PHARMACOKINETIC AND

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).

Glodman J et al. Current Medical Research and Opinion, DOI: 10.1080/03007995.2017.1335192

Hyperinsulinemic-euglycemic clamp procedure

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

Glodman J et al. Current Medical Research and Opinion, DOI: 10.1080/03007995.2017.1335192

 Definition of key PK/PD parameters
relevant to insulin therapy

Parameter Definition Clinical relevance

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)

PD measurement of the amount of glucose

Area under the
Calculated from the graph of infused (indicates total daily insulin effect
curve (glucose
glucose infusion rate over time /glucose-lowering effect) and allows evaluation
infusion rate)
of the cumulative glucodynamic activity

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

Glodman J et al. Current Medical Research and Opinion, DOI: 10.1080/03007995.2017.1335192

 Definition of key PK/PD parameters
relevant to insulin therapy

Parameter Definition Clinical relevance

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

Glodman J et al. Current Medical Research and Opinion, DOI: 10.1080/03007995.2017.1335192

 Measuring basal insulin PK/PD profiles

• 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

Peak (hours) Duration of Half-life Dosing

action (hours) (hours) frequency
NPH insulin 4=8 8-14 4 Once or twice
daily
Insulin detemir 4-7 Up to 24 5-7 Once or twice
100 U/mL daily
Insulin glargine 8-12 Up to 24 12 Once daily
100 U/mL
Insulin glargine Close to peakless >24 19 Once daily
300 U/mL
Insulin Close to peakless 26+ 25 Once daily
degludec

Glodman J et al. Current Medical Research and Opinion, DOI: 10.1080/03007995.2017.1335192

Example of time-to-reach steady state without inappropriate accumulation of basal
insulin using a simplified one- compartment model (10 U, with t1⁄2 ~ 24 hours)

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

Schematic representation of how inappropriate stacking could occur with too-early

administration of a hypothetical rapid- acting insulin. If a corrective dose of insulin is
administered while a previous dose of (prandial) insulin is still available, this can result in
excessive glucose-lowering action and hypoglycemia.
Tim Heise T and Meneghini LF. Endocr Pract. 2014;20:75-83
 Why study PK/PD of basal insulin analogs?

PHARMACOKINETICS PHARMACODYNAMICS Clinical outcomes of

How the body affects the How the drug affects the insulin
drug the body Desired and
Plasma insulin concentration PD established by assessing
over time • Onset of action adverse effects
• Duration of action
• Peak action (if any)
• Total metabolic activity (amount of
glucose infused to maintain
euglycemia)

infusion rate
concentration

Glucose
Insulin

Time Time

Concentration/
exposure to drug
within the body

HbA1c, glycated hemoglobin

Adapted from Porcellati F et al. Diabetes Care 2015:38:2237−2240
 Basal insulin analogs:
Importance of PK/PD profile

Characteristic Potential clinical benefit

• Once-daily injection,
• Duration of action ≥24 h
flexible injection timing
• Flat PK profile
(evenly distributed insulin exposure) • Reduced incidence of
• Flat PD profile hypoglycemia
(GIR peak:trough ratio close to 1)
• Facilitates insulin
• Low within-subject,
titration
between-day variability in
• Lower risk of
insulin exposure (PK) and action (PD)
hypoglycemia

Becker RHA et al. Diabetes Care 2015;38:637−643

From smaller volume to distinct PK/PD profile: Difference
between Gla-300 and Gla-100

Reduction of volume by 2/3

Same number
of units Smaller surface area

Gla-100 Gla-300

Smaller volume of injection

for Gla-300 vs. Gla-100
Gla-100 Gla-300
Smaller subcutaneous
depot for Gla-300 vs. Gla- For illustrative purposes only
100
Different absorption kinetics
“more gradual release”

Distinct Gla-300 PK/PD

profile compared to Gla-100

Dailey G, Lavernia F. Diabetes Obes Metab 2015;17:1107–14; Steinstraesser A, et al. Diabetes

Obes Metab 2014;16:873–6; Becker RH, et al. Diabetes Care 2015;38:637–43; Becker RH, et al.
Diabetes Obes Metab 2015;17:261–7
 Gla-300 PK/PD
Euglycemic Clamp

PK/PD Profile

PK/PD Profile

Gla-300 presents a
more stable and
prolonged profile vs.
Gla-100

Double-blind, randomized, 2-treatment, 2-period (2 x 8 days), 2-sequence crossover euglycemic

clamp study in two parallel cohorts in T1DM (N=30)
PD, pharmacodynamic; PK, pharmacokinetic; T1DM type 1 diabetes Cohort 1 – Gla-300 0.4 U/kg per day vs Gla-100 0.4 U/kg per day.
Becker RHA et al. Diabetes Care 2015;38:637−643
 Gla-300 PK/PD
Within-day fluctuation
Euglycemic Clamp

53% 47%
Within-day
PK/PD Profile
GIR, mg/kg/min

0-12fluctuation
hours 12-24 hours

Gla-300 presents a Low within-day Average GIR

more stable and fluctuation
prolonged profile vs.
Gla-100 29% 24% 23% 23%

0-6 hours 6-12 hours 12-18 hours 18-24 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

PD, pharmacodynamic; PK, pharmacokinetic; T1DM type 1 diabetes

Becker RHA et al. Diabetes Care 2015;38:637−643. Adapted from Becker RHA et al. Diabetes Obes Metab 2015;17:261−267
 Gla-300 PK/PD
Between-day
variability Euglycemic Clamp

Within-day Between-day
PK/PD Profile
fluctuation variability

Gla-300 presents a Low within-day Low between-day

more stable and fluctuation variability
prolonged profile vs.
Gla-100

Single-center, double-blind, randomized, two-treatment, two-period crossover study (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

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

Gla-300 presents a Low within-day Low between-day More constant 24-

more stable and fluctuation variability hour glucose
prolonged profile profile
vs. Gla-100 with Gla-300 vs.
Gla-100

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

Ratios of annualized rates of confirmed or severe hypoglycemia*

At any time (24 h) Nocturnal (00:00−05:59 h)

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