ABSTRACT

OBJECTIVES

An ibuprofen (IBU)/acetaminophen (APAP) fixed-dose combination (FDC) for over-the-counter (OTC) use was developed with the goal of providing the same effective analgesic activity as full doses of the individual monocomponents, while reducing individual monocomponent drug exposures. Here, the safety and tolerability of the FDC is characterized using pooled safety data from phase 1–3 clinical trials in the FDC development program.

METHODS

We conducted a pooled safety analysis of data from 7 clinical trials: three phase 1 pharmacokinetic trials, a phase 2 proof-of-concept trial, and three phase 3 trials (a single- and a multiple-dose trial in a dental pain model and a single-dose trial in an induced-fever model). Safety and tolerability of the FDC were assessed by adverse events (AEs) for the total group and subgroups (age, sex, race).

RESULTS

A total of 1,477 participants were enrolled in the 7 trials; 715 were treated with FDC IBU/APAP, 432 with IBU monotherapy, 330 with APAP monotherapy, and 156 with placebo. Most subjects were white (86.5%), and 44% were female. Two trials enrolling 195 adolescents accounted for 13.2% of the overall study population. All-causality treatment-emergent AEs (TEAEs) occurred in 19.7% of the 1477 participants. Nausea (13.5%), vomiting (7.4%), dizziness (4.5%), headache (1.2%), and feeling hot (1.0%) were the only TEAEs reported in ≥1% of subjects. Treatment-related AEs occurred in 1.8% of the subjects in the overall population. The incidence of AEs, including treatment-related AEs, was consistently lower in all active treatment groups than in the placebo group; this also applied to subgroups according to sex, race, and age, including adolescents aged 12–17 years. The higher rate of AEs with placebo was likely due to lack of pain/fever control.

CONCLUSION

Single-dose or short-course FDC IBU/APAP OTC use was well tolerated, with an AE profile similar to its IBU and APAP monocomponents.

ClinicalTrials.gov Registration

NCT01559259; NCT02912650; NCT02837952; NCT02761980. The pharmacokinetic studies (n = 3) did not require registration.

中文翻译：

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布洛芬和对乙酰氨基酚固定剂量组合的安全性和耐受性：1-3 期临床试验的汇总分析

摘要

目标

开发了一种用于非处方 (OTC) 使用的布洛芬 (IBU)/对乙酰氨基酚 (APAP) 固定剂量组合 (FDC)，其目标是提供与单组分全剂量相同的有效镇痛活性，同时减少个体单组分药物暴露。在这里，FDC 的安全性和耐受性使用 FDC 开发计划中 1-3 期临床试验的汇总安全数据进行表征。

方法

我们对 7 项临床试验的数据进行了汇总安全性分析：三项 1 期药代动力学试验、一项 2 期概念验证试验和三项 3 期试验（一项针对牙痛模型和诱导发热模型中的单剂量试验）。FDC 的安全性和耐受性通过总组和亚组（年龄、性别、种族）的不良事件 (AE) 进行评估。

结果

共有 1,477 名参与者参加了 7 项试验；715 人接受 FDC IBU/APAP 治疗，432 人接受 IBU 单药治疗，330 人接受 APAP 单药治疗，156 人接受安慰剂治疗。大多数受试者是白人 (86.5%)，44% 是女性。两项纳入 195 名青少年的试验占整个研究人群的 13.2%。1477 名参与者中有 19.7% 发生了全因果治疗出现的 AE (TEAE)。恶心 (13.5%)、呕吐 (7.4%)、头晕 (4.5%)、头痛 (1.2%) 和感觉热 (1.0%) 是仅有 1% 的受试者报告的 TEAE。总体人群中 1.8% 的受试者发生了与治疗相关的 AE。AE 的发生率，包括治疗相关的 AE，在所有活性治疗组中始终低于安慰剂组；这也适用于根据性别、种族和年龄划分的亚组，包括 12-17 岁的青少年。安慰剂组的 AE 发生率较高可能是由于缺乏疼痛/发烧控制。

结论

单剂量或短程 FDC IBU/APAP OTC 使用耐受性良好，AE 曲线与其 IBU 和 APAP 单组分相似。

ClinicalTrials.gov 注册

NCT01559259; NCT02912650；NCT02837952；NCT02761980。药代动力学研究（n = 3）不需要注册。