The oldest oral antidiabetic drugs active against type 2 diabetes are SUR they increase pancreatic insulin secretion More recently repaglinide a meglitinide has been added to the available agents that stimulate ID: 914132
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Slide1
DRUG DEVELOPEMENT
Examples of antidiabetic drugs
Slide2The
oldest
oral antidiabetic drugs active against type 2 diabetes are SUR, they increase pancreatic insulin secretion. More recently, repaglinide, a meglitinide, has been added to the available agents that stimulate pancreatic insulin secretion. Biguanides increase the sensitivity of the liver to circulating insulin, thereby participating in a reduction in the level of excess glucose produced by that organ in type 2 diabetes.PPAR-g activators act at a number of sites to lower blood glucose levels. They also improve the hepatic sensitivity to insulin. To decrease the rapid influx of carbohydrate from ingested food, a-glucosidase inhibitors are used to slow the digestion of starches and the absorption of glucose and several other sugars.
2
Current Medications for Treatment of Diabetes (1)
Slide3Current Medications for Treatment of Diabetes (2)
Safer and more effective medications are needed
Sulfonylureas
Meglitinides
Metformin
Thiazolidinediones
α-Glucosidase inhibitorsInsulin
Hypoglycemia, weight gainHypoglycemia, weight gainGI intoleranceEdema, weight gainGI intoleranceHypoglycemia, weight gain
Drug Class
Side Effects
3
Slide4Sites of Action by Therapeutic Options Presently Available to Treat Type 2 Diabetes
GLUCOSE ABSORPTION
GLUCOSE PRODUCTION
Biguanides
(
Thiazolidinediones
)
MUSCLE
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidenediones
(
Biguanides
)
PANCREAS
INSULIN Secretion/replacement
Sulfonylureas
Meglitinides
Exenatide
DPP4 Inhibitors
Insulin
ADIPOSE TISSUE
LIVER
alpha-
glucosidase
inhibitors
INTESTINE
Adapted from
Sonnenberg and Kotchen.
Curr Opin Nephrol Hypertens
1998;7(5):551–5
STOMACH
DELAYED EMPTYING
Exenatide
,
Pramlintide
BRAIN
Endocannabinoid
Receptor Blockers
Exenatide
Pramlinitide
4
Slide5Incretin
effect
5In 1902, Bayliss and Starling found that one factor may act on the intestinal endocrine pancreas in response to food taken orally, and in 1906.Moore and his colleagues have tried to treat diabetes by injecting extracts of duodenal mucosa. Still the bar and chose the term 'incretin' (insulin secretion Intestine) to describe the hormonal activity released in the intestine, which stimulates insulin secretion.
Slide6Incretin
concept
6
Slide7Incretin
concept: reality
7
Slide8GLP-1 advantage
8
Slide9Dipeptidyl
-peptidase IV
9
Slide10DPP-4 Inhibitors: Early
Target
10
Slide11Merck’s
DPP-4
Inhibitor Program11
Slide12Pharmacologic
and Physiologic Actions of GLP-1
12
Slide13Adapted from Deacon CF, et al.
Diabetes
. 1995;44:1126-1131.GLP-1 Secretion and InactivationIntestinalGLP-1release
GLP-1 (7-36)
active
Mixed meal
GLP-1 (9-36)
inactive(>80% of pool)
DPP-4T1/2 = 1 to 2 min13
Slide14Inhibition of DPP-4 Increases Active GLP-1
GLP-1 (9-36)
inactiveIntestinalGLP-1release
Mixed meal
GLP-1 (7-36)
active
DPP-4
Adapted from Rothenberg P, et al.
