ESSENTIALS OF

PHARMACOKINETICS AND

DRUG ADMINISTRATION IN PICU

Dre Caroline Fonzo-Christe

Pharmacist, HUG Geneva

CAS DE

PHARMACIE CLINIQUE

Mercredi 25 juin 2014

2

“what the body does to a drug” Pharmacokinetics

-> profile of drug concentration over time

1. Absorption

2. Distribution

3. Metabolism

4. Excretion

Drug administration“what YOU do to a drug”

The right dose for

the right effect

How not to loose

the drug before

reaching the patient

3

YOUR DAILY LIFE IN PICU

From the smallest to the biggest one…

Critically ill children….

High risk IV drugs…

VARIABILITY

4

Adapted from : Tomlin S, EAHP 2014

Survival

phase

Adaptation

Growth,

proliferation

Differentiation

Puberty

Sexual

maturation

<500 g >100kg

Respiratory

distress

syndrome

Necrotising

enterocolitis

Patent ductus

arteriosus

Neonatal asphyxia

Neonatal sepsis

Metabolic disease

Meningitis

Bronchiolitis

Cardiac surgery

Trauma

Near-drowning

Peritonitis

Intoxication

Asthma

Anorexia

nervosa

MEDICATION PROCESS

http://www.ismp.org

5

Non electronic

WHAT INFLUENCE DRUG EFFECT?

6

IV

High concentrations

Drug incompatibilities

In-line filters, infusion

material

Low flow, dead space

Drug effect

Exposition

Receptors

A

D

M

E

Ontogenesis

Pharmaco-

genetics

Environment

Nutritional state

Critically ill

ECMO, CRRT

Drug interactions

Co-morbidities

Drug preparation

and administration

SOME REFRESH ON PK PARAMETERS

7

2 MAIN PK PARAMETERS

Volume of distribution (Vd) Initial (loading) dose

to reach a Cpeak

Clearance Maintenance dose

to maintain a certain Css8

Adapted from Vaughan K,

Dell Children’s Medical Center of Central Texas

VOLUME OF DISTRIBUTION VD

Small Vd : drug mainly within systemic circulation Plasma volume (Vd 0.05 L/kg): large MW or high protein binding (ex. heparin, aspirin)

Extracellular water (Vd 0.2 L/kg): ex. penicillins, gentamicin, vancomycin

Total body water (Vd 0.6 L/kg): ex. paracetamol, indometacine, vancomycin

Large Vd (2-10 L/kg): drug distributed into peripheral

compartments (ex. morphine, hydromorphone, fentanyl)

Useful to determine intial dose

9

Starkey ES et al. Arch Dis Child Educ Pract Ed 2015;100:37-43

Cmax = dose Vd

CLEARANCE CL

CL tot = CL hepatic + CL renal

Hepatic clearance

10

Allorge D, Loriot A. Ann Biol Clin 2004;62:499-511

Starkey ES et al. Arch Dis Child Educ Pract Ed 2015;100:37-43

Phase 1: oxidation, demethylation

by enzymes (CYP450)

Phase II: conjugation

Phase III: excretion – elimination

(renal or biliary)

Drug transport proteines:

P-gP (P-glycoproteine)

MRP (Multidrug resistance protein)

hydrophilic

hydrophobic

Cell

protection

• Renal clearance: unchanged /metabolites

• Glomerular filtration: aminoglycosides, digoxin

• Proximal tubular secretion: penicillins, furosemide

PHARMACOKINETIC PARAMETERS

11

100%

50%

12.5%

25%

6.3 %

1 T1/2

3 %Time, hours

Co

nce

ntr

ation

, m

g/L

Cmax = Peak concentration

Minimal therapeutic concentration

Cmin = Trough concentration

AUC Therapeutic rangeArea under the curve

Cmax = dose

Vd

Vd: Volume of distribution

Elimination half-life T1/2 = ln2 x Vd

CL

T1/2: Time taken for plasma concentration to halve

CL Clearance

ln2 = 0.693

STEADY-STATE

Absorption or infusion rate balanced by

elimination rate Plasma concentration does not increase anymore

Time to reach steady-state: 4-5 T1/2

Time to be completely eliminated: 4-5 T1/2

12

Half-life : 12 hours

Starkey Es et al. Arch Dis Child Educ Pract Ed 2015;100:37-43

Intermittent dosing (x mg at each interval (ex. 12 h)

