CLASE. FARMACOTERAPIA PEDIATRIA. CFEG. 2015medicina-ucr.com/.../CLASE.-FARMACOTERAPIA-PEDIATRIA.-CFEG.-2015.pdf · FARMACOTERAPIA PEDIATRIA Dr. Carlos Fernando Estrada Garzona Departamento

FARMACOTERAPIA� PEDIATRIA

Dr. Carlos Fernando Estrada GarzonaDepartamento de FarmacologíaUniversidad de Costa Rica

ALTERACIONES FARMACOCINETICAS

n engl j med

349;12

www.nejm.org september

18

,

2003

The

new england journal

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Figure 1. Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants, Children, and Adolescents.

Physiologic changes in multiple organs and organ systems during development are responsible for age-related differences in drug disposi-tion. As reflected by Panel A, the activity of many cytochrome P-450 (CYP) isoforms and a single glucuronosyltransferase (UGT) isoform is markedly diminished during the first two months of life. In addition, the acquisition of adult activity over time is enzyme- and isoform-specif-ic. Panel B shows age-dependent changes in body composition, which influence the apparent volume of distribution for drugs. Infants in the first six months of life have markedly expanded total-body water and extracellular water, expressed as a percentage of total body weight, as compared with older infants and adults. Panel C shows the age-dependent changes in both the structure and function of the gastrointestinal tract. As with hepatic drug-metabolizing enzymes (Panel A), the activity of cytochrome P-450 1A1 (CYP1A1) in the intestine is low during early life. Panel D summarizes the effect of postnatal development on the processes of active tubular secretion — represented by the clearance of para-aminohippuric acid and the glomerular filtration rate, both of which approximate adult activity by 6 to 12 months of age. Panel E shows age dependence in the thickness, extent of perfusion, and extent of hydration of the skin and the relative size of the skin-surface area (reflected by the ratio of body-surface area to body weight). Although skin thickness is similar in infants and adults, the extent of perfusion and hydra-tion diminishes from infancy to adulthood. Data were adapted from Agunod et al.,

4

Rodbro et al.,

5

Poley et al.,

9

Gibbs et al.,

21

Okah et al.,

24

West et al.,

27

Friis-Hansen,

38

Young and Lietman,

39

Hines and McCarver,

40

Treluyer et al.,

41

Kinirons et al.,

42

Pynnönen et al.,

43

Aranda et al.,

44

Miller et al.,

45

Barrett et al.,

46

Murry et al.,

47

and Robillard et al.

48

Changes in Gastrointestinal Function

Perc

enta

ge o

f Adu

lt Ac

tivity

Birth 1 wk 2 wk 3 wk 1 mo 3 mo 1–3 yr 4–6 yr 5–10 yr Adult

Hydrochloric acid productionBile acid secretionIntestinal and body length

Intestinal glutathione conjugation

Intestinal CYP1A1

250

200

150

100

50

0

Perfusion

Hydration

Pre-termneonate

Full termneonate

Infant Child Adolescent Adult

Integumentary Development

Thickness

Body-surfacearea: weightPe

rcen

tage

of A

dult

Activ

ityPe

rcen

tage

of T

otal

Body

Wei

ght

180

140

100

60

160

120

80

40

20

0<24hr

1–7days

8–28days

1–3mo

3–12mo

1–10yr

CYP3A4

Age

Age

Age

Age

CYP1A2

CYP2D6

UGT2B7

Changes in Metabolic CapacityA

B

E

D

C

800

600

400

200

0

160

120

80

40

01–2days

2–4wk

2mo

6mo

1yr

2yr

6yr

12yr

Para

-am

inoh

ippu

ric A

cid

Cle

aran

ce (m

l/m

in/1

.73

m2 )

Para-aminohippuric

acid

Glo

mer

ular

Filt

ratio

n Ra

te(m

l/m

in/1

.73

m2 )

Glomerularfiltration

Acquisition of Renal Function100

80

60

40

20

0Birth 3

mo6

mo9

mo1yr

5yr

10yr

20yr

40yr

Total body waterExtracellular waterBody fat

Developmental Changes in Distribution Sites

The New England Journal of Medicine Downloaded from nejm.org by CARLOS ESTRADA on March 10, 2013. For personal use only. No other uses without permission.