Diabetes. 2000;49(suppl 1):A39.DPP-4inhibitor
GLP-1 (7-36)active1/13/201414
Slide151/13/2014
15
Slide16…. but Active GLP-1 (or GIP) is Cleaved Rapidly by DPP-4
GLP-1 (Active)
HA EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2GLP-1 (Inactive)
EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH
2
DPP-4 t
½
~ 1 min
Inhibit
Stabilize16
Slide17Dipeptidyl
Peptidase IV (DPP-4)
First Isolated from rat liver in 1966Identical to CD26, a marker for activated T cellsIts role in energy homeostasis was discovered which led to the first patent application in 1996Cell surface serine dipeptidase belonging to the prolyl-oligo-peptidase familyWidely expressed, and has Specificity for P1 Pro >> Ala17
Slide18Dipeptidyl
Peptidase IV Inhibition for the
Treatment of Type 2 DiabetesThe dipeptidyl peptidase (DPP)-4 inhibitors, which enhance glucose-dependent insulin secretion from pancreatic β cells by preventing DPP-4-mediated degradation of endogenously released incretin hormones, represent a new therapeutic approach to the management of type 2 diabetes mellitus. The 'first-in-class' DPP-4 inhibitor, sitagliptin, was approved in 2006; it was followed by vildagliptin (available in the EU and many other countries since 2007), saxagliptin (in 2009), alogliptin (in 2010, presently only in Japan) and linagliptin, which was approved in the US in May 2011. At the pharmacodynamic level, the data available so far indicate a similar glucose-lowering efficacy of DPP-4 inhibitors, either as monotherapy or in combination with other hypoglycaemic drugs, a similar weight-neutral effect, and a comparable safety and tolerability profile. 18DIABETES, VOL. 54, OCTOBER 2005
Slide19Chronic Inhibition of
Dipeptidyl
Peptidase-4 With a Sitagliptin Analog Preserves Pancreatic -Cell Mass and Function in a Rodent Model of Type 2 DiabetesThe effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic -cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fatdiet (HFD) streptozotocin (STZ)-induced diabetic mice.Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA1c, and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2–3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive -cells in islets, leading to the normalization of -cell mass and -cell–to–-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may
offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease.
Diabetes
55:1695–1704
, 200619
Slide20Experimental model (1)
20
A mutation occurred in a colony of outbred Zucker rats in the laboratory of Dr. Walter Shaw at Eli Lilly Research Laboratories in Indianapolis, IN in 1974–75. Part of this colony containing the mutation was moved to Indiana University Medical School (IUMS), to the laboratory of Dr. Julia Clark in 1977. Several groups of animals with diabetic lineage were identified and rederived in 1981. Inbreeding of selected pairs from this rederivation was done in the laboratory of Dr. Richard Peterson at IUMS. An inbred line of ZDF rat was established in 1985. To Genetic Models, Inc. in 1991. To Charles River in 2001.Zucker Diabetic Fatty (ZDF)
Rat
| Charles River
Ideal
For: Type 2 diabetes*, hyperlipidemia, glucose intolerance, obesity, hyperinsulinemia
Slide21Experimental model (2)
Mice models for diabetes and research
21
Slide22Streptozotocin
induced diabetic rats
Intra-venous injection of 60mg/kg dose of Streptozotocin in adult wistar rats, makes pancreas swell and at last causes degeneration in Langerhans islet beta cells and induces experimental diabetes mellitus in the 2–4 days. Streptozotocin induces one type of diabetes which is similar to diabetes mellitus with non-ketosis hyperglycemia in some animal species. Three days after degeneration of beta cells, diabetes was induced in all animals.22
Slide23Pharmacodynamics of
Sitagliptin
: OGTT in Lean Mice
Mouse DPP-4: IC
50
= 69 nM
Glucose AUC
DPP-4 Inhibition
(uncorrected)Active GLP-1
20 min post Glucose, 80 min post Compound
Sitagliptin, mg/kg
Sitagliptin, mg/kg
Sitagliptin, mg/kg
DPP-4 Inhibition
23
