Dosing of Convalescent Plasma and Hyperimmune Anti-SARS-CoV-2 Immunoglobulins: A Phase I/II Dose-Finding Study.

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2024-04-01 Epub Date: 2024-03-01 DOI:10.1007/s40262-024-01351-w
Sammy Huygens, Tim Preijers, Francis H Swaneveld, Ilona Kleine Budde, Corine H GeurtsvanKessel, Birgit C P Koch, Bart J A Rijnders
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引用次数: 0

Abstract

Background and objective: During the COVID-19 pandemic, trials on convalescent plasma (ConvP) were performed without preceding dose-finding studies. This study aimed to assess potential protective dosing regimens by constructing a population pharmacokinetic (popPK) model describing anti-SARS-CoV-2 antibody titers following the administration of ConvP or hyperimmune globulins (COVIg).

Methods: Immunocompromised patients, testing negative for anti-SARS-CoV-2 spike antibodies despite vaccination, received a range of anti-SARS-CoV-2 antibodies in the form of COVIg or ConvP infusion. The popPK analysis was performed using NONMEM v7.4. Monte Carlo simulations were performed to assess potential COVIg and ConvP dosing regimens for prevention of COVID-19.

Results: Forty-four patients were enrolled, and data from 42 were used for constructing the popPK model. A two-compartment elimination model with mixed residual error best described the Nab-titers after administration. Inter-individual variation was associated to CL (44.3%), V1 (27.3%), and V2 (29.2%). Lean body weight and type of treatment (ConvP/COVIg) were associated with V1 and V2, respectively. Median elimination half-life was 20 days (interquartile range: 17-25 days). Simulations demonstrated that even monthly infusions of 600 mL of the ConvP or COVIg used in this trial would not achieve potentially protective serum antibody titers for > 90% of the time. However, as a result of hybrid immunity and/or repeated vaccination, plasma donors with extremely high antibody titers are now readily available, and a > 90% target attainment should be possible.

Conclusion: The results of this study may inform future intervention studies on the prophylactic and therapeutic use of antiviral antibodies in the form of ConvP or COVIg.

Clinical trial registration number: NL9379 (The Netherlands Trial Register).

Abstract Image

新陈代谢血浆和超免疫抗 SARS-CoV-2 免疫球蛋白的剂量:I/II期剂量测定研究。
背景和目的:在 COVID-19 大流行期间,对康复血浆(ConvP)进行了试验,但之前没有进行剂量测定研究。本研究旨在通过构建群体药代动力学(popPK)模型,描述给予 ConvP 或超免疫球蛋白(COVIg)后的抗 SARS-CoV-2 抗体滴度,从而评估潜在的保护性给药方案:免疫力低下的患者尽管接种了疫苗,但抗 SARS-CoV-2 尖峰抗体检测结果为阴性,他们接受了以 COVIg 或 ConvP 输注形式提供的一系列抗 SARS-CoV-2 抗体。popPK 分析使用 NONMEM v7.4 进行。蒙特卡洛模拟评估了预防 COVID-19 的潜在 COVIg 和 ConvP 给药方案:结果:共招募了 44 名患者,其中 42 名患者的数据被用于构建 popPK 模型。具有混合残余误差的两室消除模型最能描述给药后的纳布-滴度。个体间差异与 CL(44.3%)、V1(27.3%)和 V2(29.2%)有关。瘦体重和治疗类型(ConvP/COVIg)分别与 V1 和 V2 有关。中位消除半衰期为 20 天(四分位间范围:17-25 天)。模拟结果表明,即使每月输注 600 毫升试验中使用的 ConvP 或 COVIg,也无法在超过 90% 的时间内达到潜在的保护性血清抗体滴度。然而,由于混合免疫和/或重复接种,现在可以随时获得抗体滴度极高的血浆供体,因此达到 > 90% 的目标应该是可能的:本研究的结果可为今后以 ConvP 或 COVIg 形式使用抗病毒抗体进行预防和治疗的干预研究提供参考:临床试验注册号:NL9379(荷兰试验注册)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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