Drug Metabolism and Pharmacokinetics Research Department, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan
Drug Metabolism and Pharmacokinetics Research Department, Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Drug Metab Dispos. 2023 Oct;51(10):1428-1435. doi: 10.1124/dmd.123.001425. Epub 2023 Jul 19.
Several modified antisense oligonucleotides (ASOs) have recently been approved for clinical use. Some are phosphorodiamidate morpholino oligomers (PMOs), which, unlike other nucleic acids, are not negatively charged. Thus, PMOs differ from other ASOs in their pharmacokinetic (PK) properties. Drugs with a PMO backbone have been administered to Duchenne muscular dystrophy pediatric patients; however, appropriate methodologies are not currently available to predict their human PK from nonclinical data. In this study, we used viltolarsen as a representative PMO to investigate the applicability of the allometric scaling approach to human PK prediction. We first summarized the nonclinical and clinical PK data for viltolarsen as showing high total clearance, low serum protein binding, metabolic resistance, and urinary excretion as the unchanged drug in both animals and humans. We then investigate the PK of viltolarsen in mice, rats, cynomolgus monkeys, and dogs and used the results, with body weight, to extrapolate to humans by several methods. The estimate of human total clearance obtained from cynomolgus monkeys was the best, and body weight may be the key factor in accurately predicting human total clearance. In contrast, all of the well-known prediction methods for the volume of distribution at steady state gave underestimates. However, the human PK profiles predicted from the PK parameters in cynomolgus monkeys fit the observed human plasma concentrations well. These results are expected to contribute to the further development of PMOs. SIGNIFICANCE STATEMENT: We investigated how to predict the human PK of phosphorodiamidate morpholino oligomers from nonclinical data. The estimates of human PK parameters and profiles determined from cynomolgus monkeys by an allometric scaling approach were the most suitable, and the cynomolgus monkey body weight may be the key factor in accurately predicting human total clearance.
几种改良的反义寡核苷酸 (ASO) 最近已获准用于临床。有些是磷酸二酰胺吗啉寡聚物 (PMO)，与其他核酸不同，它们不带负电荷。因此，PMO 在药代动力学 (PK) 特性上与其他 ASO 有所不同。具有 PMO 骨架的药物已被用于杜氏肌营养不良症儿科患者；然而，目前尚无适当的方法可根据非临床数据预测其人体 PK。在这项研究中，我们使用 viltolarsen 作为代表性 PMO，研究了种属间外推法在人体 PK 预测中的适用性。我们首先总结了 viltolarsen 的非临床和临床 PK 数据，结果表明该药在动物和人体内均具有高总清除率、低血清蛋白结合率、代谢稳定性和原形药物经尿液排泄等特点。然后，我们研究了 viltolarsen 在小鼠、大鼠、食蟹猴和犬体内的 PK，并使用体重等数据通过多种方法外推至人体。从食蟹猴获得的人体总清除率估计值最佳，而体重可能是准确预测人体总清除率的关键因素。相比之下，所有已知的预测方法均低估了稳态分布容积。然而，从食蟹猴 PK 参数预测的人体 PK 曲线与观察到的人体血浆浓度拟合良好。这些结果有望为 PMO 的进一步发展做出贡献。
我们研究了如何从非临床数据预测 PMO 的人体 PK。种属间外推法从食蟹猴获得的人体 PK 参数和曲线估计值最适合，而食蟹猴体重可能是准确预测人体总清除率的关键因素。