Css = steady-state concentration

Continuous infusion (mg/h)

3 PAPERS

13

Kearns GL et al. N Engl J Med 2003;349:1157-67

MORE PAPERS

14

https://www.sciencedirect.com/science/article/pii/B9780323401395000334

Anderson BJ. Anaesthesia & Intensive Care Medicine 2017,18:68-74

ONTOGENESIS AND PK

15

Samardzic J et al. Int J Pharmaceutics 2015;492:335–337

renal

CLhepatic

CL

Bioavailability Vd

DISTRIBUTION16

1. Absorption

2. Distribution3. Metabolism

4. Excretion

BODY WATER

17

Anderson BJ. Anaesthesia & Intensive Care Medicine 2017,18:68-74

Fat: 0.7% 12%

BODY COMPOSITION

80% water

12% fat

60% water

20% fat

Neonates

• larger Vd for hydrophilic

drugs (aminoglycosides)

-> risk of underdosing

• lower Vd for fat-soluble drugs

(fentanyl, midazolam)

-> risk of toxicity

Kearns GL et al. N Engl J Med 2003;349:1157-67

18

Vd

VD IN NEONATES

Gentamicin dose has to be increased (in mg/kg) to

reach the same plasma concentration

19

Kearns GL et al. N Engl J Med 2003;349:1157-67

Neofax 2010

Increased volume of distribution means increase the dose (initial

dose in mg/kg), to " fill up all the spaces " and reach target

concentrations

Vd

Cmax = dose

Vd

HEPATIC METABOLISM20

1. Absorption

2. Distribution

3. Metabolism4. Excretion

METABOLIC CAPACITY

AND DEVELOPMENT

21

de Wildt SN, et al. Arch Dis Child 2014

Choonara I, et al. Arch Dis Child 2014;99:1143–1146

Neonates

• Reduced hepatic clearance

-> risk of toxicity

Child

• Increased hepatic clearance

for some drugs

-> risk of underdosing

Hepatic

ClearanceBIRTH

IMPACT ON HALF-LIFE

midazolam

CYP3A4

ibuprofen

CYP2C9,

2C19

indomethacin

CYP2C9

caffeine

CYP1A2

morphine

UGT2B7

paracetamol

UGT1A6,1A9

T1/2 NN 6-12h PNA 3j: 43h

PNA 5j: 27h

PNA<2sem:

20h

PNA>2sem:

11h

NN: 72-96h Premature:

10-20h

NN: 8h

NN: 2-5h

Sulphation

T1/2 child 1-1.5h 1-2h - 5h (at 9

months)

1-2h

Sulphation

T1/2 adult 1.5-3.5h 2-4h - 3-5h 2-4h 1-3h

Glucuro-

conjugation

22

PNA: post natal age

NN: neonate Reduced hepatic clearance and longer half-life in NN

Increased hepatic clearance in childhood

Metabolic clearance of drugs matures at different rates, depending on the

drug metabolism pathways involved.

RENAL EXCRETION23

1. Absorption

2. Distribution

3. Metabolism

4. Excretion

RENAL FUNCTION

Kearns GL et al. N Engl J Med 2003;349:1157-67

Proximal

tubular

secretion

Adult values (100 – 120 ml/min)

at about 1 year24

Reduced renal clearance in

the first year of age for:

• Drugs with high renal

excretion (aminoglycosides,

penicillines, furosemide)

• Active metabolites

(morphine-6-glucuronide,

1-OH-midazolam et 1-OH-

midazolam-glucuronide)

Renal

Clearance

CLEARANCE IN NEONATES

A decreased clearance requires a longer dosing interval

to maintain trough concentrations low (to limit toxicity)

for gentamicin

25

Kearns GL et al. N Engl J Med 2003;349:1157-67

Neofax 2010

Decreased clearance means longer half-life and higher plasma

concentrations. Need to increase dosing interval !

