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PHAMCODYNAMIC OF
GLARGINE U300
Ketut Suastika
Division of Endocrinology and Metabolism Department of Internal
Medicine, Faculty of Medicine Udayana University-Sanglah
Hospital, Denpasar
Definition of PK-PD
• Pharmacokinetic
• What the body does to a drug, explaining the movement of a drug
into, through, and out of the body (i.e. the concentration of the
drug in the body tissues over time).
• Adjustable factors, such as dose, dosage form, dose frequency and
route of administration, affect PK parameters
• Pharmacodynamic
• The effect of a drug on the body (i.e. interactions and/or signaling
events that occur in cells and organs in response to the drug), that
results in intended (and unintended) drug effects, and are
presented as parameters over time [10].
• The PD parameters of an insulin provide important information on
the glucose-lowering effect of insulin therapy and, therefore,
information on potential clinical efficacy and safety (with regard to
hypoglycemia).
E G F
Frequent blood Manual or IV glucose to
glucose automatically maintain target
measurement blood glucose level
D
Glucose
Liver
+ Blood/Plasma
+ Muscle
production
glucose
- - B
-
Plasma Insulin
+ + + A
Study Insulin Pancreas IV Insulin
Administration administration
to reach target
C H blood glucose
level
To reach the study target blood glucose level, IV insulin is administered during the feedback period prior to the clamp (A). The euglycemic
clamp procedure aims to assess the glucose-disposing effect (B) of the administered study insulin (C). Normally, insulin results in lowering of
blood glucose levels; glucagon is then released, leading to hepatic release of glucose (D), which would confound the true glucose-disposing
effect of the insulin. This is prevented by regularly monitoring the blood glucose level (E) and keeping it constant by IV glucose infusion (F), a
procedure that can be conducted manually or automatically (G). Any residual insulin production by the pancreas (H; eg, patients with T2D) will
confound the effect of the study insulin. IV, intravenous ; T2D, type 2 diabetes
Area under the Calculated from the graph of PK measurement of the total amount of insulin
curve (insulin insulin concentration over time absorbed (allows evaluation of bioavailability)
concentration)
Duration of The time interval between Affects number of daily doses (insulins with
action insulin injection and the time shorter duration of action require more
point when blood glucose frequent dosing)
concentrations increases from
the clamped glucose level to a
predetermined threshold value
Glucose infusion The amount of glucose infused Affects number of daily doses (insulins with
rate over time to maintain blood shorter half-lives require more frequent dosing)
glucose at the clamp level
Half-life The time necessary for the Affect number of daily doses (insulins with
(elimination) insulin concentration to shorter half-lives require more frequent dosing )
decrease by 50% (derived from
the slope of decline in insulin
concentrations after reaching
maximum concentrations)
Early glucose The time to 50% of the Affects dosing interval (insulins with a slower
infusion rate- maximum glucose infusion rate onset of action require closer monitoring of
t50% blood glucose levels initially to maintain control)
(sometimes Less relevant for long-acting basal insulins with a
used as duration of action > 24 hours that reach steady
pareameter for state basal insulin activity by overlapping action
onset of action) profiles of consecutive once- daily basal insulin
administrations
• The glucose clamp technique is the gold standard for studying basal insulin
PK/PD profiles1,2
• Hyperinsulinemic–euglycemic clamp is a method of assessing insulin
sensitivity/resistance3
• Participants receive a high dose insulin infusion
which induces a hyperinsulinemic state3
• The subsequent drop in glucose concentration is
prevented with a variable glucose infusion that
‘clamps’ glucose at a predetermined level1
• Glucose infusion rate (GIR) represents the glucose
necessary to compensate for hyperinsulinemia1
• GIR is a PD parameter for insulin preparations
• The PK parameter is represented by the serum
insulin concentration
1. Arnolds S et al. Int J Clin Pract 2010;64:1415-24; 2. DeFronzo RA et al. Am J Physiol 1979;237:E214; 3. Tam CS et al. Diabetes Care
2012;35:1605-10
PK/PD characteristics of basal insulin analogs
Because dosing
frequency is
approximately
equal to half-life,
insulin only
accumulates until
steady state is
reached, at which
time the daily
injected dose is
balanced by
elimination.
Tim Heise T and Meneghini LF. Endocr Pract. 2014;20:75-83
Hypothetical examples of profiles of insulins
with various half-lives
Accumulation from first dose to steady state (top panel, A) and perturbations following various types of common dosing errors as
indicated by arrows, when introduced at steady state (bottom panel, B).
Tim Heise T and Meneghini LF. Endocr Pract. 2014;20:75-83
Insulin Stacking Versus Therapeutic Accumulation:
Understanding The Differences
infusion rate
concentration
Glucose
Insulin
Time Time
Concentration/
exposure to drug
within the body
Same number
of units Smaller surface area
Gla-100 Gla-300
PK/PD Profile
PK/PD Profile
Gla-300 presents a
more stable and
prolonged profile vs.
Gla-100
53% 47%
Within-day
PK/PD Profile
GIR, mg/kg/min
0-12fluctuation
hours 12-24 hours
Single-center, double-blind, randomized, two-treatment, two-period crossover study in adults with T1DM (N=50)
Multiple once-daily dosing for 6 days with two different Gla-300 formulations:
1) Standard reference cartridge formulation. 2) Test formulation with enhanced stability.
Euglycemic clamp after dosing on Day 6
Within-day Between-day
PK/PD Profile
fluctuation variability
GIR, glucose infusion rate; INS, serum insulin concentration; LLOQ, lower limit of quantification; PD, pharmacodynamic; PK, pharmacokinetic; T1DM type 1 diabetes. Adapted from Becker
RHA et al. Diabetes Care 2015;38:637−643; Becker RHA et al. Diabetes Obes Metab 2015;17:261−267
Gla-300 PK/PD
CGM Data
Euglycemic Clamp Clinical Study
Within-day Between-day
PK/PD Profile CGM data
fluctuation variability
Randomized,
CGM, continuous glucose monitoring; PD,multicenter, 16-week,
pharmacodynamic; open-label,
PK, pharmacokinetic; T1DM,parallel-group,
type 1 diabetes two-period crossover study in 59 patients with T1DM
Becker RHA et al. Diabetes Care 2015;38:637−643. Becker RHAOnce-daily
et al. DiabetesGla-300
Obes Metab
or Gla-100 given in thefrom
2015;17:261−267; Adapted morning or evening
Bergenstal RM et al. Diabetes Care. 2017;40:554-560
Gla-300 vs Gla-100: CGM study in T1DM
Safety population. *Rate ratio and 95% CI based on rate of hypoglycemia events per participant-year of exposure during the on-treatment period, morning and evening injection
groups combined
CGM, continuous glucose monitoring; CI, confidence interval; T1DM, type 1 diabetes
Bergenstal RM et al. Diabetes Care. 2017;40:554-560
PK/PD Gla300:
More ideal as basal
insulin than older
basal insulin