Abstract：
BACKGROUND: Makena (17-hydroxyprogesterone caproate) was approved by the United States Food and Drug Administration for the prevention of recurrent spontaneous preterm birth in 2011 under the accelerated approval pathway, but fundamental pharmacokinetic or pharmacodynamic (Phase 1 and Phase 2) studies were not performed. At the time, there were no dose-response or concentration-response data. The therapeutic concentration was not known. The lack of such data brings into question the dosing regimen for 17-hydroxyprogesterone caproate and if it was optimized.
OBJECTIVE: The purpose of this study was to evaluate the dosing regimen for 17-hydroxyprogesterone by analyzing 3 data sets in which the 17-hydroxyprogesterone caproate pharmacology was evaluated, namely the Maternal-Fetal Medicine Omega 3 study, the Obstetric-Fetal Pharmacology Research Units study, and the Obstetrical-Fetal Pharmacology Research Centers study. If an inappropriate dosing regimen could be identified, such information could inform future studies of pharmacotherapy in pregnancy.
METHODS: Data from the Omega 3 study were used to determine if plasma concentration was related to spontaneous preterm birth risk and if a threshold concentration could be identified. Data from the Obstetric-Fetal Pharmacology Research Units study were used to determine the half-life of 17-hydroxyprogesterone caproate and to develop a model to simulate drug concentrations with various dosing regimens. Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes.
RESULTS: Analysis of the Omega 3 data set indicated that the risk for spontaneous preterm birth decreased as the log concentration of 17-hydroxyprogesterone caproate increased (odds ratio, 0.04; 95% confidence interval, 0.00-0.90). A steady state concentration of >9 ng/mL (equivalent to >8 ng/mL at 25-28 weeks) was associated with the lowest risk for spontaneous preterm birth (hazard ratio, 0.52; 95% confidence interval, 0.27-0.98; P=.04); this concentration was not achieved in 25% of subjects who received the 250 mg weekly dose. In the Obstetrical-Fetal Pharmacology Research Units study, the adjusted half-life (median and interquartile range) of 17-hydroxyprogesterone caproate was 14.0 (11.5-17.2) days. Simulations indicated that with the 250 mg weekly dose, >5 weekly injections were required to reach the 9 ng/mL target; however, those with the shortest half-life (corresponding to higher clearance), never reached the targeted 9 ng/mL concentration. In 75% of subjects, a loading dose of 500 mg weekly for 2 weeks followed by 250 mg weekly achieved and maintained the 9 ng/mL concentration within 2 weeks but in those 25% with the shortest half-life, concentrations exceeded the 9 ng/mL target for only 3 weeks. In the Obstetrical-Fetal Pharmacology Research Centers study, all 65 subjects who received a weekly dose of 500 mg exceeded the 9 ng/mL steady state.
CONCLUSIONS: The dosing regimen for 17-hydroxyprogesterone caproate was inadequate. There is a significant inverse relationship between drug concentration and spontaneous preterm birth. The risk was lowest when the concentration exceeded 9 ng/mL, but 25% of women who received the 250 mg weekly dose never reached or maintained this concentration. The drug\'s long half-life necessitates a loading dose to achieve therapeutic concentrations rapidly. The omission of basic pharmacologic studies to determine the proper dosing may have compromised the effectiveness of 17-hydroxyprogesterone caproate. Future pharmacotherapy trials in pregnancy must first complete fundamental pharmacology studies.
OBJECTIVE: The purpose of this study was to evaluate the dosing regimen for 17-hydroxyprogesterone by analyzing 3 data sets in which the 17-hydroxyprogesterone caproate pharmacology was evaluated, namely the Maternal-Fetal Medicine Omega 3 study, the Obstetric-Fetal Pharmacology Research Units study, and the Obstetrical-Fetal Pharmacology Research Centers study. If an inappropriate dosing regimen could be identified, such information could inform future studies of pharmacotherapy in pregnancy.
METHODS: Data from the Omega 3 study were used to determine if plasma concentration was related to spontaneous preterm birth risk and if a threshold concentration could be identified. Data from the Obstetric-Fetal Pharmacology Research Units study were used to determine the half-life of 17-hydroxyprogesterone caproate and to develop a model to simulate drug concentrations with various dosing regimens. Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes.
RESULTS: Analysis of the Omega 3 data set indicated that the risk for spontaneous preterm birth decreased as the log concentration of 17-hydroxyprogesterone caproate increased (odds ratio, 0.04; 95% confidence interval, 0.00-0.90). A steady state concentration of >9 ng/mL (equivalent to >8 ng/mL at 25-28 weeks) was associated with the lowest risk for spontaneous preterm birth (hazard ratio, 0.52; 95% confidence interval, 0.27-0.98; P=.04); this concentration was not achieved in 25% of subjects who received the 250 mg weekly dose. In the Obstetrical-Fetal Pharmacology Research Units study, the adjusted half-life (median and interquartile range) of 17-hydroxyprogesterone caproate was 14.0 (11.5-17.2) days. Simulations indicated that with the 250 mg weekly dose, >5 weekly injections were required to reach the 9 ng/mL target; however, those with the shortest half-life (corresponding to higher clearance), never reached the targeted 9 ng/mL concentration. In 75% of subjects, a loading dose of 500 mg weekly for 2 weeks followed by 250 mg weekly achieved and maintained the 9 ng/mL concentration within 2 weeks but in those 25% with the shortest half-life, concentrations exceeded the 9 ng/mL target for only 3 weeks. In the Obstetrical-Fetal Pharmacology Research Centers study, all 65 subjects who received a weekly dose of 500 mg exceeded the 9 ng/mL steady state.
