简报：孕期和产后多替拉韦的血浆蛋白结合率和游离浓度。

Brief Report: Dolutegravir Plasma Protein Binding and Unbound Concentrations During Pregnancy and Postpartum.

机构信息

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA.

School of Medicine, University of California, San Diego, La Jolla, CA.

出版信息

J Acquir Immune Defic Syndr. 2023 Dec 1;94(4):332-336. doi: 10.1097/QAI.0000000000003281.

DOI:10.1097/QAI.0000000000003281

PMID:37884053

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10686188/

Abstract

BACKGROUND

Clinical interpretation of the reduced dolutegravir (DTG) plasma concentrations reported during pregnancy is complicated by its high plasma protein binding. Plasma proteins significantly decrease during pregnancy, and understanding changes in DTG protein binding and its therapeutically active unbound concentrations are necessary to evaluate the impact of pregnancy changes on DTG pharmacokinetics.

METHODS

Retrospective assessment of plasma samples from pregnant women living with HIV enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s study receiving 50 mg DTG film-coated tablets once daily as part of clinical care. Unbound and total DTG concentrations were determined predose (C0) and at maximum (Cmax) concentrations during the second trimester (2T), third trimester (3T), and postpartum (PP). Percentage unbound was calculated as the ratio of ultrafiltrate unbound DTG concentration to total DTG concentration.

RESULTS

Twenty-nine mothers were included for protein binding evaluations; 15, 27, and 23 from the 2T, 3T, and PP, respectively. DTG % unbound for C0 and Cmax were significantly different by stage of pregnancy, with 3T significantly higher compared with PP; 1.02% vs. 0.69% (P = 0.0067) for C0 and 0.76% vs. 0.46% for Cmax (P = 0.0056). Median (IQR) unbound concentrations for C0 were 6.3 (4.7-18.4) for the 2T, 8.0 (5.6-16.9) for the 3T, and 13.3 (8.4-22.7) ng/mL PP, significantly different between 2T and PP (P = 0.0039), but not different between 3T and PP (P = 0.46).

CONCLUSION

Lower total DTG plasma concentrations during pregnancy coincide with temporal decreases in DTG protein binding, resulting in comparable unbound DTG concentrations during the 3T and PP.

摘要

背景

怀孕期间报告的多拉韦林（DTG）血浆浓度降低，其血浆蛋白结合率高，临床解释较为复杂。怀孕期间血浆蛋白显著下降，了解 DTG 蛋白结合及其治疗活性未结合浓度的变化，对于评估妊娠变化对 DTG 药代动力学的影响是必要的。

方法

回顾性评估了参与国际母婴儿科青少年艾滋病临床试验网络 P1026s 研究的 HIV 感染者孕妇的血浆样本，这些孕妇在临床护理中接受 50mg DTG 薄膜包衣片，每日一次。在妊娠中期（2T）、妊娠晚期（3T）和产后（PP）时，测定了预剂量（C0）和最大浓度（Cmax）时的游离和总 DTG 浓度。未结合百分比计算为超滤游离 DTG 浓度与总 DTG 浓度的比值。

结果

共有 29 名母亲接受了蛋白结合评估；分别有 15、27 和 23 名母亲来自 2T、3T 和 PP 期。C0 和 Cmax 的 DTG %未结合因妊娠阶段而异，3T 期显著高于 PP 期；C0 时分别为 1.02%和 0.69%（P=0.0067），Cmax 时分别为 0.76%和 0.46%（P=0.0056）。2T 期 C0 的中位（IQR）未结合浓度为 6.3（4.7-18.4）ng/mL，3T 期为 8.0（5.6-16.9）ng/mL，PP 期为 13.3（8.4-22.7）ng/mL，2T 期与 PP 期显著不同（P=0.0039），但 3T 期与 PP 期无差异（P=0.46）。