Department of Clinical Pharmacology, Medical School, Université de la Méditerranée; Assistance Publique Hôpitaux de Marseille, Marseille, France.
Clin Pharmacokinet. 2010 Jul;49(7):455-63. doi: 10.2165/11531290-000000000-00000.
Adrenal insufficiency is caused by primary adrenal failure or by impairment of the corticotropic axis. In both situations, cortisol secretion is deficient, and hydrocortisone is a logical replacement therapy. However, no consensus guideline for dosing has been published, and clinicians adapt the dose empirically after only a clinical evaluation. Under this regimen, some patients receiving an inappropriately high dose of cortisol feel comfortable and also have an increased risk of adverse effects. We performed a pharmacokinetic study of cortisol in patients with adrenal insufficiency to evaluate plasma concentrations when the dosing was based on clinical examination and to develop a model allowing optimization of drug dosing.
This was a prospective, open-label study in two endocrinology departments and a clinical investigation centre (Assistance Publique Hôpitaux de Marseille, Marseille, France).
Fifty patients with primary (n = 20) or secondary (n = 30) adrenal insufficiency were recruited. All patients were given their usual hydrocortisone replacement regimen. Blood samples for cortisol measurements were drawn at 0600, 0800, 1000, 1200, 1400, 1600, 1800, 2000, 2200 and 0000 h. The observed values were compared with the known physiological range throughout the day (0800, 1600 and 0000 h). A population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling software (NONMEM). The final pharmacokinetic model was then used to simulate several hydrocortisone dosing scenarios.
Thirteen different treatment regimens for 50 patients were observed. The cortisol plasma concentrations were compared with the physiological range and showed that 79%, 55% and 45% of patients were over- or under-treated at 0800, 1600 and 2400 h, respectively. The cortisol concentrations showed wide variability and were best described using a one-compartment model with zero-order input and first-order elimination. The pharmacokinetic parameters (intersubject variability) were the following: duration of absorption 0.54 hour, volume of distribution 38.7 L (39.7%) and clearance 12.1 L/h (23.2%). The proportional residual error was 32.3%. This final model was then used to simulate 18 different dosing regimens. The regimen with the highest proportion of simulated patients within the physiological targets was 10 + 5 + 5 mg at 0730, 1200 and 1630 h, respectively. However, even with this regimen, about 54%, 44% and 32% of patients would remain over- or under-treated at 0800, 1600 and 2400 h, respectively.
Most patients with adrenal insufficiency are imperfectly treated with hydrocortisone relative to their plasma cortisol concentrations. Using simulation, a standard dosing regimen is suggested, which increases the proportion of patients within the physiological target concentrations. However, an individualized dose adjustment would be more accurate.
肾上腺功能不全是由原发性肾上腺衰竭或促皮质激素轴功能障碍引起的。在这两种情况下，皮质醇分泌都不足，氢化可的松是一种合理的替代治疗药物。然而，目前尚未发布关于剂量的共识指南，临床医生仅在进行临床评估后凭经验调整剂量。在这种治疗方案下，一些接受不适当高剂量皮质醇的患者会感到舒适，但也会增加不良反应的风险。我们对肾上腺功能不全患者的皮质醇进行了药代动力学研究，以评估根据临床检查进行给药时的血浆浓度，并开发一种可以优化药物剂量的模型。
这是在法国马赛公立医院（马赛，法国）的两个内分泌科和一个临床研究中心进行的前瞻性、开放标签研究。
招募了 50 名原发性（n=20）或继发性（n=30）肾上腺功能不全患者。所有患者均接受常规氢化可的松替代治疗。在 06:00、08:00、10:00、12:00、14:00、16:00、18:00、20:00、22:00 和 00:00 时采集血样进行皮质醇测量。将观察到的数值与全天已知的生理范围（08:00、16:00 和 00:00 时）进行比较。使用非线性混合效应建模软件（NONMEM）进行群体药代动力学分析。然后，使用最终的药代动力学模型模拟几种氢化可的松给药方案。
观察了 50 名患者的 13 种不同治疗方案。将皮质醇血浆浓度与生理范围进行比较，结果显示，800 时、1600 时和 0000 时分别有 79%、55%和 45%的患者治疗过度或不足。皮质醇浓度的变异性很大，使用零阶输入和一阶消除的一室模型可以很好地描述。药代动力学参数（个体间变异性）如下：吸收半衰期 0.54 小时，分布容积 38.7 L（39.7%），清除率 12.1 L/h（23.2%）。比例残差为 32.3%。然后，使用该最终模型模拟了 18 种不同的给药方案。模拟生理靶标范围内患者比例最高的方案为 07:30 时给予 10+5+5 mg，12:00 时给予 10+5+5 mg，16:30 时给予 5+5+5 mg。然而，即使采用这种方案，800 时、1600 时和 2400 时仍有约 54%、44%和 32%的患者治疗过度或不足。
大多数肾上腺功能不全患者的皮质醇治疗相对血浆皮质醇浓度不理想。通过模拟，建议使用标准给药方案，这可以增加处于生理靶浓度范围内的患者比例。然而，个体化的剂量调整会更准确。
