Vildagliptin
-
Upload
sirinoot-jantharangkul -
Category
Health & Medicine
-
view
173 -
download
2
Transcript of Vildagliptin
VV ildagliptini ldagliptinVILDAGLIPTIN:VILDAGLIPTIN:
DPPDPP -- IV INHIBITORIV INHIBITOR
By sirinoot Jantharangkul4827038
VVildagliptinildagliptin
Generic name: VildagliptinBrand name: GalvusTreatment for: type 2 diabetesselective inhibitor of dipeptidyl- peptidase IV (DPP-IV)
T2DM (Type 2 diabetes mellitus)
The incidence is increasing
There are approximately 110 mill ion people with diabetes at present but this number wil l reach over and the 220 mill ion by the year 2010
Introduction
T2DM (Type 2 diabetes mellitus) A disease of progressive β-cell
dysfunction in presence of insulin resistance
Leading to gradual loss of glycemic control
The pathological loss of β-cell function may be the result of a number of factors including β-cell secretory defects glucotoxicity due to hyperglycemia l ipotoxicity due to disl ipidemiapossibly abnormalit ies in secretion or
response to incretin hormones
Introduction
ปจัจ ุบนัพบว ่า คนไข้ T2DM ทุกรายจะม ีการตอบสนองต่อ
ผลของฮอร ์โมนอินคร ิต ิน ลดน้อยลง จึงเปน็หล ักการส ำาคญัทีน่ ำามาใช้เปน็
แนวทางในการพัฒนายา กลุ่มใหม่ท ี่ใช ้ในการร ักษาผูป้ ่วยเบา
หวานชนิดที่ 2 ในปจัจ ุบนั
Introduction
T2DM (Type 2 diabetes mellitus)
Incretin Hormones Introduction
Incretin are hormones released from the gastrointestinal tract
Response to nutrient ingestion that potentiate glucose-stimulated insulin secretion from islet beta cells
“ในคนปกติพบว่า อ ินคร ิต ินฮอร ์โมนมผีลมากถงึร ้อยละ 50-70 ท ีจ่ะกระต ุ้นต ับอ ่อนให้
สร ้างฮอร ์โมนอินซลู ิน”
The 2 predominant incretins GIP (glucose-dependent insulinotropic peptide)GLP-1 (glucagon l ike peptide-1)
Incretin Hormones
GIP(Glucose-dependent insulinotropic polypeptide)
42-amino acid polypeptide Secreted from the K-cells after ingestion of carbohydrates fat and amino acids
duodenum proximal jejunum
“ fat being the most potent st imulator of GIP secretion”
GIP acts through a specif ic GIP-receptor in the β-cell plasma membrane The binding of GIP at the receptor on pancreatic β-cell enhances exocytosis of insulin contain in granules
GLP-1 is a 30 amino acid peptide
Stored in the L-cells - i leum - colonReleased in response to meal
ingestion with l ipids and carbohydrates being most potent in stimulating secretion
The mechanism of the insulinotropic action
- specif ic GLP-1 receptor belonging to the
glucagon subfamily of G-protein-coupled
receptors
GLP-1 (glucagon-like peptide-1) Introduction
GLP-1 GIP
Insulin
Glycogen-synthesis Glucose-uptake Lipogenesis
++
++
++
++
++
L-cells K-cells
StomachGastricemptying
BrainSatiety
-
++
Beneficial effects of GLP-1 Stimulation of insulin secretion Suppression of glucagon secretion Stimulation of insulin biosynthesis Slowing of gastric emptying Induction of a sense of satiety and
fullness Reduction in food intake Stimulation of proliferation and
suppression of apoptosis in β-cells
Actions of Glucagon-Like Peptide-1Introduction
DPP-4 (Dipeptidyl peptidase-4)
The enzyme that rapidly inactivates GLP-1
His Ala Glu Gly ThrPheThr SerAsp
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Ile Ala Trp Leu Val Lys Gly Arg Gly
Val
Ser
Glu
Phe
Glu Gly ThrPheThr SerAsp
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Ile Ala Trp Leu Val Lys Gly Arg Gly
Val
Ser
Glu
Phe
DPPIV
GLP-1 (9-37)GLP-1 (9-37)InactiveInactive
GLP-1 (7-37)GLP-1 (7-37)ActiveActive
Two new classes of agents The incretin mimetics