Copyright © 2003 Massachusetts Medical Society. All rights reserved.

n engl j med

349;12


18, 2003

The

new england journal

of

medicine

1157

review article

drug therapy

Alastair J.J. Wood, M.D.,

Editor

Developmental Pharmacology —Drug Disposition, Action, and Therapy

in Infants and Children

Gregory L. Kearns, Pharm.D., Ph.D., Susan M. Abdel-Rahman, Pharm.D., Sarah W. Alander, M.D., Douglas L. Blowey, M.D.,

J. Steven Leeder, Pharm.D., Ph.D., and Ralph E. Kauffman, M.D.

From the Departments of Pediatrics (G.L.K.,S.M.A.-R., S.W.A., D.L.B., J.S.L., R.E.K.),Pharmacology (G.L.K., D.L.B., J.S.L., R.E.K.),and Pharmacy Practice (S.M.A.-R.), Univer-sity of Missouri at Kansas City; and the Di-visions of Pediatric Pharmacology and Med-ical Toxicology (G.L.K., S.M.A.-R., S.W.A.,D.L.B., J.S.L., R.E.K.), Emergency Medicine(S.W.A.), and Nephrology (D.L.B.), Chil-dren’s Mercy Hospitals and Clinics — bothin Kansas City, Mo. Address reprint requeststo Dr. Kearns at the Division of PediatricPharmacology and Medical Toxicology, De-partment of Pediatrics, Children’s MercyHospitals and Clinics, 2401 Gillham Rd.,Kansas City, MO 64108, or at [email protected].

N Engl J Med 2003;349:1157-67.

Copyright © 2003 Massachusetts Medical Society.

nfants and children are far different from adults in terms of

societal, psychosocial, behavioral, and medical perspectives. More than 100 yearsago Dr. Abraham Jacobi, the father of American pediatrics, recognized the impor-

tance of and need for age-appropriate pharmacotherapy when he wrote, “Pediatricsdoes not deal with miniature men and women, with reduced doses and the same classof disease in smaller bodies, but . . . has its own independent range and horizon.”

1

As our knowledge of normal growth and development has increased in the past severaldecades, so has our recognition that developmental changes profoundly affect the re-sponses to medications and produce a need for age-dependent adjustments in doses.

Before the integration of developmental pharmacology into clinical and therapeuticdecision making, numerous approaches to determining pediatric drug doses were rec-ommended (e.g., formulas such as Young’s rule and Clark’s rule). Some of these ap-proaches use discrete age points, whereas others use allometric principles (i.e., thosebased on relative body size) that generally assume there are predictable, linear relationsbetween mass (e.g., cell mass and body weight) and body-surface area among infants,children, adolescents, and adults.

2

However, human growth is not a linear process;age-associated changes in body composition and organ function are dynamic and canbe discordant during the first decade of life. Thus, simplified dosing approaches arenot adequate for individualizing drug doses across the span of childhood.

3

As a result,the use of dosing equations has largely been replaced by adjustment (or normalization)of the drug dose for either body weight or body-surface area. Although such guidelinesare generally adequate for initiating therapy, they may fall short when it comes to con-tinued or long-term treatment, since maintenance therapy must be individualized onthe basis of developmental differences in pharmacokinetics, pharmacodynamics, orboth. Thus, the provision of safe and effective drug therapy for children requires a fun-damental understanding and integration of the role of ontogeny in the disposition andactions of drugs.

