Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, 2333CC, Leiden, The Netherlands.
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands.
Pharm Res. 2024 Apr;41(4):637-649. doi: 10.1007/s11095-024-03677-3. Epub 2024 Mar 12.
Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs.
We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFR (GFR at birth), and an Emax model dependent on PNA (with GFR, PNA (PNA at which half of is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations.
In the GFR model, GFR varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA, and current weight for GFR. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well.
GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.
早产儿肾小球滤过率（GFR）何时以及能否赶上足月同龄人尚不清楚。本研究旨在建立一个从出生到 18 岁（早产儿和足月儿）的 GFR 成熟模型。其次，将该功能应用于不同经肾脏排泄的药物的数据中。
我们结合了整个儿童期（早产儿和足月儿）发表的菊粉清除值和血清肌酐（Scr）浓度。假设菊粉清除率等于 GFR，Scr 反映肌酐合成率/GFR。我们开发了一个由 GFR（出生时的 GFR）和依赖于 PNA 的 Emax 模型组成的 GFR 函数（GFR，PNA（达到一半的 GFR）和 Hill 系数）。最终的 GFR 模型用于预测庆大霉素、妥布霉素和万古霉素的浓度。
在 GFR 模型中，GFR 与出生体重呈线性关系，而在基于 PNA 的 Emax 方程中，GA 是 PNA 的最佳协变量，体重是 GFR 的最佳协变量。最终模型表明，对于 26 周 GA 出生的儿童，绝对 GFR 分别为 40 周 GA 出生的儿童的 1 个月、6 个月、1 年、3 年和 12 岁时 GFR 的 18%、63%、80%、92%和 96%。使用 GFR 成熟方程的 PopPK 模型很好地预测了整个早产儿直至 18 岁的经肾脏清除抗生素的浓度。
早产儿的 GFR 在 3 岁左右赶上足月儿，这意味着在此年龄以下，应考虑减少经肾脏清除的药物剂量。
