Date of Award

Winter 1-4-2020

Document Type

Dissertation

Degree Name

PharmD

Department

Department of Pharmacy Practice

First Advisor

Dr. Leslie Edward Lewis

Abstract

Background: Irregularity in temperature regulation and control of breathing during the first few days are the reasons for the abrupt deaths in preterm neonates, of which apnea in premature neonates constitutes the major reason for these deaths. Methylxanthine’s (aminophylline and caffeine) are used in its treatment. Majority of the hospitals follow a standard treatment regimen for both aminophylline and caffeine irrespective of preterm’s age and body weight which leads to toxic or sub-therapeutic concentrations of the drug. Using Physiologically based pharmacokinetic modelling (PBPK), various drug characteristics and its deportment can be studied. This helps in predicting the Pharmacokinetic parameters of the drug which in turn aids in the individualization of dosing regimen with respect to body weight and postnatal age. Objectives: To develop a PBPK model for aminophylline and caffeine to aid in optimizing and individualizing the dosage regimen with respect to body weight and postnatal age for the treatment of apnea in preterm neonates. Methodology: Anonymized data of 108 and 61 preterm neonates with apnea from a previously reported study were obtained for building an aminophylline and caffeine model respectively. The data was obtained from a previous study conducted at NICU of Kasturba Hospital, Manipal University. Preterm neonates with less than or equal to 34 weeks of gestational age and greater than 6 apneic episodes in 24 hrs were included in the study. A standard treatment protocol of 5mg/kg loading dose and 2mg/ kg maintenance dose for every 8 hours and a standard dosing regimen of 10mg/kg loading dose followed by 2.5mg/kg maintenance dose for every 24 hours were used in this PBPK model development for aminophylline and caffeine respectively. Pk-Sim software package was employed to build a predictive model. The predictions were compared to the reported data through visual inspection and also by pharmacokinetic parameters comparison. Results: Subgroup simulations provided evidence for the maturation of enzymes with the progression of time, which in turn increases the clearance for both aminophylline and caffeine, which can be interpreted from the visual predictive curve. The study also provides an evidence of decreased half-life of the drug in the body, where t1/2 of 32.83 hrs and 29.87 hrs was reported in the Sub-groups PNA 1-6 and PNA > 6 respectevely in the aminophylline group. Similarly, t1/2 of 67.04 hrs and 57.5 hrs was reported in the subgroups PNA 0-10 and PNA > 10 respectively in the caffeine group. These results also provide an evidence for an improved renal function with age in both the case groups (aminophylline and caffeine). Conclusions: The study provides an evidence for the maturation of enzymes with the time and alteration of drug characteristics like the volume of distribution and clearance concerning covariates body weight and postnatal age. Hence it provides evidence in delivering optimized concentrations of the drug when dosing regimen is individualized with respect to body weight and postnatal age.

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