Oral Glucose Tolerance Test
Slide24Potential Importance of Selective Inhibition for the Treatment of Type 2 Diabetes
DPP-IV is a member of a family of serine peptidases that includes
quiescent cell proline dipeptidase (QPP), DPP8, and DPP9.To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. Assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of anti-hyperglycemic agents.24
Slide25QPP Selective
DPP-8/9 Selective
DPP-4 Selective
DPP-9
> 100,000
11,000
55
DPP-8
69,000
22,000
38
FAP
> 100,000
> 100,000
> 100,000
DPP-4
27
1900
30,000
PEP
> 100,000> 100,000> 100,000QPP/DPP-2> 100,00019
14,000APP> 100,000> 100,000> 100,000prolidase> 100,000
> 100,000> 100,000IC50, nMEnzymeSelective Inhibitors25
Slide26Rat toxicity studies
R
ats 3–4 weeks of age were obtained from Charles River Laboratories, Wilmington, NC. At 6 weeks of age, rats (five rats per sex per group) were administered vehicle (0.5% methylcellulose) or compound (10, 30, and 100 mg kg-1 day-1) by oral gavage (5 ml/kg). Animals were observed daily for physical signs of toxicity. During the 2nd week of dosing, all rats were anesthetized with isoflurane, and blood samples were taken for determination of complete blood counts. In addition, serum samples from fasted rats were analyzed for a complete panel of clinical chemistry parameters. Urine was collected overnight for routine urinalysis. At termination of the study, all rats were killed, and a complete necropsy was conducted. An extensive list of tissues were dissected from all rats, weighed, fixed in 10% neutral buffered formalin, and processed by routine histology methods for microscopic examination.26
Slide27Acute dog tolerability studies.
Purpose-bred
Beagle dogs were obtained from Marshall Farms, North Rose, NY. All dogs were acclimated for at least 4 weeks before study initiation. All compounds were formulated as aqueous suspensions in 0.5% methylcellulose and orally administered via gavage at a dose volume of 5 ml/kg.Following oral dosing, all animals were observed for several hours at frequent intervals and clinical signs of toxicity recorded for each dog.27
Slide28Two-week toxicity study conducted in DPP-IV–deficient mice
Male and female DPP-IV–deficient and
wild-type (C57BL/6) mice were obtained at 6 weeks of age from Taconic Farms and acclimated for 2 weeks before the initiation of dosing. DPP-IV–deficient mice (six mice per sex per group) were administered vehicle (0.25% methylcellulose) or the DPP8/9-selective inhibitor (30, 100, and 300 mg kg1 day1) via oral gavage (5 ml/kg). Wild-type mice were administered compound at 300 mg kg-1 day-1. Animals were observed daily for physical signs of toxicity. At the completion of the 2-week study, a terminal blood sample was collected by cardiac puncture for complete blood counts. A necropsy was conducted and liver and spleen organ weight were recorded. Selected tissues were fixed in 10% neutral buffered formalin and processed by routine histology methods for microscopic examination. Tissue sections from all control and treatment groups were evaluated.All in vivo procedures described above were conducted in laboratories accredited by AAALAC (Association for the Assessment and Accreditation of Laboratory Animal Care) International. All experimental protocols were approved by the Institutional Animal Care and Use Committee of Merck Research Laboratories.28
Slide29G. Lankas,
et al.
,
Diabetes
2005
,
54, 2988Comparative Toxicity Study29
Slide30Potential Importance of Selective Inhibition for the Treatment of Type 2 Diabetes
Conclusion
“Off-target” peptidase inhibition (i.e. inhibition of other DPP family peptidases such as DPP8/9) can produce severe toxicity in preclinical speciesVariables that may determine degree of toxicityCell penetration Unlike DPP-4, DPP8/9 are intracellular proteinsExtent of inhibition of DPP8 and/or DPP9Not known if inhibition of both enzymes (or how much) is required to producetoxicities Intraspecies differences in DPP8/9 inhibition
from Demuth
et al. Biochim.
