 and 24-hours post-ingestion of aspirin. Plasma obtained was analysed for SA levels through liquid chromatography mass spectrometry (LCMS). Pharmacokinetic values of area under the curve (AUC(t-24)), point of maximum concentration (Cmax), time of maximum concentration (Tmax), volume of distribution (Vd), clearance (CL) and elimination half-life (t½) were analysed for statistical significance with SPSSv25 Results: Pregnant women had a 40% ± 4% reduction in AUC(t-24) (p <0.01) and 29% ± 3% reduction in Cmax (p<0.01) with a 44% ± 8% increase in CL (p<0.01) in comparison to non-pregnant women when 100 mg of aspirin was administered. The reduction in AUC(t-24), however, was minimized with the use of 150mg of aspirin in pregnant women, with which, the AUC(t-24) was closer to that achieved with the use of 100mg aspirin in non-pregnant women. There was a 4-hour delay (p<0.01) in the Tmax, 47% ± 3% reduction in Cmax (p<0.01) and a 48% ± 1% increase in Vd (p<0.01) with the use of 100mg EC aspirin compared to non-EC aspirin with no difference in the overall AUC. There was no difference in the pharmacokinetics of aspirin between morning and night dosing. Conclusion(s): There is a reduction in the total drug metabolite concentration of aspirin in pregnancy and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric coated and non-enteric coated aspirin and between morning and night dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings.
KW - aspirin
KW - dosage
KW - drugs
KW - pharmacokinetics
KW - preeclampsia
KW - pregnancy
UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:51239
U2 - 10.1016/j.ajog.2019.04.027
DO - 10.1016/j.ajog.2019.04.027
M3 - Article
VL - 221
SP - 255.e1-255.e9
JO - American Journal of Obstetrics and Gynecology
JF - American Journal of Obstetrics and Gynecology
IS - 3
ER -