Cl

26

OPIOIDS T1/2 , Vd, onset Metabolism Particularities

Fentanyl

The shortest onset of

action and the most

potent

The most lipophilic

Adult: 2–4h

Child: 11-36h (long-term

infusion)

0-14y: 5-30 L/kg

Adult: 4-6 L/kg

Onset of action IV: < 1 min

CYP3A4 -> inactive

metabolites

No active metabolite

Highly lipophilic (fat,

muscle) -> T1/2

prolongation with

infusion duration

Thorax rigidity (-> IV

over 3-5 min)

Morphine

Active metabolite

Adult: 2-4h

Premature: 10–20h

NN: 8h

Child: 1–2h

Adult: 1-6 L/kg

Onset of action: IV 5-10

min, PO: 30 min

No CYP but

glucuronidation

Active metabolite (6-Mô-

glucuronide) -> risk of

accumulation in renal

insufficiency

Hydromorphone

5-10x more potent than

Morphine

Adult: 2–4h

Adult: 4 L/kg

Onset of action IV: 5min,

PO: 15-30 min

No CYP but

glucuronidation

No active metabolite

Methadone

Very long T1/2

CAVE QT

Risk of IA

Adult: 35h (8-60h)

Child: 20h (3-62h)

Adult: 1–8 L/kg

NN: 2.5 L/kg

Onset of action IV: 15-20

min, PO: 30–60 min

CYP2D6, 3A4… No active metabolite

Risk of IA and QT

prolongation and

accumulation in hepatic

impairment

27

Alpha2 agonists T1/2 Metabolism Particularities

Dexmedetomidine

Affinity α2 1600:1

Adult: 3h

Premature: 7h

NN: 3h

Child: 1.5h

NN: 2 - 6 L/kg

Onset of action IV: 15 min

Glucuronidation

and CYP2A6

No active metabolites

T1/2 increase in hepatic

impairment

Bradycardia

Clonidine

Affinity α2 200:1

Adult: 12 -16h

NN: 40 – 70h

Child: 8 – 12h

Adult: 3 L/kg

Onset of action PO: 30-60 min

No CYP but

glucuronidation

No active metabolites

T1/2 increase in renal

impairment (-> 40h)

Hypotension, rebound

effect

Benzodiazepines T1/2 Metabolism Particularities

Midazolam

Active metabolites

Risk of IA

Adult: 3h

Premature: 6–12h

Child: 1-1.5h

NN: 1 L/kg

Adult: 1–3 L/kg

Onset of action IV: 3-5 min, PO

10-20 min

CYP3A4 -> active

metabolites (1-OH-

midazolam)

Active metabolites ->

risk of accumulation in

renal/hepatic

impairment

Risk of IA

T1/2 increase hepatic

impairment

Lorazepam

No active

metabolites

Long T1/2

Adult: 12-16h

NN: 40h

Child: 6-17h

NN: 0.2-3 L/kg

Adult: 1 L/kg

Onset of action IV: 2-3 min

No CYP but

glucuronidation

No active metabolite

CRITICALLY ILL AND PHARMACOKINETIC

28

IMPACT ON DRUG PK

29

Roberts JA et al. Lancet Infect Dis 2014;14:498-509

Therapeutic failure Toxicity Therapeutic

failure or

Toxicity

Ex. ABs Ex. ABs

Ascites

IMPACT ON DRUG PK

30

Roberts JA et al. Lancet Infect Dis 2014;14:498-509

Udy AA et al. Clin Pharmacokinet 2010; 49:1-16

Sime FB et al. Curr Opin Pharmacol 2015;24:1-6

Therapeutic failure

Ex. ABs Ex. ABs

Ascites

Clinical implications for time-dependent (t>MIC) ABs

• More frequent dosing (shorter dosing interval)

• Increased total daily dose

• Continuous/extended infusions?