Biophys. Acta
2005, 1751, 33DPP-430
Slide31DPP-4 Inhibitor Program - Objective
Identify
a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus with the following characteristics
:
>1000-fold selectivity over other
proline
peptidases, especially DPP-8 and DPP-9
Half-life suitable for BID or preferably QD dosingStructure lacking reactive electrophile as a serine trap, e.g.,
31
Slide32Common Lead Discovery Methods
Biological screening of compounds
Substrate or active-structure based designEnzyme – inhibitor crystal structure32
Slide33β-Amino acid proline amides
IC
50 = 1.9 μMβ-Amino piperazinesIC50 = 11 μMScreening Leads33
Slide34Sitagliptin
:
In Vitro Potencyand Selectivity
DPP-9
DPP-8
FAP
DPP-4
DPP-6
PEP
QPP/DPP-2
APP
prolidase
not active
DPP-4 Gene Family
Other Proline Specific Enzymes
IC
50
, (
n
M)> 10000048000
> 100000> 10000018> 100000> 100000> 100000not active
Selectivity Ratio> 50002700> 5000> 50001> 5000> 5000
> 500034
Slide35PK Properties of Sitagliptin
1 mg/kg IV, 2 mg/kg PO
35
Slide36JANUVIA
TM
(sitagliptin)Launched, Oct. 2006
Selective inhibition of DPP-4, in particular with respect to DPP-8 and/or DPP-9, provides an improved safety profile in preclinical species.
Sitagliptin is a potent and selective DPP-4 inhibitor, very well tolerated in pre-clinical toxicity studies and in human clinical trials.
In patients with type 2 diabetes, once daily administration of sitagliptin stabilizes active GLP-1 and GIP, reduces glucose excursion, enhances insulin levels, suppresses glucagon levels, and
improves glycemic control.
JANUVIA™ (sitagliptin) was approved by the FDA as a new treatment for type 2 diabetes.36
Slide37Back-up Objective
Identify a specific DPP-4 inhibitor as a back-up
to sitagliptinPotency equivalent to or better than sitagliptinIncreased half-life suitable for QD dosingStructural diversity
Slide38Active-Structure Based Design
Sitagliptin
is a triazolopyrazine Triazolopyrazines are reported as bioisosters of amides
TL, 41, (2000) 4533 & Ann Rep Med Chem
38
Slide39R = Di-Fluoro phenyl
β
-AA series
Design
39
Slide40SAR Summary
Loss of potency
Not promising
Less potent
α
isomer more
potent than
β
Less potent,Good selectivityImproved PKα isomer more potent than β
R-isomer more potent than S-isomerSubstituted benzyl/aryl most potent
Less potentShort half-life
R = 2,4,5 tri-F
Best potency and PK
40
Slide41Pharmacokinetics…
T
1/2(h)124.3
1.5
Cl
p
(mL/min/kg)
88
949351
Foral(%)
41%94%45%49%
nAUC
(
m
M h/mpk)
0.18
0.16
0.39
0.25
*PK parameters were obtained following a iv (1 mg/kg) or po (2 mg/kg) doseRat PK41
Slide42Oral Bioavailability
* Estimated
** Low %F due to first pass effect42
Slide43Stability in Liver Microsomes and Hepatocytes
Liver Microsomes
at 1 mM, 1 mg/mL proteinHepatocytesat 1 m
M, 1 M cells/mL
0.0
20.0
40.0
60.0
80.0
100.0
0
10
20
30
40
50
60
70
Time (min)
% Parent Remaining
RLM
DLM
MLM
HLM
0.0
20.0
40.0
60.080.0
100.0020406080100120
Time (min)% Parent RemainingRLMDLMMLM
HLM
43
Slide44Pharmacodynamics…
Glucose AUC
DP-IV inhibition
(uncorrected)
Active GLP-1
Lean Mice, 0 min post Glucose, 70 min post Compound
Mouse DP-IV: IC
50
= 26.8 nM
Dose, mg/kg
Dose, mg/kg
Dose, mg/kg
44
Slide45Summary Results
Structurally diverse – unique right hand side
PotentSelectiveEfficacious in OGTT modelExcellent PK profileMetabolically stable in human microsome preparation14 weeks rat and dog safety OKKept on hold as an insurance back-up to sitagliptin45
Slide46Most Common Lead Discovery Methods
Biological screening of compounds
Substrate or active-structure based designEnzyme – inhibitor crystal structureCrystal structure of DPP-4 reported in 200246
Slide47Structure of DPP-4 Complex with
val-pyr
and
Sitagliptin
Sitagliptin
IC
50
= 18 nM
Val-pyr
IC
50 = 1600 nM47
Slide48Computer Modeling
H-Bonding Salt Bridge
IC
50
= 4.4 nM
H-Bonding Salt Bridge
48
Slide49IC
50
= 0.6 nM
H-Bonding Salt Bridge
No Room!!