absorption of drugs

A variety of methods are used to administer drugs to children, the most common ofwhich involve extravascular routes. A therapeutic agent administered by means of anyextravascular route must overcome chemical, physical, mechanical, and biologic barriersin order to be absorbed. Developmental changes in absorptive surfaces such as the gas-

i



n engl j med

349;12


18

,

2003

The

new england journal

of

medicine

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4

Rodbro et al.,

5

Poley et al.,

9

Gibbs et al.,

21

Okah et al.,

24

West et al.,

27

Friis-Hansen,

38

Young and Lietman,

39

Hines and McCarver,

40

Treluyer et al.,

41

Kinirons et al.,

42

Pynnönen et al.,

43

Aranda et al.,

44

Miller et al.,

45

Barrett et al.,

46

Murry et al.,

47


48


Perc

enta

ge o

f Adu

lt A

ctiv

ity




Intestinal CYP1A1

250

200

150

100

50

0

Perfusion

Hydration

Pre-termneonate

Full termneonate



Thickness


rcen

tage

of A

dult

Act

ivity

Perc

enta

ge o

f Tot

alBo

dy W

eigh

t

180

140

100

60

160

120

80

40

20

0<24hr

1–7days

8–28days

1–3mo

3–12mo

1–10yr

CYP3A4

Age

Age

Age

Age

CYP1A2

CYP2D6

UGT2B7


B

E

D

C

800

600

400

200

0

160

120

80

40

01–2days

2–4wk

2mo

6mo

1yr

2yr

6yr

12yr

Para

-am

inoh

ippu

ric A

cid

Cle

aran

ce (m

l/m

in/1

.73

m2 )

Para-aminohippuric

acid

Glo

mer

ular

Filt

ratio

n Ra

te(m

l/m

in/1

.73

m2 )



80

60

40

20

0Birth 3

mo6

mo9

mo1yr

5yr

10yr

20yr

40yr





n engl j med

349;12


18, 2003

The

new england journal

of

medicine

1157

review article

drug therapy


Editor






N Engl J Med 2003;349:1157-67.





1



2


3


absorption of drugs


i



n engl j med

349;12


18

,

2003

The

new england journal

of

medicine

1160



4

Rodbro et al.,

5

Poley et al.,

9

Gibbs et al.,

21

Okah et al.,

24

West et al.,

27

Friis-Hansen,

38

Young and Lietman,

39

Hines and McCarver,

40

Treluyer et al.,

41

Kinirons et al.,

42

Pynnönen et al.,

43

Aranda et al.,

44

Miller et al.,

45

Barrett et al.,

46

Murry et al.,

47


48


Perc

enta

ge o

f Adu

lt A

ctiv

ity




Intestinal CYP1A1

250

200

150

100

50

0

Perfusion

Hydration

Pre-termneonate

Full termneonate



Thickness


rcen

tage

of A

dult

Act

ivity

Perc

enta

ge o

f Tot

alBo

dy W

eigh

t180

140

100

60

160

120

80

40

20

0<24hr

1–7days

8–28days

1–3mo

3–12mo

1–10yr

CYP3A4

Age

Age

Age

Age

CYP1A2

CYP2D6

UGT2B7


B

E

D

C

800

600

400

200

0

160

120

80

40

01–2days

2–4wk

2mo

6mo

1yr

2yr

6yr

12yr

Para

-am

inoh

ippu

ric A

cid

Cle

aran

ce (m

l/m

in/1

.73

m2 )

Para-aminohippuric

acid

Glo

mer

ular

Filt

ratio

n Ra

te(m

l/m

in/1

.73

m2 )



80

60

40

20

0Birth 3

mo6

mo9

mo1yr

5yr

10yr

20yr

40yr





n engl j med

349;12


18, 2003

The

new england journal

of

medicine

1157

review article

drug therapy


Editor






N Engl J Med 2003;349:1157-67.