CONCLUSIONS: The dosing regimen for 17-hydroxyprogesterone caproate was inadequate. There is a significant inverse relationship between drug concentration and spontaneous preterm birth. The risk was lowest when the concentration exceeded 9 ng/mL, but 25% of women who received the 250 mg weekly dose never reached or maintained this concentration. The drug\'s long half-life necessitates a loading dose to achieve therapeutic concentrations rapidly. The omission of basic pharmacologic studies to determine the proper dosing may have compromised the effectiveness of 17-hydroxyprogesterone caproate. Future pharmacotherapy trials in pregnancy must first complete fundamental pharmacology studies.
摘要：
背景：Makena（己酸17-羟孕酮）于2011年在加速批准途径下被FDA批准用于预防复发性自发性早产，但未进行基本药代动力学或药效学（阶段1和阶段2）研究。当时,没有剂量-反应或浓度-反应数据.治疗浓度未知。这些数据的缺乏质疑17-羟孕酮己酸酯的给药方案是否被优化。
目的：本研究的目的是通过分析评估己酸17-羟孕酮药理学的三个数据集来评估17-羟孕酮的给药方案：母胎医学Omega3研究，产科-胎儿药理学研究单位研究和产科-胎儿药理学研究中心研究。如果可以识别出不适当的给药方案，这些信息可以为未来的妊娠药物治疗研究提供信息。
方法：使用Omega3研究的数据来确定血浆浓度是否与自发性早产风险相关，以及是否可以确定阈值浓度。来自产科-胎儿药理学研究单位研究的数据用于确定17-羟基孕酮己酸酯的半衰期，并开发模型以模拟各种给药方案的药物浓度。来自产科-胎儿药理学研究中心研究的数据用于确定剂量和安全性结果之间的关系。
结果：对Omega3数据集的分析表明，随着17-羟孕酮己酸酯的对数增加，自发性早产的风险降低[比值比（95CI）0.04（0.00-0.90）]。稳态浓度>9ng/ml（相当于在25-28周时>8ng/ml）与自发性早产的最低风险相关[风险比（95CI）0.52（0.27-0.98，p=0.04）];在接受250mg每周剂量的受试者中，有25％未达到该浓度。在产科-胎儿药理学研究单位研究中，17-羟孕酮己酸酯的校正半衰期(中位数和IQR)为14.0(11.5-17.2)天.模拟表明，每周250毫克的剂量，>5每周注射需要达到9ng/ml的目标;然而，半衰期最短的那些(对应于较高的清除率)，从未达到目标9ng/ml浓度。在75%的科目中，每周500mg的负荷剂量持续2周，然后每周250mg达到并在两周内保持9ng/ml的浓度，但在半衰期最短的25％中，浓度超过9ng/ml目标仅3周。在产科-胎儿药理学研究中心的研究中，所有65名接受每周500mg剂量的受试者均超过9ng/ml稳态。
结论：己酸17-羟孕酮的给药方案不充分。药物浓度与自发性早产之间存在显著的负相关。当浓度超过9ng/ml时，风险最低，但25％接受250mg每周剂量的女性永远不会达到并保持这一浓度。该药物的长半衰期需要负荷剂量以迅速达到治疗浓度。省略确定适当剂量的基本药理学研究可能会损害17-羟基孕酮己酸酯的有效性。未来的妊娠药物治疗试验必须首先完成基础药理学研究。
目的：本研究的目的是通过分析评估己酸17-羟孕酮药理学的三个数据集来评估17-羟孕酮的给药方案：母胎医学Omega3研究，产科-胎儿药理学研究单位研究和产科-胎儿药理学研究中心研究。如果可以识别出不适当的给药方案，这些信息可以为未来的妊娠药物治疗研究提供信息。
方法：使用Omega3研究的数据来确定血浆浓度是否与自发性早产风险相关，以及是否可以确定阈值浓度。来自产科-胎儿药理学研究单位研究的数据用于确定17-羟基孕酮己酸酯的半衰期，并开发模型以模拟各种给药方案的药物浓度。来自产科-胎儿药理学研究中心研究的数据用于确定剂量和安全性结果之间的关系。
结果：对Omega3数据集的分析表明，随着17-羟孕酮己酸酯的对数增加，自发性早产的风险降低[比值比（95CI）0.04（0.00-0.90）]。稳态浓度>9ng/ml（相当于在25-28周时>8ng/ml）与自发性早产的最低风险相关[风险比（95CI）0.52（0.27-0.98，p=0.04）];在接受250mg每周剂量的受试者中，有25％未达到该浓度。在产科-胎儿药理学研究单位研究中，17-羟孕酮己酸酯的校正半衰期(中位数和IQR)为14.0(11.5-17.2)天.模拟表明，每周250毫克的剂量，>5每周注射需要达到9ng/ml的目标;然而，半衰期最短的那些(对应于较高的清除率)，从未达到目标9ng/ml浓度。在75%的科目中，每周500mg的负荷剂量持续2周，然后每周250mg达到并在两周内保持9ng/ml的浓度，但在半衰期最短的25％中，浓度超过9ng/ml目标仅3周。在产科-胎儿药理学研究中心的研究中，所有65名接受每周500mg剂量的受试者均超过9ng/ml稳态。
结论：己酸17-羟孕酮的给药方案不充分。药物浓度与自发性早产之间存在显著的负相关。当浓度超过9ng/ml时，风险最低，但25％接受250mg每周剂量的女性永远不会达到并保持这一浓度。该药物的长半衰期需要负荷剂量以迅速达到治疗浓度。省略确定适当剂量的基本药理学研究可能会损害17-羟基孕酮己酸酯的有效性。未来的妊娠药物治疗试验必须首先完成基础药理学研究。
