Abstract
Therapeutic hypothermia (TH) is standard treatment for neonates (≥36 weeks) with perinatal asphyxia (PA) and hypoxic–ischemic encephalopathy. TH reduces mortality and neurodevelopmental disability due to reduced metabolic rate and decreased neuronal apoptosis. Since both hypothermia and PA influence physiology, they are expected to alter pharmacokinetics (PK). Tools for personalized dosing in this setting are lacking. A neonatal hypothermia physiology-based PK (PBPK) framework would enable precision dosing in the clinic. In this literature review, the stepwise approach, benefits and challenges to develop such a PBPK framework are covered. It hereby contributes to explore the impact of non-maturational PK covariates. First, the current evidence as well as knowledge gaps on the impact of PA and TH on drug absorption, distribution, metabolism and excretion in neonates is summarized. While reduced renal drug elimination is well-documented in neonates with PA undergoing hypothermia, knowledge of the impact on drug metabolism is limited. Second, a multidisciplinary approach to develop a neonatal hypothermia PBPK framework is presented. Insights on the effect of hypothermia on hepatic drug elimination can partly be generated from in vitro (human/animal) profiling of hepatic drug metabolizing enzymes and transporters. Also, endogenous biomarkers may be evaluated as surrogate for metabolic activity. To distinguish the impact of PA versus hypothermia on drug metabolism, in vivo neonatal animal data are needed. The conventional pig is a well-established model for PA and the neonatal Göttingen minipig should be further explored for PA under hypothermia conditions, as it is the most commonly used pig strain in nonclinical drug development. Finally, a strategy is proposed for establishing and fine-tuning compound-specific PBPK models for this application. Besides improvement of clinical exposure predictions of drugs used during hypothermia, the developed PBPK models can be applied in drug development. Add-on pharmacotherapies to further improve outcome in neonates undergoing hypothermia are under investigation, all in need for dosing guidance. Furthermore, the hypothermia PBPK framework can be used to develop temperature-driven PBPK models for other populations or indications. The applicability of the proposed workflow and the challenges in the development of the PBPK framework are illustrated for midazolam as model drug.
Highlights
Perinatal AsphyxiaDespite advances in perinatal medicine, the incidence of perinatal asphyxia (PA, a clinical condition comprising perinatal hypoxia, hypercarbia and combined metabolic and respiratory acidosis) has not decreased in the last decade (Albrecht et al, 2019)
PA occurs in 5.4/1,000 live born neonates, with 1.8/1,000 live births diagnosed with hypoxic– ischemic encephalopathy (HIE) (Pokorna et al, 2015)
To provide an initial illustration regarding the potential feasibility of Physiologybased PK (PBPK) modeling to predict the impact of therapeutic hypothermia (TH) on PK, midazolam was chosen as a model drug based on: (i) the availability of a significant amount of clinical PK data, in neonates; (ii) its PK profile, in view of the fact that it is an intermediate extraction ratio (ER) drug
Summary
Perinatal AsphyxiaDespite advances in perinatal medicine, the incidence of perinatal asphyxia (PA, a clinical condition comprising perinatal hypoxia, hypercarbia and combined metabolic and respiratory acidosis) has not decreased in the last decade (Albrecht et al, 2019). Hypoxic– ischemic injury to the brain may result in persistent neurological impairment. This brain injury is secondary to the hypoxic– ischemic event as well as the reoxygenation–reperfusion after resuscitation (oxidative stress with production of free radicals) (Solevag et al, 2019). Besides the immediate cell death (necrosis), delayed death (apoptosis) of neuronal cells can occur after a hypoxic insult. This apoptosis process substantially contributes to the permanent brain damage after PA (Solevag et al, 2019). Epilepsy, mental retardation, cerebral visual impairment, learning, and behavioral problems can occur as long term consequences (Albrecht et al, 2019)
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