Centre for Human Drug Research, Leiden, the Netherlands.
Leiden University Medical Center, Leiden, the Netherlands.
Pharmacol Res Perspect. 2020 Apr;8(2):e00574. doi: 10.1002/prp2.574.
This research was planned to build a Pharmacokinetic/Pharmacodynamic (PK/PD) model of 5-hydroxytryptophan (5-HTP) challenge study including a circadian rhythm component of cortisol and to predict serum cortisol based on saliva cortisol. Data from three 5-HTP challenge studies in healthy volunteers were collected. Serum 5-HTP, saliva, and serum cortisol were sampled as PK and PD marker. The population PK/PD modeling approach was applied. A baseline model of serum cortisol was built to assess the circadian rhythm before a pharmacodynamic model was used to evaluate the drug effect of the 5-HTP on cortisol. Finally, linear and power function relationships were tested to predict serum cortisol based on saliva cortisol. The PK of 5-HTP could be described using a one-compartment model with a transit compartment. The typical value for clearance was 20.40 L h and showed inter-study variability. A cosine function was chosen and properly described the circadian rhythm of serum cortisol. A linear approximation model was applied to fit the 5-HTP PD effect on cortisol data with a slope of 4.16 ng mL h. A power function provided a better description than a linear function to relate the saliva and serum cortisol. In conclusion, a circadian rhythm component was built in the PK/PD model of the 5-HTP challenge test which could better improve the understanding of the stimulating effect on HPA with cortisol change. After the 5-HTP challenge, saliva cortisol correlated well with serum cortisol and was predictable by a population PK-PD model.
这项研究旨在构建 5-羟色氨酸（5-HTP）挑战研究的药代动力学/药效学（PK/PD）模型，包括皮质醇的昼夜节律成分，并基于唾液皮质醇预测血清皮质醇。收集了来自三项健康志愿者 5-HTP 挑战研究的数据。采集血清 5-HTP、唾液和血清皮质醇作为 PK 和 PD 标志物。应用群体 PK/PD 建模方法。建立血清皮质醇的基线模型，以评估药效学模型之前的昼夜节律，然后使用该模型评估 5-HTP 对皮质醇的药物作用。最后，测试线性和幂函数关系，以基于唾液皮质醇预测血清皮质醇。5-HTP 的 PK 可以使用具有转运隔室的单室模型来描述。清除率的典型值为 20.40 L/h，表现出研究间变异性。选择了余弦函数，并适当描述了血清皮质醇的昼夜节律。线性近似模型用于拟合 5-HTP 对皮质醇数据的 PD 效应，斜率为 4.16 ng/mL/h。幂函数比线性函数更能描述唾液和血清皮质醇之间的关系。总之，在 5-HTP 挑战试验的 PK/PD 模型中构建了昼夜节律成分，这可以更好地了解皮质醇变化对 HPA 的刺激作用。在 5-HTP 挑战后，唾液皮质醇与血清皮质醇相关性良好，并可通过群体 PK-PD 模型预测。