• TDM

ANTIBIOTICS CLASSIFICATION

31

= Concentration-dependentAminoglycosides

Metronidazole

= Concentration and time-

dependent (exposition –

dependent)Vancomycin*

Fluoroquinolones*

Macrolides

= Time-dependentCarbapenems

Cephalosporines

Penicillins

Vancomycin *

Minimum inhibitory concentration

Roberts JA et al. Lancet Infect Dis 2014;14:498-509

Jamal JA et al. Curr Opin Crit Care 2012; 18:460–471

Adapted from Huttner A. Séminaire MAS Genève 2015

* May differ depending on publication

IMPACT ON DRUG PK

32

Roberts JA et al. Lancet Infect Dis 2014;14:498-509

Therapeutic failure

Ex. ABs Ex. ABs

Ascites

Clinical implications for hydrophilic drugs ABs

-> Depending on protein binding and renal function

• Loading dose

• Supplementary dose if puncture? «peritoneal dialysis»

• TDM

Vanco

Mero

Teico

IMPACT ON DRUG PK

33

Roberts JA et al. Lancet Infect Dis 2014;14:498-509

Therapeutic

failure or

Toxicity

Ex. ABs

ECMO: IMPACT ON PK

34

Shekar K et al. J Crit Care 2012; 27: 741.e9–741.e18

Often ECMO and CRRT combined !

DRUG SEQUESTRATION

Key factors: drug stability, lipophilicity and protein binding

Dependent of

oxygenator and circuit type (silicone vs polypropylene hollow

fiber membrane, coated vs uncoated circuit) 35

Shekar K et al. Critical Care 2015;19:164

Shekar K et al. J Crit Care 2012; 27: 741.e9–741.e18

-90%

NS

Clinical implications

• For ABs, do TDM

• For analgesia, morphine first

choice (titration)

SEDATION/ANALGESIA

Lipophilic drugs: sequestration

Clonidine, ketamine: no data

Dexmedetomidine: adsorption to PVC?

36

Shekar K et al. Crit Care 2012; 16: R194

Wagner D et al. Perfusion. 2013 ;28:40-6

Lipophilic

Lipophilic

Hydrophilic

Clinical implications

• Titration and use of

sedation/analgesia scores

• Morphine first choice for

analgesia

DRUG INTERACTION

NICU

• Immature hepatic and renal clearance

• Difficult to predict, no data

• At risk patients (?) if: • Presence of drug inhibitors or inducers

• Nephrotoxic drugs (cumulative effect)

PICU

• Cardiac patients (Drugs and QT)

• Transplant (immunosuppressive

agents)

• Epilepsia, Tuberculosis

37

Clinical implications

• Be careful at the beginning and the

end of a treatment

• Need to monitor effect and/or TDM

• Stop of inhibitor -> Normal CYP

activity after 4 T1/2

• Stop of inducer -> Normal CYP

activity >2w after inducer has

disappeared from blood

Amiodarone Multiple CYPs

Fluconazole Multiple CYPs

QT-PROLONGATION AND DRUGS

Mechanism

Dose-dependent blockade of potassium ion channels (Ikr) prolonged cardiacrepolarisation may lead to TdP (torsades de pointe)

Drug related risk factors

Renal or hepatic failure

Drug interactions with hepaticmetabolism inhibition

Management

Use lowest effective dose

Monitoring of baseline values and at steady state (4 T1/2)

38

Beitland S et al. Acta Anaesthesiol Scand 2014; 58: 266–272

Trinkley KE et al. Curr Med Res Opin2013;29:1719-26

QT-PROLONGATION AND TDP

https://www.crediblemeds.org/

39

40

“what the body does to a drug” Pharmacokinetics

-> profile of drug concentration over time

1. Absorption

2. Distribution

3. Metabolism

4. Excretion

Drug administration“what YOU do to a drug”

The right dose for the

right effect

How not to loose the

drug before reaching

the patient

ISSUES WITH DRUG ADMINISTRATION

41

Sherwin CMT et al. Arch Dis Child 2014; 99:590-4

DRUG DISPENSING42

DISPENSING AND SYRINGE ACCURACY

43

Morecroft CW, et al. Arch Dis Child 2013;98:831–832

Right dose?

