Newer Insulins in Pediatrics

8/6/2019 Newer Insulins in Pediatrics

1/24


2/24

Newer Insulins In Type 1 DMNewer Insulins In Type 1 DM

Dr. Kishore ChandkiRegistrar, PICU & SCBU

Dr. Sandeep JulkaConsulting Endocrinologist


3/24

H istoryH istory

1921 : Discovery & isolation of Insulin by1921 : Discovery & isolation of Insulin byBanting & BestBanting & Best1930s : Protamine Zinc Insulin (PZI) was1930s : Protamine Zinc Insulin (PZI) wasintroducedintroduced1940s: NPH was introduced1940s: NPH was introduced1950s: Lente series introduced by Hagedorn1950s: Lente series introduced by Hagedorn1970s: Highly purified Insulins1970s: Highly purified Insulins1980s : Human Insulins by rDNA1980s : Human Insulins by rDNA

To date, >300 analogues have been idenified!To date, >300 analogues have been idenified!


4/24

Newer InsulinsNewer Insulins

Ultrashort actingUltrashort actingAspart (Novorapid)Aspart (Novorapid)

LisproLispro

Glulisine (Apidra):Glulisine (Apidra): 4 yrs 4 yrs

Short actingShort acting

Regular & VelosulinRegular & Velosulin

Intermediate actingIntermediate acting

Neutral Protein H agedorn / IsophaneNeutral Protein H agedorn / IsophaneLenteLente

Long actingLong acting

Glargine (Lantus)Glargine (Lantus)

Detemir (Levemir)Detemir (Levemir)


5/24


TypeType StartsStarts PeaksPeaks DurationDuration

LisproLispro(H umalog)(H umalog)

55--10 min10 min 0.50.5--1.5 hrs1.5 hrs 33--4 hrs4 hrs

RegularRegular 30 min30 min 22--4 hrs4 hrs 55--8 hrs8 hrs

NP H NP H

& Lente& Lente

11--2 hrs2 hrs 66--10 hrs10 hrs 1212--20 hrs20 hrs

GlargineGlargine 1.5h1.5h NoneNone 1818--30 hrs30 hrs


6/24


Newer modified insulin for novel ways of Newer modified insulin for novel ways of deliverydelivery

Inhaled insulinInhaled insulin

Oral insulinOral insulin


7/24


Clear Solution pH4

pH 7.4

Precipitation

Dissolution

Capillary Membrane

Insulin in Blood

Hexamers Dimers Monomers

10-3M 10-5M 10-8M

Pharmacokinetics of Insulin :Pharmacokinetics of Insulin :


8/24

Regular InsulinRegular Insulin

F ormerlyF ormerly fastestfastest actingactingProblemsProblems ::OptimumOptimum timetime 3030 minmin before before mealsmeals

DifficultDifficult toto useuse if if timingtiming /intake/intake of of mealsmeals isisirregular irregular PostprandialPostprandial hyper hyper-- && hypohypo--glycemiaglycemia

PreparationPreparation of of choicechoice for for DKADKA //hyperosmolar hyperosmolar comacoma // acuteacute infectionsinfections / / perioperative perioperative

VelosulinVelosulin : : BufferedBuffered regular regular insulininsulin for for pump pump

usersusers


9/24

Insulin Lispro ( H umalog)Insulin Lispro ( H umalog)

R eversalR eversal of of aminoamino acidsacids atat BB 2828 (( pro pro line)line)andand BB 2929 ((lyslys ine)ine) toto lysinelysine -- proline, proline, hencehencenamename LisproLispro

AdvancementAdvancement inin ss..cc.. therapytherapyItIt dissociatesdissociates rapidlyrapidly intointo monomersmonomersF aster F aster absorptionabsorption andand onsetonset-- 55 -- 1515 minmin

Shorter Shorter durationduration of of actionaction:: 33 44 hrshrsBecauseBecause of of rapidrapid onsetonset of of actionaction cancan be beadministeredadministered withwith // after after mealsmeals ee..gg.. toddlerstoddlers


