索塔洛尔剂量优化胎儿心跳动:一个怀孕生理学基础的药理动力学模型研究研究
Hedwig van Hove1, Joyce E M van der Heijden1, Anne van Uden1
1Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands.
Prenatal diagnosis
|February 27, 2026
概括
优化对胎儿心动减速的索塔洛尔剂量至关重要. 怀孕生理学基础的药理动力学 (PBPK) 模型表明,每日剂量低于400毫克或分剂量可以改善胎儿治疗,同时最大限度地减少对母亲的毒性.
科学领域:
- 药理学 药理学是指药理学的学科.
- 孕产妇和胎儿医学 孕产妇和胎儿医学
- 计算机建模 计算建模
背景情况:
- 胎儿低心率需要在怀孕期间进行有效的治疗.
- 索塔洛尔是使用的,但需要谨慎的剂量,以平衡疗效和母亲的安全性.
- 怀孕会改变药物的药理动力学,需要优化剂量策略.
研究的目的:
- 通过使用妊娠生理学基础药理动力学 (PBPK) 模型,建立一个针对胎儿心动减速的优化索塔洛尔剂量策略.
- 确定剂量方案,最大限度地提高胎儿的治疗度,同时最大限度地降低母亲的QT延长风险.
主要方法:
- 开发和验证一个包含生理变化和胎盘转移的妊娠PBPK模型.
- 模拟以评估当前的索塔洛尔剂量建议,并探索替代方案.
- 定义的目标范围:母体度<2.5 mg/L,胎儿Ctrough的0.4-1.0 mg/L.
主要成果:
- 模型预测与现有的孕产妇和胎儿暴露数据保持一致.
- 每天480毫克,16%的母体度超过了毒性值,90%的胎儿治疗水平.
- 将剂量降低到每天400毫克,使母亲的过度暴露率降低到0.1% (87%的胎儿治疗水平).
- 将480毫克分为三个剂量,使母亲的过度暴露减少到0.3%,并实现了95%的胎儿目标.
结论:
- 怀孕的PBPK建模有效地优化了胎儿的索塔醇治疗.
- 建议每天使用≤400毫克的索塔醇剂量.
- 将240毫克或更高的剂量分为三个剂量,可以优化胎儿的疗效和母亲的安全.
相关概念视频
01:15Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions
54
PK–PD modeling has significantly influenced FDA regulatory decisions, particularly drug approval, dosage optimization, and labeling. These models integrate pharmacokinetics (PK) and pharmacodynamics (PD) to predict drug behavior and effects, aiding in optimizing dosing regimens and enhancing the probability of clinical trial success.One notable example is Nesiritide (Natrecor®), a recombinant human brain natriuretic peptide for treating acute decompensated congestive heart failure...
54
01:31Adrenergic Antagonists: ɑ and β-Receptor Blockers
1.3K
Third-generation β-blockers, such as labetalol and carvedilol, represent a significant advancement in managing cardiovascular conditions. Unlike conventional β-blockers, which can induce peripheral vasoconstriction, third-generation drugs block α1 adrenoceptors. This promotes vasodilation through several mechanisms, such as increased nitric oxide production, inhibition of calcium ion entry, opening of potassium ion channels, and antioxidant action. Labetalol, for instance, is...
1.3K
01:29Drug Dosing: Infants and Children
434
Pediatric patient dosages diverge from adults due to disparities in body surface area, total body water, and extracellular fluid per kilogram of body weight. The dosing regimen considers the variations in pharmacokinetics and pharmacology across distinct age groups, encompassing preterm newborns, infants, young children, older children, and adolescents. Calculation of pediatric patient doses is predicated on determining body surface area, which exhibits a superior correlation with the child's...
434
01:01Dosage Regimens: Partial Pharmacokinetic Parameters
229
It is not uncommon for complete drug pharmacokinetic profiles to remain elusive in pharmacokinetics. This necessitates certain educated assumptions by pharmacokineticists to determine appropriate dosage regimens without comprehensive pharmacokinetic data from animal or human studies. One prevalent assumption is setting the bioavailability factor, denoted as F, to 1 or 100%. This assumption caters to the scenario where a drug doesn't achieve full systemic absorption, resulting in the patient...
229
01:15Pharmacodynamic Models: Logarithmic Concentration–Effect Model
44
The log-linear model is a pharmacological framework used to describe the relationship between drug concentration and its effect. This model is particularly relevant when the observed effects range between 20% and 80% of the drug’s maximum effect (Emax), where a near-linear relationship is observed between the log of drug concentration and the measured effect. However, the log-linear model does not predict the maximum possible effect (Emax) or the effect at zero drug concentration,...
44
01:09Pharmacodynamic Models: Additive and Proportional Drug Effect Model
41
Drug response models describe how pharmacological agents interact with biological systems to produce measurable effects. Baseline responses are inherent physiological activities without a drug significantly influencing the observed pharmacological outcomes. Depending on the drug response model employed, these baseline responses may combine with the drug's effect in either an additive or proportional manner.Additive Drug Response ModelIn the additive model, the drug effect is independent of the...
41