44

Arenas_Lopez S et al. Arch Dis Child 2017, doi: 10.1136/archdischild-2016-312492

De Giorgi I, 2007 http://pharmacie.hug-ge.ch/rd/posters/jfsph06_idg_precision_seringues.pdf

Take at least 25% of

the volume of a syringe

to limit variability

SEDATION / ANALGESIA

Pharmaceutical

compounding by

hospital pharmacists

45

DRUG INCOMPATIBILITIES46

DRUG PRECIPITATION

47

B.Braun, KIK 2.1 2002 and Drug incompatibility 2011 www.safeinfusiontherapy.com

HUG

caspofungine + heparin

EMULSION CRACKING

Albumin 20% and 3-in-1 parenteral nutrition

Oiling out

Bouchoud L et al. JPEN J Parenter Enteral Nutr. 2013;37:416-24

48

+ 10min + 30minT0

Pharmacie HUG

TYPE OF REACTIONS

Physico - chemical

• Acid-base reactions (pH)

• Solubility

• Emulsion cracking

• Oxydo-reduction

• …

Consequences

• Precipitates (visible)

• Colour change (visible)

• Gaz production (visible)

• pH change (invisible)

• concentration (invisible)

• Catheter occlusion

• Renal and pulmonary embolism

• Reduction of therapeutic effect

• Toxic effects (peroxides)

patient

49

50

ACIDS AND BASES

From: KIK 2.1,

BBraun, 2002

Acid drug molecule basic drug solution

Basic drug molecule acidic drug solution

Don’t mix or infuse

on Y-site

acidic with basic

drug solutions!

Molecule Drug

solution

Molecule Drug

solution

Furosemide (acid) pH 9 Furosemide (acid) pH 9

Vancomycin (base) pH 3 Midazolam (base) pH 4

From: KIK 2.1, BBraun, 2002

51

SOLVENT (DILUENT)

Furosemide in Glucose 5% From: KIK 2.1, BBraun, 2002

Glucose 5% - 20% pH = 3.5 - 6.5 amiodarone, amphotericine B

noradrenaline, nitroprussiate

NaCl 0.9% pH = 5.0 - 7.0 erythromycine, furosemide, phenytoin

Solvent pH Appropriate for

CLINICAL INCIDENTS

Knowles JB et al. JPEN 1989;13:209-13

Hill SE et al. JPEN 1996;20:81-87

McNearney T et al. Dig Dis Sci 2003;48:1352-4

RECENT DATA: DRUG - DRUG

Kalikstad B et al. Arch Dis Child 2010;95:745-748

Zhao B et al. Am J Health-Syst Pharm 2014;71:901-902

Lack of DATA

in NICU

Case-reports of

catheter occlusion

53

CONCLUSION AND KEY MESSAGES

54

KEY MESSAGES

1. Increased Vd means increase the initial dose to “fill up all spaces”

2. Decreased CL means increase dosing interval

3. Critically ill patients:

Hyperdynamic states -> Increased CL means increase frequency for AB’s that need t>MIC

Ascites -> loss of hydrophilic drugs, do TDM and consider dose adaptation for “peritoneal dialysis” if puncture

ECMO -> variable effects, increase the initial dose and do TDM for antibiotics and titration for sedation/analgesia

4. Ask the pharmacist for drug compatibilities, dispensing issues and drug compounding

55

KEY HOME MESSAGE

FROM THE PHARMACIST

56

Prescribing the right dose is not

sufficient…

Don’t forget to ask yourself

where is the drug and

how much drug has been given !

57