10/24

Insulin Lispro ( H umalog)Insulin Lispro ( H umalog)

Less variability in absorptionLess variability in absorptionAdvantages:Advantages:

Mimics physiological insulin profileMimics physiological insulin profile

Better control of postprandialBetter control of postprandialhyperglycemiahyperglycemiaLesser risk of post absorptiveLesser risk of post absorptive

hypoglycemiahypoglycemiaSite does not influence actionSite does not influence actionProblem with fatty foods : Ideally suited for Problem with fatty foods : Ideally suited for several well spaced meals in a dayseveral well spaced meals in a day


11/24

Insulin Aspart (Novorapid)Insulin Aspart (Novorapid)Proline at B 28 replaced with Aspartic acidProline at B 28 replaced with Aspartic acid

Produced by rDNA : Saccharomyces cerevisiaeProduced by rDNA : Saccharomyces cerevisiae(bakers yeast)(bakers yeast)

No formation of dimers / hexamersNo formation of dimers / hexamers

Pharmacokinetic profile similar to LisproPharmacokinetic profile similar to Lispro

Less variability in absorptionLess variability in absorption

Approved for treatment of DKA (s.c. only)Approved for treatment of DKA (s.c. only)

Should be injectedShould be injected immediately beforeimmediately before the meal. Butthe meal. But

when necessary, may be given just after a mealwhen necessary, may be given just after a meal


12/24

Insulin Glulisine (Apidra)Insulin Glulisine (Apidra)Amino acid asparagine at position B3 is replaced byAmino acid asparagine at position B3 is replaced bylysine and the lysine in position B29 is replaced bylysine and the lysine in position B29 is replaced byglutamic acidglutamic acid

For adults with type 2 diabetes or adults and childrenFor adults with type 2 diabetes or adults and children(4 years and older) with type 1Should be injected(4 years and older) with type 1Should be injected 15 15 min beforemin before or within 20 minor within 20 min after after the mealthe meal

When insulin glulisine was given before meals, blood

When insulin glulisine was given before meals, blood

glucose measurements were lower than when it wasglucose measurements were lower than when it wasgiven after meals: studiesgiven after meals: studies

Limited data in type 1 DMLimited data in type 1 DM


13/24

Intermediate Acting InsulinsIntermediate Acting Insulins

NPH, Lente NPH, Lente

Onset: 2Onset: 2-- 4 hrs4 hrs

Peak: 4Peak: 4 -- 10 hrs10 hrs

Duration: 12Duration: 12 - - 18 hrs18 hrs

Dose to dose variation ++Dose to dose variation ++Problem of midnight hypoglycemia & shortProblem of midnight hypoglycemia & shortduration of controlduration of control


14/24

Intermediate Acting InsulinsIntermediate Acting Insulins

NP H / Isophane Insulin :NP H / Isophane Insulin :

2 parts of crystalline Zn & 1 part Protamine Zn2 parts of crystalline Zn & 1 part Protamine Zn

Onset & duration same as LenteOnset & duration same as Lente No excess Protamine unlike Lente, hence No excess Protamine unlike Lente, hencedoesnt delay absorption of admixed regular doesnt delay absorption of admixed regular

insulininsulinUsually given with regular/lispro insulinUsually given with regular/lispro insulin

R equires acute mixing with lispro : NPLR equires acute mixing with lispro : NPL


15/24

Insulin Glargine (Lantus)Insulin Glargine (Lantus)

R eplacement of R eplacement of gglycine with aspar lycine with aspar agineagine atatA21 and addition of 2 arginine at B30A21 and addition of 2 arginine at B30Change of solubilityChange of solubility

Prolonged insulin absorptionProlonged insulin absorptionOnset: 2Onset: 2 -- 4 hrs4 hrsPeakless activity (no hypos)Peakless activity (no hypos)