Rotate
The Same
Salt Bridge
New
H-Bonds
Plenty of
Room
Computer Modeling
49
Slide50Rigid Analogs:
A New Generation of DPP-4 Inhibitors
Best Fit
50
Slide51Sitagliptin and Cyclohexylamine in the DPP-4 Active Site
51
Slide52?
5,6-Heterocycles: A Better Fit?
52
Slide53H-bond acceptor
H-bond donor
Cyclohexylamine Derivatives
Increasing selectivity:
3D QSAR Model
Y. Gao,
et al., Bioorg. Med. Chem. Lett.
2007, 17, 3877
heteroatoms and/orpolar groups preferred53
Slide54Cyclohexylamine Derivatives
Y. Gao,
et al., Bioorg. Med. Chem. Lett.
2007
,
17
, 3877
54
Slide55Cyclohexylamine
Derivatives
Y. Gao,
et al., Bioorg. Med. Chem. Lett.
2007
,
17, 3877 R = HPoor PK (high Clp, low %F)hERG IC50 = 37 µm
R = CF3Good PK propertieshERG IC50 = 4.8 µMQTc in CV dog55
Slide56Summary
Structurally diverse middle ring designed by collaboration between MedChem, Structural biology and modeling groups
PotentSelectiveEfficacious in OGTT modelExcellent PK profilePromising novel lead for development of a new generation of DPP-4 inhibitors56
Slide5757
Slide580
3
6
9
12
0
100000
200000
300000
400000
Time After Meal (h)
Plasma Exendin-4 Concentration (pg/mL)
Exendin-4 in the Gila Monster
Exendin-4 was originally
isolated from the
salivary secretions of
the Gila
monster
Exendin-4 was subsequently found to circulate as a meal-related peptide in this animal
Data from Young AA. Insulin Resistance and Insulin Resistance Syndrome 2002, 235-26258
Slide59Exenatide
(
Byetta)Synthetic exendin-4In clinical studies, exenatide exhibited actions that are similar to those of GLP-1:Stimulation of insulin secretion only when blood glucose concentrations are elevatedSuppression of postprandial glucagon secretionSlowing of gastric emptying59
Slide60Acute Meal Challenge Study: Postprandial Glucose and Glucagon Concentrations
60Plasma Glucagon (pg/mL) Plasma Glucose (mmol/L)
0
5
10
15
20
Exenatide or Placebo
Standardized Breakfast
0
60
120
180
240
300
Time (min)
0
120
180309060150Time (min)
50100150200250
Exenatide or PlaceboStandardized BreakfastPlaceboExenatide 0.1 µg/kgPlaceboExenatide 0.1 µg/kg
Data from Kolterman OG, et al. J Clin Endocrinol Metab 2003; 88:3082-3089n=20Mean ± SE
Slide61Exenatide
(
Byetta)Pen prefill- one month’s supplyGiven bid, 30-60 minutes prior to meal (250 cal)Nausea experienced by almost all initially, typically remits within daysStart at 5 mcg BID, then increase to 10 mcg BID after 1 monthCurrent indication: failing SFU, metformin, or bothNot FDA approved with insulin or monotherapyPancreatitis warning61
Slide62Typical Results?