ExenatideLiraglutide DAC:GLP-1
The DPP-IV inhibitorsVildagliptin(LAF237)Sitagliptin (MK 0431)
Incretin-based therapies
Exenatide
Vildagliptin
•the f irst in a new class of oral antidiabetic agents
•known as dipeptidyl peptidase IV inhibitors
(DPP-IV) inhibitors
"incretin enhancers"
(2S)-([(3-hydroxyadamantan-1-yl )amino]acetyl)-pyrrolidine-2-carbonitri le
Mechanism of action
Absorption/Distributionrapidly and almost completely absorbed (~85% of administered
dose) after oral administrationthe pharmacokinetics are not
affected by foodT max : 1–2hoursplasma protein binding 4-17%
PharmacokineticsPharmacokinetics
Metabolism/Elimination half- l i fe : 1.5–4.5 hr Most of the drug is metabolised with hydrolysis of the cyano moiety dominating (55%) A fraction (22%) is also excreted
unchanged by the kidneys. minimally metabolised by the major cytochrome P450 enzymes
PharmacokineticsPharmacokinetics
neither an inhibitor nor an inducer of P450 enzymes
Drug interactionsDrug interactions
monotherapy and in combination with other antidiabetic treatments has proved to be well tolerated for periods up to 52 weeks
HHypoglycaemiaypoglycaemia is low and similar to that with metformin or rosiglitazone
No apparent weight gainweight gain or edemaedemaGI side effectsGI side effects is comparable to placebo
and is much less than in metformin- treated patients
CCardiac adverse eventsardiac adverse events and HHypertensionypertension with vildagliptin is comparable to placebo and is also less than with metformin
Side EffectsSide Effects
Vildagliptin is taken orally and is l ikely to be administered once daily.
Oral 50 and 100 mg in cl inical tr ial in type 2 DM
No adjustment of dose is necessary in either heptic or renal insufficiency
Dosage and administrationDosage and administration
Summary
Vildagliptin is the first of a new class of drugs for the treatment of Type 2 diabetes.
This group of drugs wil l be known as DPP-IV (dipeptyl peptidase-IV) inhibitors.
Reduces blood glucose concentrations by enhancing the effects of
“ incretins”
Summary
Well tolerated - low rates of adverse effects in clinical tr ials
Not associated with weight gain
Clinical Clinical studies 1studies 1Clinical Clinical
studies 1studies 1
Phase III Trial Design for Study 2309 . Long-term LAF237 Monotherapy Drug naïve patients with T2DM and HbA1c 7.5-11% Objective - HbA1c reduction at 12 months and maintenance
to 2 years
Source: Study 2309 data on fi le17 London Pharmaceutical Pipeline Event 2005 / Ameet Nathwani
52 Week Data with Monotherapy Confirm Earlyand Sustained Reductions in HbA1c
Both LAF237 and Metformin DemonstrateBody Weight Neutrality Unlike SUs1 and TZDs2
LAF237 is Better Tolerated than Metformin
LAF237 Has a Superior GI Tolerability Profileto Metformin
Clinical Clinical studies 2studies 2Clinical Clinical
studies 2studies 2
Phase III Trial Design for Study 2329 . LAF237Dose Comparison
Drug naïve patients with T2DM and HbA1c 9-11% Primary objective: HbA1c reduction from baseline . LAF237 50 mg
and 100 mg total daily dose Pioglitazone used as a positive control for study validation
LAF237 Demonstrates Excellent Responder Rates
LAF237 Achieves Excellent, Dose-proportionalReductions in HbA1c
Clinical Clinical studies 3studies 3Clinical Clinical
studies 3studies 3
Phase IIb Trial Design for Study 1202- LAF237Dose-ranging Study
Drug naïve patients with T2DM and HbA1c 7.5-11% Primary objective: HbA1c reduction from baseline .
