Jazz Pharmaceuticals, Inc., Palo Alto, California, USA.
IQVIA, Overland Park, Kansas, USA.
Clin Transl Sci. 2023 May;16(5):898-909. doi: 10.1111/cts.13499. Epub 2023 Mar 16.
JZP458 is a recombinant Erwinia chrysanthemi asparaginase for patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who have developed hypersensitivity to Escherichia coli-derived asparaginases. A population pharmacokinetic (PopPK) model was developed for intramuscular (i.m.) JZP458 using serum asparaginase activity (SAA) data from 166 patients with ALL/LBL enrolled in a phase II/III study conducted in collaboration with the Children's Oncology Group (AALL1931; NCT04145531). The pharmacokinetics of i.m. JZP458 is best characterized by a one-compartment model with mixed-order absorption and linear elimination, with body surface area included as an allometric covariate on JZP458 SAA clearance and volume, and race (i.e., Black/African American) and disease subtype (i.e., T-cell ALL) as covariates on JZP458 SAA clearance. The PopPK model was used to simulate SAA profiles to estimate the likelihood of achieving nadir SAA (NSAA) levels greater than or equal to 0.1 IU/mL with different dosing regimens. Model-based simulations suggest when JZP458 is administered i.m. at 25/25/50 mg/m Monday/Wednesday/Friday (MWF), 92.1% of subjects (95% confidence interval [CI]: 90.9%, 93.3%) are expected to achieve the last 72-h (after 50 mg/m dose) NSAA level greater than or equal to 0.1 IU/mL, and 93.8% (95% CI: 92.7%, 94.9%) are expected to achieve the last 48-h (after 25 mg/m dose) NSAA level greater than or equal to 0.1 IU/mL. When JZP458 is administered 25 mg/m i.m. every 48 h, 93.8% (95% CI: 92.7%, 94.8%) are expected to achieve the last 48-h NSAA level greater than or equal to 0.1 IU/mL. These data supported the i.m. dose of 25 mg/m every 48 h or 25/25/50 mg/m on a MWF dosing schedule in patients with ALL/LBL.
JZP458 是一种重组欧文氏菌天冬酰胺酶，用于对大肠杆菌衍生的天冬酰胺酶产生过敏反应的急性淋巴细胞白血病（ALL）/淋巴母细胞淋巴瘤（LBL）患者。采用协作儿童肿瘤组（AALL1931；NCT04145531）进行的 II/III 期研究中纳入的 166 例 ALL/LBL 患者的血清天冬酰胺酶活性（SAA）数据，建立了 JZP458 的群体药代动力学（PopPK）模型。JZP458 的肌肉内（i.m.）药代动力学最好用具有混合顺序吸收和线性消除的单室模型来描述，体表面积作为 JZP458 SAA 清除率和体积的比例模型协变量，种族（即黑人/非裔美国人）和疾病亚型（即 T 细胞 ALL）作为 JZP458 SAA 清除率的协变量。PopPK 模型用于模拟 SAA 谱，以估计不同给药方案下达到 SAA 水平低于 0.1IU/mL 的可能性。基于模型的模拟表明，当 JZP458 以 25/25/50mg/m 剂量周一/三/五（MWF）肌肉内给药时，92.1%（95%置信区间[CI]：90.9%，93.3%）的受试者有望达到最后 72 小时（50mg/m 剂量后）的 SAA 水平大于或等于 0.1IU/mL，93.8%（95%CI：92.7%，94.9%）的受试者有望达到最后 48 小时（25mg/m 剂量后）的 SAA 水平大于或等于 0.1IU/mL。当 JZP458 以 25mg/m 剂量每 48 小时肌肉内给药时，93.8%（95%CI：92.7%，94.8%）的受试者有望达到最后 48 小时的 SAA 水平大于或等于 0.1IU/mL。这些数据支持 ALL/LBL 患者 JZP458 以 25mg/m 剂量每 48 小时或 25/25/50mg/m 剂量 MWF 给药方案。