1



2


3


absorption of drugs


i



n engl j med

349;12


18

,

2003

The

new england journal

of

medicine

1160



4

Rodbro et al.,

5

Poley et al.,

9

Gibbs et al.,

21

Okah et al.,

24

West et al.,

27

Friis-Hansen,

38

Young and Lietman,

39

Hines and McCarver,

40

Treluyer et al.,

41

Kinirons et al.,

42

Pynnönen et al.,

43

Aranda et al.,

44

Miller et al.,

45

Barrett et al.,

46

Murry et al.,

47


48


Perc

enta

ge o

f Adu

lt A

ctiv

ity




Intestinal CYP1A1

250

200

150

100

50

0

Perfusion

Hydration

Pre-termneonate

Full termneonate



Thickness


rcen

tage

of A

dult

Act

ivity

Perc

enta

ge o

f Tot

alBo

dy W

eigh

t

180

140

100

60

160

120

80

40

20

0<24hr

1–7days

8–28days

1–3mo

3–12mo

1–10yr

CYP3A4

Age

Age

Age

Age

CYP1A2

CYP2D6

UGT2B7


B

E

D

C

800

600

400

200

0

160

120

80

40

01–2days

2–4wk

2mo

6mo

1yr

2yr

6yr

12yr

Para

-am

inoh

ippu

ric A

cid

Cle

aran

ce (m

l/m

in/1

.73

m2 )

Para-aminohippuric

acid

Glo

mer

ular

Filt

ratio

n Ra

te(m

l/m

in/1

.73

m2 )



80

60

40

20

0Birth 3

mo6

mo9

mo1yr

5yr

10yr

20yr

40yr





n engl j med

349;12


18, 2003

The

new england journal

of

medicine

1157

review article

drug therapy


Editor






N Engl J Med 2003;349:1157-67.





1



2


3


absorption of drugs


i



n engl j med

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, 2003

The new england journal of medicine

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Infant dose if volume of distribution is <0.3liter per kilogram = infant’s body-surface area(in square meters ÷ 1.73 m2) ¬ the adult dose

and

Infant dose if volume of distribution (deter-mined from the literature) is ≥0.3 liter perkilogram = infant’s body weight (in kilo-grams ÷ 70 kg) ¬ the adult dose.

This approach is useful only in determining the doseas opposed to the dosing interval, in that the equa-tions contain no specific variable that describes po-tential age-associated differences in drug clearance.

The advances in pediatric clinical pharmacologyduring the past decade stem from an enhanced un-

derstanding of the influence of growth and devel-opment on the disposition and actions of drugs.The expanded scope of clinical trials involvingchildren afforded by the provisions of the BestPharmaceuticals for Children Act of 200295 andan ethical construct for conducting drug researchin children that is viewed as permissive (as opposedto restrictive)96 will facilitate improvements in drugtherapy for this age group. Ensuing research intothe ontogeny and pharmacogenomics of transport-ers, receptor systems, and cell signaling will alsoelucidate the developmental events that affect thetreatment of childhood diseases and their responseto drug treatment.97 The ultimate goal of providinginfants and children with safe and effective drugtherapy must be kept clearly in sight and will bemade possible by specifically including them in clin-ical trials.

conclusions

* The usual doses in adults were adjusted for an average ideal adult body weight of 70 kg. All other doses reflected average ranges recommend-ed in a widely used pediatric handbook.93 Unless otherwise noted, all drugs are given intravenously. The information contained in this table is intended only to illustrate the influence of developmental differences in drug disposition and action on average dose requirements among the age groups and is not meant to convey specific dose recommendations.

† The initial oral doses of captopril are given.

