Exploring
the Intra-tracheal route for Bronchopulmonary Dysplasia Therapy in Extreme
Preterms
Abin
Chandrakumar, Pharm.D
MS Pharmacology & Therapeutics
Student | University of Manitoba, Canada
Graduate Research Assistant | Children’s
Hospital Research Institute of Manitoba ,
Canada.
Having
decided to pursue academics further, I was in the quest of graduate student
positions in labs focusing on clinical studies during the Pharm.D internship
period at Al Shifa College of Pharmacy. Halfway
through my internship, I was offered a funded graduate student position by Dr.
Geert W‘t Jong at his clinical research unit at
the University of Manitoba. I joined the Department of Pharmacology &
Therapeutics as agraduate student under
the supervision of Dr.‘t Jong and has been associated with his team in several
studies this year. The studies that I am currently part of includes a Phase
I/II clinical trial and a large provincial database study.For the former, I was
able to work in close collaboration with pharma-industry, receiving extensive
training in regulatory submissions and clinical trial management. Through this
article, I would like to share the background of the trial, which I anticipate
will help the readership of Shifa ClinPharm to get an overview of the topic and
plan novel collaborative research in this area.
Background:
Preterm
infants, defined as those born at less than 37 weeks gestational age, have
lungs which are not structurally and functionally developed completely. The surfactantis lipoproteins secreted by type
II pneumocytes (specialized alveolar epithelial cells) and helps prevent thecollapse of smaller alveoli due to high surface
pressure by reducing the surface tension. Infants who are born preterm might
not have sufficient surfactant in terms of biochemical quality and quantity
which combined with the structural immaturity of the lung precipitates neonatal
respiratory distress syndrome (formerly known as hyaline membrane disease). The
lack of surfactants can lead to atelectasis, a condition characterized by the
non-uniform filling of the terminal airways leading to alveolar collapse.
Infants born in the initial stages of thesaccular
stage of lung development still have incompletely developed alveoli as well as
immature type II pneumocytes and therefore require surfactant administration to
maintain the terminal airway patency. Many of these infants require oxygen
supplementation and/or mechanical ventilation to sustain life. Although these
strategies have helped reduce mortality of infants as premature as 24 weeks
gestational age, the long-term sequelae associated with the barotrauma and volutrauma of this supplemental therapies lead
to the development of permanent lung injury called as the Bronchopulmonary
Dysplasia (BPD). The definition of BPD has evolved over time and the currentdiagnostic criteria differentiate between infants born before and
after 32 weeks gestational age.Although not all infants who receive the
supplemental oxygenation and ventilation develop these conditions, those
children who develop this condition can have reduced quality of life with developmental
delay and recurrent pulmonary complications.
Steroids in Bronchopulmonary Dysplasia
Prevention:
Steroids
were found to reduce theincidence and severity of BPD when administered
systemically to preterm infants receiving oxygen supplementation. In addition to reducing the underlying
inflammatory response associated with BPD, steroids also increase surfactant
production, accelerates lung cell differentiation, reduces vascular
permeability, and increases lung fluid resorption. Regardless of the mechanism,
corticosteroids have positive results in the treatment of preterm infants with
BPD. However, the systemic use of steroids in
this population can lead to neurodevelopmental and cognitive adversities. In
the light of emerging short term and long term adverse outcomes, American
Academy of Pediatrics and the Canadian Pediatric Society discouraged post-natal
use of steroids in 2002. It was recommended that the therapy should only be
used under exceptional circumstances and only with the understanding and agreement
of parents outside randomized trials. This lead to a drastic reduction in both
studies and clinical use of postnatal
corticosteroids. Further studies shifted their attention to alternatives like
Vitamin A, macrolides, leukotriene receptor antagonists, pulmonary vasodilators
etc.whichalthough demonstrated potential, lacked definitive evidence of
therapeutic efficacy.Furthermore,
administration of steroids locally into the lungs as an inhalation to prevent
the long-term adversities associated with the systemic drug exposure was
considered in several studies. But, this method
is technically challenging in this age group and there are concerns over the
distribution of the drug to the terminal region of the respiratory tract where
the drug needs to act.