LAF237 20 mg,50 and 100 mg vs. placebo
LAF237 Demonstrates Excellent, DoseproportionalReduction in HbA1c
LAF237 New Phase IIb/III Data Summary
Reduces HbA1c levels in a dose- proportional, cl inically meaningful manner in monotherapy and combination with insulinSustains meaningful HbA1c reductions out to one yearHas neutral body weight effects associated with HbA1c
improvementsIs very well tolerated
Is associated with fewer severe hypoglycemic episodes when added to insulin
Has the ideal profi le as .f irst drug of choice. for combination treatment due to eff icacy and safety profi le, lack of drug-drug interactions and complementary mechanism of action
LAF237 New Phase IIb/III Data Summary
Biguanides
Metformin or Metformin ER (Glucophage)Inhibits hepatic glucose production and
decreases insulin resistanceLowers FBS 40-60 mg/dl and A1c 1-2 %Pros: no hypoglycemia and small weight
lossCons: GI intolerance, contraindicated in
renal insufficiency and acute CHF
Thiazolidinediones
Pioglitazone (Actos) or Rosiglitazone (Avandia)Decrease insulin resistance and improve beta
cell functionLowers FBS 30-60 mg/dl and A1c 0.5-1.9 %Pros: no hypoglycemia and safe in CRICons: weight gain, edema, risk of CHF and cost
Combination Drugs
SU + metformin (Glucovance, Metaglip)SU + TZD (Avandaryl)Metformin + TZD (Avandamet and
Actoplusmet)Lower A1c 2 – 4 %Pros: cost savings, convenience, improved
adherenceCons: limited flexibility
Combination Drugs
SU + metformin (Glucovance, Metaglip)SU + TZD (Avandaryl)Metformin + TZD (Avandamet and
Actoplusmet)Lower A1c 2 – 4 %Pros: cost savings, convenience, improved
adherenceCons: limited flexibility
Incretin Mimetics
Exenatide (Byetta)Mechanism of Action:
- increases insulin secretion - decreases glucagon secretion - delays gastric emptying - promotes satiety and weight loss - increases beta cell mass
Lowers FBS 10-20 mg/dl, A1c 1%
Prevalence of T2DM Projected to Double Within 25 Years
Incretin Mimetics
Pros: no hypoglycemia, weight lossCons: GI intolerance, requires injection and
refrigerationNewer agents in development
- liraglutide (acylated GLP-1 analogue) - exenatide-LAR - vildagliptin, sitagliptin (DPP-IV inhibitors; orally active, but weight neutral)
Prandial Regulators
Meglitinides - repaglinide (Prandin) - nateglinide (Starlix)
Stimulate insulin secretion Lower A1c 1-2 % (Prandin) or 0.5-1 % (Starlix) Short half-life; dosed tid with meals Pros: less hypoglycemia than SU, potential CV
benefit Cons: cost, requires frequent dosing
Prandial Regulators
Alpha-glucosidase inhibitors - precose (Acarbose) - miglitol (Glyset)
Delay carbohydrate absorptionLower FBS 20-30 mg/dl, A1c 0.5-1 %Pros: no hypoglycemia, weight neutral,
possible CV benefitCons: GI intolerance, cost, frequent dosing
Approachs to Type 2 Diabetes
Insulins
Basal insulins - glargine (Lantus): peakless, 24 hr - detemir (Levemir): small peak, ≤ 24 hr
Pros: less hypoglycemia, BS variability and weight gain than NPH; usually given once daily
Cons: cost
Insulins
Rapid acting insulins- lispro (Humalog)
- aspart (Novolog) - glulisine (Apidra)
Pros: improved PPG, less hypoglycemia, and improved convenience when compared with regular insulin
Cons: cost
Inhaled Insulin
Exubera (inhaled powdered insulin)Pros: kinetics similar to rapid acting
injectable insulin analogs, does not require injection
Cons: inhaler device, contraindicated in smokers and patients with lung disease, limited ability to titrate dose, and cost
Insulin Mixtures
Humalog 75/25 and 50/50Novalog mix 70/30Pros: improved PPG, less hypoglycemia
and preferred pen delivery compared with Humulin 70/30
Cons: cost
Pramlintide
Pramlintide (Symlin); a synthetic amylin analogue
Mechanism of Action: - inhibits glucagon secretion - slows gastic emptying - promotes satiety and weight loss
Pros: lowers PPG, lowers A1c 0.5 % and promotes weight loss
Cons: GI intolerance, hypoglycemia, another injection, and cost
DPP-IV Inhibitors (liptins)
Sites of Action for Oral Therapies for Type 2 DM