Not magic wand for
everyone-15% no effect evidence for loss of treatment responseFullness sensation- Gastric or CNS?Relearning to eat- satiety senseData support 20% fewer calories ingestedExpense and insurance coverage62
Slide63Trends
HbA1c and weight loss do not correlate
Prandial insulin dose decreases dramaticallyMinimal basal insulin dose changeFor women, weight loss persists in physically active, in men not associatedLiraglutide- daily administration Phase 3 Trials63
Slide6497
%
of homology with the native sequence.Liraglutide has a structure very close to GLP-1, it differs only by one AA (Lys 34 replaced by Arg)To this is added a spacer peptide (gamma-glutamic acid) with a fatty acid (palmitic acid).Half-life: twelve hours and 30 minLIRAGLUTIDE 64
Slide65LIRAGLUTIDE: comparison
65
Slide66Structure modification leads to
66
Slide67It was obtained by
substitution of an amino acid (lysine at position 34 replaced by arginine) and acylation by
adding a C16 fatty acid (palmitic acid to lysine at position 26). These changes confer increased resistance to the action of the dipeptidyl peptidase-4 enzyme (DPP-4) and a binding capacity of albumin, resulting in a extended from 11 to 13 hours half-life compatible with a single subcutaneous injection daily.LIRAGLUTIDE PHARMACOKINETIC1/13/201467
Slide68Liraglutide
differs from
exenatide, first, by the structure (97% homology with the human GLP-1 versus 53% for exenatide) and the enhancement of antibody production (about 50% versus 10% for liraglutide without a neutralizing effect), and, secondly, by its kinetics: half-life of exenatide is short (3-4 hours), requiring subcutaneous injection two times a day.Liraglutide (as exenatide) differs from DPP-4 inhibitors by the concentration of GLP-1 induced. LIRAGLUTIDE versus EXENATIDE1/13/201468
Slide69Indications: In combination with metformin and / or sulfonylurea if the balance is not achieved.
No AMM alone, possible use of
detemir in addition of Liraglutide.LEAD-clinical trialIts effects are also more marked on glycemic control (HbA1c, fasting glucose, postprandial), the weight and slowing of gastric emptying.The LEAD-5 study demonstrated that liraglutide decreased HbA1c similar to ultra-long acting insulin analogue, glargine, and also significantly reduced body weight compared with glargineLiraglutide induced significant and persistent weight loss from admission up to 6 months after discharge, while no change in body weight after discharge was noted in the insulin group. Liraglutide produced significant improvements in all major scores of eating behavior questionnaire items and such effect was maintained at 6 months after discharge. LIRAGLUTIDE: efficacy1/13/201469
Slide70Weight loss correlated significantly with the decrease in scores for recognition of weight and constitution, sense of hunger, and eating style.
Conclusion:
Liraglutide produced meaningful long-term weight loss and significantly improved eating behavior in obese patients with type 2 diabetes.LIRAGLUTIDE: efficacy (2)1/13/201470
Slide71Différents types d’Insuline
Very short acting insulin
analogues: Insulin aspart (Novorapid)Insulin lispro (Humalog)Insulin glulisine (Apidra)Intermediate acting:Isophane/ NPH eg.InsulatardLong acting:insulin Zinc suspension eg.Ultratard Insulin analogues eg. Glargine, Detemir Long acting insulin analogues include:
Glargine (
Lantus
) and
detemir (Levemir)Biphasic (premixed)- mixture of short and intermediate:Novomix 30, Mixtard 3071
Slide72Insulin analogues
72
Les analogues Lispro and Aspart ont été les 1ers introduits sur le marché. Ils coagulent moins (moins d’agrégats, moins d’hexamères que l’insuline standard soluble). Le délai d’action est plus court et leur effet ne perdure pas par rapport à l’insuline standard soluble.