Table 1. Examples of Age-Specific Usual Doses of Drugs Commonly Used in Pediatric Medicine.*

Drug Average DosePrimary Determinants of Difference

in Age-Related Doses

Neonates Infants Children Adults

Gentamicin 2.5 mg/kg every 12 hr

2.5 mg/kg every 6–8 hr

2.5 mg/kg every 8 hr

1–2 mg/kg every 8 hr

Pharmacokinetic: apparent renal clear-ance and apparent volume of distri-bution

Ceftazidime 50 mg/kg every 12 hr

50 mg/kg every 8 hr

50 mg/kg every 8 hr

14–28 mg/kg every 8–12 hr

Pharmacokinetic: apparent renal clear-ance and apparent volume of distri-bution

Clindamycin 15 mg/kg every 8 hr

10 mg/kg every 6–8 hr


8–12 mg/kg every8–12 hr

Pharmacokinetic: apparent hepatic clearance

Carbamazepine Not established 3–10 mg/kg every 8 hr


5–8 mg/kg every12 hr


Phenytoin 2.5–4.0 mg/kg every 12 hr


2.3–2.6 mg/kg every 8 hr

2 mg/kg every 12 hr


Phenobarbital 3–4 mg/kg every 24 hr




Pharmacokinetic: apparent hepatic clearance, followed by apparent volume of distribution

Theophylline 0.5 mg/kg/hr 0.6–0.7 mg/kg/hr 1.0–1.2 mg/kg/hr 0.5–0.7 mg/kg/hr Pharmacokinetic: apparent hepatic clearance

Digoxin 4–8 µg/kg every 24 hr

7.5–12.0 µg/kg every 24 hr

3–8 µg/kg every 24 hr

1.4–4.0 µg/kg every 24 hr

Pharmacokinetic (apparent renal clear-ance followed by apparent volume of distribution) and pharmacodynamic

Captopril† 0.01–0.05 mg/kg every 8–12 hr

0.15–0.3 mg/kg every 8–12 hr

0.2–0.4 mg/kg every 12–24 hr

0.2–0.4 mg/kg every 8–12 hr


Ranitidine 0.75–1.0 mg/kg every 12 hr



0.7 mg/kg every 6–8 hr

Pharmacokinetic: apparent renal clear-ance, followed by apparent volume of distribution



n engl j med

349;12


18, 2003

The

new england journal

of

medicine

1157

review article

drug therapy


Editor






N Engl J Med 2003;349:1157-67.





1



2


3


absorption of drugs


i



DOSIFICACION

PESO ( CLARK ) EDAD ( YOUNG )

Koren G. (2012). Chapter 59. Special Aspects of Perinatal & Pediatric Pharmacology. In B.G. Katzung, S.B. Masters, A.J. Trevor (Eds), Basic & Clinical Pharmacology, 12e.

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Basic & Clinical Pharmacology, 12e > Chapter 59. Special Aspects of Perinatal & Pediatric Pharmacology > Pediatric DrugDosage > Surface Area, Age, & Weight >

Table 59–6 Determination of Drug Dosage from Surface Area.1

Weight

(kg) (lb) Approximate Age Surface Area (m2)

Percent of Adult Dose

3 6.6 Newborn 0.2 12

6 13.2 3 months 0.3 18

10 22 1 year 0.45 28

20 44 5.5 years 0.8 48

30 66 9 years 1 60

40 88 12 years 1.3 78

50 110 14 years 1.5 90

60 132 Adult 1.7 102

70 154 Adult 1.76 103

1 For example, if adult dose is 1 mg/kg, dose for 3-month-old infant would be 0.18 mg/kg or 1.1 mg total.

Reproduced, with permission, from Silver HK, Kempe CH, Bruyn HB: Handbook of Pediatrics, 14th ed. Originallypublished by Lange Medical Publications. Copyright © 1983 by the McGraw-Hill Companies, Inc.

Koren G. (2012). Chapter 59. Special Aspects of Perinatal & Pediatric Pharmacology. In B.G. Katzung, S.B. Masters, A.J. Trevor (Eds), Basic & Clinical Pharmacology, 12e.

ADHERENCIA

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CLASE. FARMACOTERAPIA PEDIATRIA. CFEG. 2015medicina-ucr.com/.../CLASE.-FARMACOTERAPIA-PEDIATRIA.-CFEG.-2015.pdf · FARMACOTERAPIA PEDIATRIA Dr. Carlos Fernando Estrada Garzona Departamento