Shuhui Li1, Homa K Ahmadzia2, Dong Guo3, Elyes Dahmane1, Adam Miszta4,5, Naomi L C Luban6,7, Jeffrey S Berger8, Andra H James9, Alisa S Wolberg4, John N van den Anker10,11, Jogarao V S Gobburu1. 1. Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, M.D., USA. 2. Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, The George Washington University School of Medicine and Health Sciences, Washington, D.C., USA. 3. School of Pharmacy, University of Maryland, Baltimore, M.D., USA. 4. Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina, Chapel Hill, N.C., USA. 5. Synapse Research Institute, Maastricht, the Netherlands. 6. Division of Hematology, Children's National Hospital, Washington, D.C., USA. 7. Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA. 8. Department of Anesthesiology and Critical Care Medicine, The George Washington University School of Medicine and Health Sciences, Washington, D.C., USA. 9. Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Duke University, Durham, N.C., USA. 10. Division of Clinical Pharmacology, Children's National Hospital, Washington, D.C., USA. 11. Division of Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, University of Basel, Switzerland.
Abstract
AIMS: The population pharmacokinetics (PK) and pharmacodynamics (PD) of tranexamic acid (TXA) have not been studied to prevent postpartum haemorrhage (PPH) in pregnant women. It is unclear which TXA dose assures sufficient PPH prevention. This study investigated population PK/PD of TXA in pregnant women who underwent caesarean delivery to determine the optimal prophylactic doses of TXA for future studies. METHODS: We analysed concentration (PK) and maximum lysis (PD) data from 30 pregnant women scheduled for caesarean delivery who received 5, 10 or 15 mg/kg of TXA intravenously using population approach. RESULTS: TXA PK was best described by a two-compartment model with first-order elimination and the following parameters: clearance (between-subject variability) of 9.4 L/h (27.7%), central volume of 10.1 L (47.4%), intercompartmental clearance of 22.4 L/h (66.7%), peripheral volume of 14.0 L (13.1%) and additive error of 1.4 mg/L. The relationship between TXA concentration and maximum lysis was characterized by a sigmoid Emax model with baseline lysis of 97%, maximum inhibition of 89%, IC50 of 6.0 mg/L (65.3%), hill factor of 8.5 (86.3%) and additive error of 7.3%. Simulations demonstrated that 500 and 650 mg of TXA maintained therapeutic targets for 30 minutes and 1 hour, respectively, in 90% of patients. CONCLUSION: This is the first population PK and PD study of TXA in pregnant women undergoing caesarean delivery. Our analysis suggests that a 650 mg dose provides adequate PPH prophylaxis up to 1 hour, which is less than the currently used 1000 mg of TXA in pregnant women.
AIMS: The population pharmacokinetics (PK) and pharmacodynamics (PD) of tranexamic acid (TXA) have not been studied to prevent postpartum haemorrhage (PPH) in pregnant women. It is unclear which TXA dose assures sufficient PPH prevention. This study investigated population PK/PD of TXA in pregnant women who underwent caesarean delivery to determine the optimal prophylactic doses of TXA for future studies. METHODS: We analysed concentration (PK) and maximum lysis (PD) data from 30 pregnant women scheduled for caesarean delivery who received 5, 10 or 15 mg/kg of TXA intravenously using population approach. RESULTS: TXA PK was best described by a two-compartment model with first-order elimination and the following parameters: clearance (between-subject variability) of 9.4 L/h (27.7%), central volume of 10.1 L (47.4%), intercompartmental clearance of 22.4 L/h (66.7%), peripheral volume of 14.0 L (13.1%) and additive error of 1.4 mg/L. The relationship between TXA concentration and maximum lysis was characterized by a sigmoid Emax model with baseline lysis of 97%, maximum inhibition of 89%, IC50 of 6.0 mg/L (65.3%), hill factor of 8.5 (86.3%) and additive error of 7.3%. Simulations demonstrated that 500 and 650 mg of TXA maintained therapeutic targets for 30 minutes and 1 hour, respectively, in 90% of patients. CONCLUSION: This is the first population PK and PD study of TXA in pregnant women undergoing caesarean delivery. Our analysis suggests that a 650 mg dose provides adequate PPH prophylaxis up to 1 hour, which is less than the currently used 1000 mg of TXA in pregnant women.
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