A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

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.

Keywords: drug metabolism; neonate; pharmacokinetics; physiology-based pharmacokinetic modelling; therapeutic hypothermia.

Figure 1

Visual presentation of the sequential evaluation of the criteria used in the TOBY study to determine if therapeutic hypothermia needs to be started in neonates (Azzopardi et al., 2008).

Figure 2

Estimates of amikacin clearance (L/h) trends in early neonatal life based on pooling of reported datasets (dashed lines). There is a maturational trend in clearance related to birth weight (g) and postnatal age (PNA, days 1,2,3,4, as reflected by the colors) compared to a subgroup of term neonates undergoing therapeutic hypothermia as treatment for perinatal asphyxia (solid lines) (Cristea et al., 2017). The arrows indicate the difference in clearance between both cohorts for the respective PNA. Adapted from De Cock et al., antibiotic dosing in pediatric critically ill patients, Chapter in Antibiotic pharmacokinetic/pharmacodynamic considerations in the critically ill, Springer Nature Signapore 2018:239–263, with permission from Springer Nature (De Cock et al., 2018).

Figure 3

Strategy for neonatal hypothermia PBPK framework development. PBPK, physiology-based pharmacokinetics; DME, drug metabolizing enzymes; DT, drug transporters.

Figure 4

Median (± 90% CI) predicted systemic concentrations (C_sys) of midazolam following intravenous infusion at 0.05 mg/h/kg in 19 normothermic neonates (mean body weight 3.91 ± 0.86 kg) for 72 h (total dose 3.6 mg/kg). The solid line and the dashed lines represent the median and 5/95% percentiles. The median concentration at steady state was 0.48 µg/ml.

Figure 5

Output of a sensitivity analysis for midazolam clearance (CL) in neonates, illustrating the model-predicted impact of changes in Michaelis–Menten constant (K_m) and/or maximum reaction rate (V_max) describing the intrinsic formation CL of 1-OH midazolam by CYP3A4. The ‘dashed' circle represents the V_max/K_m values at normothermia, while the yellow arrow indicates a plausible change in V_max (rather than K_m) under conditions of hypothermia.

Figure 6

Output of a sensitivity analysis for midazolam clearance (CL) in neonates, illustrating the model-predicted impact of changes in unbound fraction in plasma (fu_plasma) assuming a fixed blood/plasma ratio (B/P ratio) of 0.55. A sensitivity analysis for the B/P ratio between 0.55 and 1.2 did not reveal any significant changes in hepatic CL. During normothermia, the reported fu value is 0.04.

Figure 7

Simulated midazolam median systemic plasma concentrations (C_sys) in neonates (n = 19; 0.05 mg/h/kg for 72 h; total dose 3.6 mg/kg) under normothermic (green line) versus hypothermic (red line) conditions. Therapeutic hypothermia (TH) was assumed to induce a 20% change in each of the following parameters: cardiac output (decreased), unbound fraction (fu, increased), blood/plasma ratio (B/P ratio, decreased) and 1-OH-midazolam formation intrinsic clearance (CL, decreased). Dashed lines represent the 90% CI for the hypothermic condition. C_ss: steady state concentration.