Clinical Pharmacology, Specialty Care, Pfizer Inc., Groton, Connecticut, USA.
Antimicrob Agents Chemother. 2013 Jan;57(1):466-74. doi: 10.1128/AAC.01473-12. Epub 2012 Nov 5.
To evaluate the exposure-response relationships for efficacy and safety of intravenous anidulafungin in adult patients with fungal infections, a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from 262 patients in four phase 2/3 studies. The plasma concentration data were fitted with a previously developed population PK model. Anidulafungin exposures in patients with weight extremities (e.g., 40 kg and 150 kg) were simulated based on the final PK model. Since the patient population, disease status, and efficacy endpoints varied in these studies, the exposure-efficacy relationship was investigated separately for each study using logistic regression as appropriate. Safety data from three studies (n = 235) were pooled for analysis, and one study was excluded due to concomitant use of amphotericin B as a study treatment and different disease populations. The analysis showed that the same dosing regimen of anidulafungin can be administered to all patients regardless of body weight. Nonetheless, caution should be taken for patients with extremely high weight (e.g., >150 kg). There was a trend of positive association between anidulafungin exposure and efficacy in patients with esophageal candidiasis or invasive candidiasis, including candidemia (ICC); however, adequate characterization of the effect of anidulafungin exposure on response could not be established due to the relatively small sample size. No threshold value for exposure could be established, since patients with low exposure also achieved successful outcomes (e.g., area under the curve < 40 mg · h/liter in ICC patients). There was no association between anidulafungin exposure and the treatment-related adverse events or all-causality hepatic laboratory abnormalities.
为了评估静脉用阿尼芬净在真菌感染的成年患者中的疗效和安全性的暴露-反应关系，对来自四项 2/3 期研究的 262 例患者的数据进行了群体药代动力学-药效学（PK-PD）分析。采用先前开发的群体 PK 模型对血浆浓度数据进行拟合。根据最终的 PK 模型，模拟了体重极端（例如 40kg 和 150kg）患者的阿尼芬净暴露情况。由于这些研究中的患者人群、疾病状况和疗效终点不同，因此分别针对每项研究使用逻辑回归进行了暴露-疗效关系的研究。对来自三项研究（n=235）的安全性数据进行了汇总分析，并排除了一项因同时使用两性霉素 B 作为研究治疗药物和不同疾病人群的研究。分析表明，无论体重如何，均可给予所有患者相同剂量的阿尼芬净。尽管如此，对于体重极高的患者（例如＞150kg）仍需谨慎。在食管念珠菌病或侵袭性念珠菌病（包括念珠菌血症）患者中，阿尼芬净暴露与疗效之间存在正相关趋势（ICC）；然而，由于样本量相对较小，无法充分确定阿尼芬净暴露对反应的影响。由于低暴露的患者也获得了成功的结果（例如，ICC 患者的 AUC＜40mg·h/L），因此无法确定暴露的阈值值。阿尼芬净暴露与治疗相关不良事件或全因肝实验室异常之间无关联。
