Relative Bioavailability of Dolutegravir (DTG) and Emtricitabine/Tenofovir Alafenamide Fumarate (F/TAF) Administered as Paediatric Tablet Formulations in Healthy Volunteers

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Lisanne A. H. Bevers, Anne E. M. Kamphuis, L. C. Wendy van der Wekken-Pas, Rory Leisegang, David M. Burger, Angela Colbers
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引用次数: 0

Abstract

Background and objective

Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together.

Methods

Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (Cmax) of each compound were within 0.70–1.43, we considered this as no clinically relevant PK interaction.

Results

A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC0–∞ and Cmax fell outside our acceptance criteria of 0.70–1.43.

Conclusions

Although TAF AUC and Cmax 90% CIs fell outside the pre-defined criteria (0.62–1.11 and 0.65–1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.

健康志愿者服用多罗替拉韦(DTG)和恩曲他滨/富马酸替诺福韦/富马酸阿拉非那胺(F/TAF)儿科片剂的相对生物利用度
背景和目标在 UNIVERSAL 项目(RIA2019PD-2882)中,我们旨在开发一种儿科多托瑞韦(DTG)/恩曲他滨(FTC 或 F)/替诺福韦-阿拉非那胺(TAF)固定剂量复方制剂。为了给这项研究提供剂量信息,我们在健康志愿者中进行了一项相对生物利用度(RBA)研究,以调查 DTG 和 F/TAF 儿科制剂一起服用时可能产生的药代动力学效应。方法参与者按随机顺序接受以下所有儿科制剂治疗:单剂量 180/22.5 毫克 F/TAF;单剂量 30 毫克 DTG;单剂量 180/22.5 毫克 F/TAF 加 30 毫克 DTG。在服药后 48 小时内测定 DTG、FTC、TAF 和替诺福韦 (TFV) 的血药浓度。如果每种化合物的曲线下面积(AUC)和最大浓度(Cmax)的几何最小二乘法平均值(GLSM)比值的 90% 置信区间(CI)在 0.70-1.43 范围内,我们就认为这没有临床相关的 PK 相互作用。对于DTG、FTC和TFV化合物,我们没有观察到儿科DTG和F/TAF制剂之间存在临床相关的PK相互作用。结论虽然 TAF AUC 和 Cmax 90% CI 值超出了预先设定的标准(分别为 0.62-1.11 和 0.65-1.01),但没有观察到对 TAF PK 有一致的影响,这可能是由于受试者之间的变异性较大。此外,与 TAF 暴露相比,TFV 暴露更具有临床相关性,这是有多种原因的。因此,我们在本研究中没有发现与临床相关的相互作用。
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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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