Duration of action: 20Duration of action: 20 - - 24 hrs24 hrs No accumulation after repeated injections No accumulation after repeated injections


16/24


pHAcidic Basic


17/24



18/24


LongLong--acting human insulin analogue for acting human insulin analogue for maintaining the basal level of insulinmaintaining the basal level of insulinR educed risk of nocturnal hypoglycemiaR educed risk of nocturnal hypoglycemia

Lower HbALower HbA 1c1c as compared to NPH in type 1as compared to NPH in type 1diabetes mellitusdiabetes mellitusCant be mixed with other insulins (pH)Cant be mixed with other insulins (pH)

Better control of fasting hyperglycemia &Better control of fasting hyperglycemia &nocturnal hypoglycemia w.r.t. NPHnocturnal hypoglycemia w.r.t. NPH


19/24

Insulin Detemir (Levemir)Insulin Detemir (Levemir)

LongLong--acting human insulin analogue for acting human insulin analogue for maintaining the basal level of insulinmaintaining the basal level of insulinLower HbALower HbA 1c1c as compared to NPH, in typeas compared to NPH, in type

1 diabetes mellitus1 diabetes mellitusStill uncertain is whether rapidStill uncertain is whether rapid- -actingactinginsulin analogs can be mixed with insulininsulin analogs can be mixed with insulindetemir for coadministrationdetemir for coadministration


20/24

Insulins Preparations : ReviewInsulins Preparations : ReviewUltra short Acting

1. Lispro H umalog 40 U/mL, 10 ml vial ~Rs. 410/-

2. Aspart Novorapid 300 U/Flexpen ~Rs. 525/-

Short Acting

1. Regular Actrapid Porcine 40 U/mL, 10 ml vial ~Rs. 130/-

Actrapid H uman /H umunsulin R

40 U/mL, 10 ml vial ~Rs. 200/-

Actrapid H uman 100 U/mL, 10ml vial ~Rs. 510/-

Intermediate ActingIntermediate Acting

1.1. NP H /IsoNP H /Isophanephane

H uminsulin N /Insulatard

40 U/mL, 10 ml vial100 U/mL, 10 ml vial

~Rs. 145/-~Rs. 460/-

2.2. LenteLente H uminsulin L/H uman Monotard

40 U/mL, 10ml vial ~Rs. 200/-

Long ActingLong Acting

1. Glargine Lantus 100 U/mL, 10 ml vial ~Rs. 2500/-


21/24

Premixed Insulins PreparationsPremixed Insulins Preparations1 H uman

Mixtard(NovoNordisk)

30 30% regular + 70%NP H

100 U/mL, 10ml vials

~Rs. 500/-



~Rs. 520/-

40 U/mL, 10ml vials

~Rs. 200/-

2 H uminsulin(Eli Lilly)

30:70 30% regular + 70%NP H


~Rs. 460/-

50:50 50% regular + 50%NP H


~Rs. 460/-

40 U/mL, 10ml vials

~Rs. 150/-

3 Insuman(Aventis)

25/75 & 50/50 40 U/mL, 10ml vials

~Rs. 165/-

4 H umalogMix

25 25% Lispro + 75%Lispro Protamine


22/24

Premixed Insulins PreparationsPremixed Insulins Preparations1 H umalog

Mix(ElliLilly)

75/25 25% lispro + 75%lispro protamin


~Rs. 500/-



~Rs. 520/-

40 U/mL, 10ml vials

~Rs. 200/-

2 Novomix(NovoNordisk)

30:70 30% aspart+ 70%protamine aspart


~Rs. 460/-

50:50 50% regular + 50%NP H


~Rs. 460/-

40 U/mL, 10ml vials

~Rs. 150/-


23/24

C onclusionC onclusion

PrimaryPrimary andand secondarysecondary prevention prevention of of complicationscomplications whichwhich requiresrequires tighttight glycemicglycemiccontrolcontrol (HbA(HbA 11cc


24/24

ThanksThanks

Documents

Newer Insulins in Pediatrics