Slide73Short acting insulin analogues
Lispro
La séquence lysine-proline est inversée au bout de la chaîne ß de l’insuline, ce qui crée un encombrement stérique et réduit la possibilité de s’agréger (moins d’hexamères). AspartLe changement d’un seul acide aminé (l’acide aspartique à la place de la proline) crée une répulsion électrostatique (répulsion de charge) et un encombrement stérique. Le délai d’action est 15 minutes et la clairance se fait en 2 à 5 heures.Steric hindrance ↓Self associationCharge repulsionSteric hindrance
73
Slide7474
Insulin
Lispro (Lys (B28), Pro (B29) human insulin
Slide75Insuline
Aspart
(B28 Aspart)75L’acide aminé proline à la position B-28 est remplacé par l’acide aspartique. Le délai d’action est ainsi plus court, 10 à 20 minutes avec un pic sérique à 45 minutes, et une durée d’action de 3 à 5 heures.
Slide76L’absorption de l’insuline humaine est plus lente à partir du muscle deltoïde et fémorale en comparaison à la région abdominale, alors que l’absorption du
Lispro
est plus rapide, meilleure et régulière quelque soit le site d’injection.76Insulin Lispro (Lys (B28), Pro (B29) human insulinInsulin lispro a été le 1er analogue d’insuline introduit en 1994. La séquence lysine-proline est inversée au bout de la chaîne ß de l’insuline, ce qui crée un encombrement stérique et réduit la possibilité de s’agréger (moins d’hexamères). Les hexamères formés par l’Insuline lispro se dissocient plus rapidement, ce qui se traduit par une absorption plus rapide à partir de la voie sous cutanée.De plus, un pic plus élevé d’insuline est obtenu avec une durée d’action plus courte en comparaison à l’insuline humaine.
L’effet commence entre 5 à 15 minutes après l’administration, atteint un pic à 1 à 1½ heures, son effet perdure entre 3 à 5 heures.
L’absorption de l’insuline dépend évidemment du site d’injection.
Slide77In
a prospective, multicenter trial, use of insulin aspart was compared with human (regular) insulin as the before meals insulin with NPH as basal insulin in patients with type 1 diabetes
. It was determined that there is a small but useful advantage for rapid acting insulin aspart as a tool to improve long-term blood glucose control, hypoglycemia and quality of life77Aspart (B28 Aspart) Human Insulin:Short acting insulin analogs
Slide7878
Slide79Long acting insulin analogues
Insulin
glargine Contient 2 molécules extra: arginine au bout de la chaîne ß ce qui modifie le point isoélectrique, réduisant ainsi la solubilité et réduisant aussi sa clairance .Insulin detemirL’Acylation de l’amine de la lysine B29 permet une fixation réversible de l’insuline à l’albumine et retarde son absorption à partir du tissu sous-cutané.Le niveau plasmatique de l’Insuline augmente doucement pour atteindre un plateau en 6–8 heures et reste non modifié pendant à peu près 24 heures, adéquat avec une administration 1 fois/jour.Bind to albumindelayed absorption
↑
isoeclectric
point
↓solubility
79
Slide80L’asparagine dans la chaîne
a
à la position 21 est remplacé par la glycine, et 2 arginines sont ajoutés à la chaîne β à la position 31 et 32. Cette modification déplace le point isoélectrique, modifiant sa solubilité à un pH acide. A pH 4.0 (ampoule), c’est complètement soluble. Après administration sous- cutanée, la solution acide est neutralisée, provoquant la formation de microprécipité et libère de petites quantités d’insulin glargine pour être absorbée lentement, donnant lieu à une concentration relativement constante sur une période de 24 heures.L’Insuline glargine 1 fois/jour paraît être meilleure (moins d’effets indésirables) tout en étant tout aussi efficace que l’insuline NPH 1 ou 2 fois/jour dans le contrôle de la glycémie chez les patients diabétiques de type 1. Pas plus d’épisode d’hypoglycémie entre les deux.80Long acting insulin analogs:Insulin Glargine
Slide81LANTUS
is produced by
recombinant DNA technology utilizing a non- pathogenic laboratory strain of Escherichia coli (K12) as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Chemically, it is 21A- Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin and has the empirical formula C267H404N72O78S6 and a molecular weight of 6063. 811
1
15
10
5
5
10
15
2020
Asn
25
30
Gly
Arg
Arg
Substitution
Extension