Local Administration of
Steroids: Evidence of Safety
Infants who develop respiratory distress are administered
with exogenous surfactants (usually obtained from bovine and porcine
sources) via endotracheal tubes and my
current research focuses on administering steroidvia this route (intratracheal)
in combination with exogenous surfactants. This strategy not only uses a common
route for achieving therapeutic goals, but the drugs supplement each other's
action. The terminal airways if collapsed, will prevent the budesonide from
reaching the distal regions and can lead to therapeutic failure. The surfactant
clears the way for steroid by opening the terminal airway by reducing the
surface tension and thus provides a larger area for the steroid to act. The steroid
helps in the maturation of type II pneumocytes and thereby increase the
endogenous surfactant production, thus supplementing the exogenously
administered one. Although there were earlier concerns regarding alteration of
the surfactant properties when combined with budesonide, especially
thecholesterol containing surfactants (eg: BLES, Survanta), the surfactometry
studies were mostly done using diluted surfactants with phospholipid
concentration of 1mg/mL. However, the clinical phospholipid concentration of
surfactants is different from each other and much higher than the concentration
used in the surfactometry studies (27mg/mL for BLES, 76mg/mL for Curosurf,
25mg/mL for Survanta). This was tested in astudy by Yeh et al, where he
determined the surface activity of Survanta in combination with Budesonide at
both low and high concentration of surfactant phospholipid concentration. He
found that the budesonide and surfactants when combined together at clinical
concentrations, did not alter the surface activity. Two clinical trials in
preterm infants were conducted using the surfactant Survanta in combination
with Budesonide (0.25mg/kg of Budesonide) by Tsu F. Yeh. The results of the
studies were promising with BPD reduction and absence of any major adverse effects
of glucocorticoid therapyin the budesonide/surfactant group. The study is still
in progress and preliminary data of the 2-4 year follow-up group did not show
any long-term impairments in growth, neuromotor or cognitive function. In
comparison to the control group. Another study in preterm lamb model also found
that there was negligible systemic exposure when budesonidewas used in
combination with a surfactant. However, the drawback associated with the
clinical trial conducted by Yeh et al is that there has been no explanation
regarding why the dose of 0.25mg/kg was administered in the clinical trial.
There have been no PK-PD studies done in infants to determine the optimal dose
that will provide maximum benefit and reduce the systemic exposure simultaneously.
Our Current Research:
BITS Study
Our clinical research unit plans to do a Phase I/II clinical
trial in preterm infants less than 29 weeks gestational age to determine the
optimal dosage of the combination. The study which has been abbreviated as BITS
(Budesonide with Intra-Tracheal Surfactants)
has received conditional Institutional Ethics Board clearance and is currently
waiting for Health Canada Division V clinical trial approval. The study is a
single dose escalation study using the combination of varying concentrations of
Budesonide with bovine lipid extract surfactant. The pharmacokinetic and
pharmacodynamics behavior of the drug will be estimated with respect to fixed
and random effect parameters using nonlinear mixed-effect modeling. Sensitivity
analysis will be used in combination with the nonlinear mixed effect modeling
to reduce the influence of any confounders that could alter the study results
and substantiate the findings. This study is done in collaboration between University
of Manitoba (Winnipeg, Canada), University of Toronto (Toronto, Canada;
tentatively included) and University of Utah (Salt Lake City, USA). The study
is funded by academic grants from Manitoba Institute of Child Health and
for-profit sponsors. The anticipated duration of this study is 16 months and we
anticipate that the study will help us establishthe platform for a large-scale
Phase III clinical trial in the near future.
It
is indelible that the clinical exposure I received at KIMS Al Shifa Hospital
during my 6 years at Al Shifa College of Pharmacy has immensely helped me in
blending in with the clinical team here. Also, the Pharm D curriculum, which
was taught to me during the 4th and 5th year comprising
of Applied Pharmacokinetics, biostatistics, Pharmacoepidemiology
and research methodology had given me the theoretical background which helped
me with a smooth transition. Also, I am
thankful to Dr. T.N.K Suriyaprakash and Dr. Dilip.C for their continuous
support that helped me gain acceptance to the University previous year and also
achieve the prestigious provincial
scholarship of Research Manitoba Graduate Studentship this year.
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