WHO 发布口服新冠抗病毒药 Molnupiravir 生物等效性指南

WHO 于 2021 年 11 月 15 日发布了关于默沙东口服新冠抗病毒药 Molnupiravir（莫纳皮拉韦） 的生物等效性（BE）指南，以帮助制药商开发向 WHO 预认证小组提交申请的产品。该指南已收录进识林 BE 数据库。

Molnupiravir 是默沙东和合作伙伴 Ridgeback Biotherapeutics 研发的首个显示成功治疗新冠的口服抗病毒药物。英国于本月初授予该药有条件许可。默沙东已向世界各国监管机构递交申请。这种药物的出现给双管齐下终止大流行提供了希望：药物治疗和预防，疫苗预防为主。

Molnupiravir 的药代动力学
Molnupiravir 是一种 5 ́-异丁酸前药，可代谢为核糖核苷类似物 N-羟基胞苷 (NHC)，然后分布到细胞中，在那里磷酸化形成具有药理活性的三磷酸核糖核苷 (NHC-TP)。Molnupiravir 在吸收/肝脏首过过程中通过存在于肠道和肝脏中的羧酸酯酶在到达体循环之前被水解为 N-羟基胞苷 (NHC)，在口服 molnupiravir 后将核苷代谢物 NHC 输送到体循环中。

每天两次口服 800 mg molnupiravir 后，达到血浆 NHC 浓度峰值的中位时间 (Tmax) 为 1.5 小时。在健康受试者中，随高脂肪餐服用一剂 200 mg molnupiravir 导致 NHC 峰值浓度 (Cmax) 降低 35%，AUC 未受到显著影响。Molnupiravir 可以在空腹或进食后服用。NHC 的有效半衰期约为 3.3 小时。NHC Cmax 和 AUC 随剂量成比例增加。

生物等效性研究设计指南
考虑到 molnupiravir 的药代动力学特性，应考虑以下有关研究设计的指南：

研究设计：推荐单剂量交叉设计

剂量：受邀产品包括 200 mg 胶囊。生物等效性可以以 1 x 200 mg 一剂执行。

空腹/餐后：由于参照 molnupiravir 可与或不与食物一起服用，因此建议进行空腹状态研究。

受试者：应招募健康志愿者。生物等效性研究中没有必要包括患者。

用于评估生物等效性的母药或代谢物数据：Molnupiravir 是 NHC 的 5 ́-异丁酸酯前药。吸收后，前药迅速转化为 NHC。因此，生物等效性应基于 NHC 的测定，因为母药 molnupiravir 在体循环中无法测量。

样本量：Molnupiravir 药代动力学参数 Cmax 和 AUC0-t 似乎具有中等的受试者内部变异性（约 22%），但可用信息有限且混杂因素可能夸大了受试者内部变异性估计。该数据可能有助于为单剂量交叉生物等效性研究计算足够的样本量。

清洗：考虑到 molnupiravir 的消除半衰期为 3.3 小时，7 天的清洗期被认为足以防止残留。

采血：在给药后的前 3 小时内应进行密集采血 , 以正确表征 molnupiravir 的 Cmax。采集超过 12 小时的血样来表征 molnupiravir 的药代动力学不是必要的。例如，可以在给药前和在 0.25、0.50、0.75、1.00、1.25、1.50、1.75、2.00、2.25、2.50、2.75、3.00、3.50、4.00、4.50、5.00、6.00、8.00、10.00、12.00 和 16.00h 采集血样。

分析考虑： WHO 药品预认证小组（PQT/MED）当前可用的信息表明，可以使用定量下限（LLOQ）为 1 ng/ml 的液相色谱串联质谱（LC-MS/MS）分析方法测量人血浆中的 NHC。生物分析方法应足够灵敏 , 以检测每种制剂（待测或对照产品）的大多数曲线中 Cmax 的 5% 的浓度。

统计考虑：NHC 的数据应满足单剂量交叉设计研究中的以下生物等效性标准：

待测与参照产品的相对平均 AUC0-t 的 90% 置信区间应在 80.00 – 125.00% 内。
待测与参照产品的相对平均 Cmax 的 90% 置信区间应在 80.00-125.00% 内。
生物豁免：基于 BCS 的 molnupiravir 生物豁免被认为是生物等效性研究的可能替代方案，前提是满足 ICH M9 指南《基于生物药剂学分类系统的生物豁免》（2019）中概述的授予基于 BCS 的生物豁免的要求和 PQT/MED 指南《ICH M9 生物药剂学分类系统 (BCS) 生物豁免指南申请 PQT/MED 特定注释》(2021) , 因为母药 molnupiravir 药物吸收后的首过效应期间，在肠细胞和肝细胞中代谢。

