JDiabSciTec 2017: PK/PD of a Novel Inhaled Insulin
Mar 27, 2017 17:40:42 GMT -5
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www.mannkindcorp.com/assets/Heinmann-JDiabSciTech-2017.pdf
Lutz Heinemann, PhD1
, Robert Baughman, PhD2
, Anders Boss, MD3
,
and Marcus Hompesch, MD4
Acknowledgments
The contents of the article and the opinions expressed within are
those of the authors, and it was the decision of the authors to submit
the manuscript for publication. The authors took responsibility for the
writing of this manuscript, including critical review and editing of
each draft, and approval of the submitted version. The authors
received writing/editorial support in the preparation of this manuscript
provided by Katherine Roberts, PhD, of Excerpta Medica,
funded by Sanofi US, Inc. The authors have not received any funding
from Sanofi US, Inc for writing this manuscript.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: LH receives, or has received, funding from companies manufacturing
insulin or developing novel insulins including Biodel, Eli
Lilly, Halozyme, Novo Nordisk, and Sanofi. RB is an employee of
MannKind Corporation. AB is an employee of Sanofi US, Inc. MH is
an employee and shareholder at Profil Institute for Clinical Research.
Excerpts follow.
Abstract
Advances in insulin treatment options over recent decades have markedly improved the management of diabetes. Despite
this, glycemic control remains suboptimal in many people with diabetes. Although postprandial glucose control has been
improved with the development of subcutaneously injected rapid-acting insulin analogs, currently available insulins are not
able to fully mimic the physiological time–action profile of endogenously secreted insulin after a meal. The delayed onset
of metabolic action and prolonged period of effect induce the risk of postprandial hyperglycemia and late postprandial
hypoglycemia. A number of alternative routes of insulin administration have been investigated over time in an attempt to
overcome the limitations associated with subcutaneous administration and to provide an improved time–action insulin
profile more closely simulating physiological prandial insulin release. Among these, pulmonary insulin delivery has shown the
most promise. Technosphere® Inhaled Insulin (TI) is a rapid-acting inhaled human insulin recently approved by the FDA for
prandial insulin therapy. In this article we discuss the pharmacokinetic and pharmacodynamic properties of TI, and, based on
key studies performed during its clinical development, the implications for improved postprandial glucose control.
Clinical trials have also indicated that TI may have other
potential benefits (which may be related to its unique PK/PD
profile) in terms of weight change and fasting plasma glucose
levels;2
In summary, TI has a PK profile that is distinct from both
subcutaneously injected RAAs and other inhaled insulins
that were previously in development. The PD profile confers
a faster onset and shorter duration of action that permits better
synchronization of prandial insulin action with glucose
absorption in the gut. In clinical practice the intrapatient and
interpatient variability of PK and PD of a given prandial
insulin (expressed as CV) is less than the variability in glucose
absorption from the gut after meals with quite diverse
carbohydrate content and preparation: for example, pizza
versus a Japanese meal with carbohydrates all at end versus
an extended Spanish lunch. The error made with carbohydrate
estimation for dose finding comes on top of this. A
rapid and short acting prandial insulin (a “precise tool”) is of
help to cover the insulin requirement with all different types
of meals to enable better (= reproducible) postprandial glycemic
control, especially in the early phase. This leads also
to a reduced risk of late postprandial hypoglycemia. An
increase in TI dose relative to subcutaneous insulin is
required, and it is feasible to introduce a supplementary postmeal
dose if required—for example, in case of a heavy meal
to manage extended postprandial hyperglycemia.
Lutz Heinemann, PhD1
, Robert Baughman, PhD2
, Anders Boss, MD3
,
and Marcus Hompesch, MD4
Acknowledgments
The contents of the article and the opinions expressed within are
those of the authors, and it was the decision of the authors to submit
the manuscript for publication. The authors took responsibility for the
writing of this manuscript, including critical review and editing of
each draft, and approval of the submitted version. The authors
received writing/editorial support in the preparation of this manuscript
provided by Katherine Roberts, PhD, of Excerpta Medica,
funded by Sanofi US, Inc. The authors have not received any funding
from Sanofi US, Inc for writing this manuscript.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: LH receives, or has received, funding from companies manufacturing
insulin or developing novel insulins including Biodel, Eli
Lilly, Halozyme, Novo Nordisk, and Sanofi. RB is an employee of
MannKind Corporation. AB is an employee of Sanofi US, Inc. MH is
an employee and shareholder at Profil Institute for Clinical Research.
Excerpts follow.
Abstract
Advances in insulin treatment options over recent decades have markedly improved the management of diabetes. Despite
this, glycemic control remains suboptimal in many people with diabetes. Although postprandial glucose control has been
improved with the development of subcutaneously injected rapid-acting insulin analogs, currently available insulins are not
able to fully mimic the physiological time–action profile of endogenously secreted insulin after a meal. The delayed onset
of metabolic action and prolonged period of effect induce the risk of postprandial hyperglycemia and late postprandial
hypoglycemia. A number of alternative routes of insulin administration have been investigated over time in an attempt to
overcome the limitations associated with subcutaneous administration and to provide an improved time–action insulin
profile more closely simulating physiological prandial insulin release. Among these, pulmonary insulin delivery has shown the
most promise. Technosphere® Inhaled Insulin (TI) is a rapid-acting inhaled human insulin recently approved by the FDA for
prandial insulin therapy. In this article we discuss the pharmacokinetic and pharmacodynamic properties of TI, and, based on
key studies performed during its clinical development, the implications for improved postprandial glucose control.
Clinical trials have also indicated that TI may have other
potential benefits (which may be related to its unique PK/PD
profile) in terms of weight change and fasting plasma glucose
levels;2
In summary, TI has a PK profile that is distinct from both
subcutaneously injected RAAs and other inhaled insulins
that were previously in development. The PD profile confers
a faster onset and shorter duration of action that permits better
synchronization of prandial insulin action with glucose
absorption in the gut. In clinical practice the intrapatient and
interpatient variability of PK and PD of a given prandial
insulin (expressed as CV) is less than the variability in glucose
absorption from the gut after meals with quite diverse
carbohydrate content and preparation: for example, pizza
versus a Japanese meal with carbohydrates all at end versus
an extended Spanish lunch. The error made with carbohydrate
estimation for dose finding comes on top of this. A
rapid and short acting prandial insulin (a “precise tool”) is of
help to cover the insulin requirement with all different types
of meals to enable better (= reproducible) postprandial glycemic
control, especially in the early phase. This leads also
to a reduced risk of late postprandial hypoglycemia. An
increase in TI dose relative to subcutaneous insulin is
required, and it is feasible to introduce a supplementary postmeal
dose if required—for example, in case of a heavy meal
to manage extended postprandial hyperglycemia.