【英文原文】

Notes on the design of bioequivalence studies with products invited for submission to the WHO Prequalification Team – Medicines (PQT/MED) are issued to aid manufacturers with the development of their product dossier. Deviations from the approach suggested below can be considered acceptable if justified by sound scientific evidence.
The current notes should be read and followed in line with the general guidelines of submission of documentation for WHO prequalification. In particular, please consult the "Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability" in: Fifty-first Report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva, World Health Organization, 2017. WHO Technical Report Series, No. 1003, Annex 6.
Below, additional specific guidance is provided on the invited immediate release products containing molnupiravir.

Pharmacokinetics of Molnupiravir
Molnupiravir is a 5 ́-isobutyrate prodrug that is metabolised to the ribonucleoside analogue N-hydroxycytidine (NHC), which distributes into cells where it is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). Molnupiravir is hydrolysed to N-hydroxycytidine (NHC) prior to reaching systemic circulation by carboxylesterases present in the intestine and liver during absorption/hepatic first pass, delivering the nucleoside metabolite NHC into systemic circulation following oral administration of molnupiravir.
Following twice daily oral administration of 800 mg molnupiravir, the median time to peak plasma NHC concentrations (Tmax) was 1.5 hours. In healthy subjects, the administration of a single 200 mg dose of molnupiravir with a high-fat meal resulted in a 35% reduction in NHC peak concentrations (Cmax), AUC was not significantly affected. Molnupiravir can be taken with or without food. The effective half-life of NHC is approximately 3.3 hours. NHC Cmax and AUC increases dose-proportionally.

Guidance for the design of bioequivalence studies:
Taking into account the pharmacokinetic properties of Molnupiravir, the following guidance with regard to the study design should be taken into account:
Study design: A single-dose cross-over design is recommended.
Dose: The EoI includes 200 mg capsules. The bioequivalence can be conducted with a dose of 1 x 200 mg.
Fasted/fed: As the comparator molnupiravir product can be taken with or without food, a fasted state study is recommended.
Subjects: Healthy volunteers should be recruited. It is not necessary to include patients in the bioequivalence study.
Parent or metabolite data for assessment of bioequivalence: Molnupiravir is the 5 ́-isobutyrate prodrug of NHC. Following absorption, the prodrug is rapidly converted to NHC. Therefore, bioequivalence should be based on the determination of NHC, since the parent molnupiravir is not measurable in the systemic circulation.
Sample size: Molnupiravir pharmacokinetic parameters, Cmax and AUC0-t, seem to possess moderate intra-subject variability (approximately 22%), although information available is limited and confounding factors might have inflated the intra-subject variability estimation. This data may facilitate the calculation of a sufficient sample size for a single-dose cross-over bioequivalence study.
Washout: Taking into account the elimination half-life of molnupiravir of 3.3 hours, a washout period of seven days is considered sufficient to prevent carry over.
Blood sampling: The blood sampling should be intensive for the first 3 hours after administration to properly characterize the Cmax of molnupiravir. It is not necessary to take blood samples beyond 12 hours for the characterization of molnupiravir pharmacokinetics. For example, samples can be taken pre-dose and at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, and 16.00h after drug administration.
Analytical considerations: Information currently available to PQT/MED indicates that it is possible to measure NHC in human plasma using LC-MS/MS analytical methodology with a LLOQ of 1 ng/ml. The bioanalytical method should be sufficiently sensitive to detect concentrations that are 5% of the Cmax in most profiles of each formulation (test or comparator).
Statistical considerations: The data for NHC should meet the following bioequivalence standards in a single-dose cross-over design study:
The 90% confidence interval of the relative mean AUC0-t of the test to reference product should be within 80.00 – 125.00%
The 90% confidence interval of the relative mean Cmax of the test to reference product should be within 80.00 – 125.00%.
Biowaiver: A BCS-based biowaiver for molnupiravir is considered a possible alternative to a bioequivalence study, provided the requirements for granting a BCS-based biowaiver are met as outlined in the ICH Guideline "Biopharmaceutics Classification System-Based Biowaivers" M9 (2019) and the PQT/MED guidance "PQT/MED-specific Annotations for the ICH M9 Guideline for Biopharmaceutics Classification System (BCS)-based Biowaiver Applications" (2021) because the parent drug molnupiravir is metabolized in the enterocytes and hepatocytes during the first-pass effect after drug absorption.
编译：识林-苜蓿

       文章来源：识林

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