Chapter 24 Clinical Applications of Pharmacokinetics

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Pediatric Considerations

The physiologic processes that determine drug disposition undergo radical changes during biological maturation (Morseli 1976, Rane and Wilson 1976, and Shirkey 1973). Thus, the processes of drug absorption, distribution, metabolism, and excretion are modified throughout infancy and childhood. These changes mean that a) drug disposition both changes during maturation and differs from biological norms, and b) a large inter patient variability in drug disposition is observed for many drugs in this patient population.

Further complications are that little data is available concerning the disposition of drugs in infants before the general release of new drugs. Also studies in infants and young children are difficult to perform because of the limited amount of sample which can be collected. The most dramatic changes occur in the first year. For children older than one year, dose adjustments can often be made on a weight or surface area basis without too many problems.

Pharmacokinetic changes

Absorption

Infants after the newborn period have a relative achlorhydria; with gastric acid secretions increasing to reach adult levels at age 3. The bioavailability of acid labile penicillins is increased in newborns.
Delayed gastric emptying and irregular intestinal peristalsis leads to slower absorption of some drugs in infants and young children.

Distribution

Total body water as a fraction of body weight decreases throughout the first year of life (see the Table 24.3.2).

Extravascular fluid is proportionately higher at an earlier age as well. In general distribution volumes expressed as volume per body weight tend to be larger in neonates than in adults and decrease towards adult values during childhood. This has been observed for ampicillin, ticarcillin, and amikacin. Binding to plasma proteins appears to be less in newborn infants compared with older children and adults. This appears to be true for both acidic and basic drugs. The presence of competing substances, such as bilirubin in premature infants, complicates the picture.

Metabolism

The various pathways of drug metabolism mature at different rates, and therefore the ability of the newborn to metabolize drugs differs both quantitatively and qualitatively from that of older subjects. No general rules can be developed and a few examples can illustrate the variety of effects observed.

Caffeine is very slowly metabolized in newborns. During the first month almost no metabolism occurs, with half-lives of about 4 days resulting from renal elimination, normally a minor pathway. Between 3 and 7 months, caffeine is metabolized similarly to adults and the half-lives change to adult values during this period. For the similar compound theophylline the half-life was 13 to 29 hours for 8 low birth weight infants. See Hale (2004) p112-3.

Glucuronidation is quite inefficient at birth, thus chloramphenicol which is normally glucuronidated in adults and has no major alternate metabolic pathway, the overall elimination is much slower in newborns compared with adults.

Sulfate conjugation is well developed at birth thus newborn acetaminophen elimination, predominantly sulfation, is not greatly different from that of adult elimination.

For drugs which undergo M-M or saturable metabolism the effect of age is interesting. For phenytoin, Km is not changed with age, but the maximum metabolism rate, Vm falls progressively with younger patients.

Excretion

Glomerular filtration and renal tubule function in premature infants and newborns is somewhat immature. GFR, normalized for body surface area, increases gradually reaching adult values at about 6 months.

Table 24.3.1 Glomerular Filtration Rate at Various Ages
Age GFR (ml/min/m2)

First four days 1

14 days 22

One year 70

Adult 70

Table 24.3.1 Glomerular Filtration Rate at Various Ages
Age	GFR (ml/min/m2)
First four days	1
14 days	22
One year	70
Adult	70

Renal tubular capacity, measured by renal clearance of p -aminohippurate, achieve adult values 1 to 2 months later. Therefore drugs which depend primarily on the renal route of elimination, such as gentamicin, ampicillin, and furosemide, have prolonged elimination times in neonates and young infants.

Table 24.3.2 Physiologic Differences between Neonates and Adults of Pharmacokinetic Importance (Hilligoss 1980)
	Neonate	Adult
Gastric acid output (mEq/10kg/hr)	0.15	2
Gastric emptying time (min)	87	65
Total body water (% of body weight)	78	60
Extracellular water (% of b.wt.)	44	19
Intracellular water (% of b.wt.)	34	41
Adipose tissue (% of b.wt.)	12	12-25
Serum albumin (gm/dL)	3.7	4.5
Glomerular filtration rate (ml/min/m²)	11	70

Table 24.3.3 Pharmacokinetic Parameter Values for Infants and Children compared with Adult values (Miles 1983)
Age group Volume term
(L/kg) Half-life
(hr) Total body clearance
(ml/min/kg)

Theophylline

Premature neonates 0.62
(0.19-1.0) 26.9
(14.4-57.7) 19
(6.3-29.9)

Infants 0.44
(0.16-0.83) 4.6
(0.8-8.6) 76
(28-156)

Children 0.44
(0.20-0.68) 3.4
(1.9-8.5) 95
(60-221)

Adults 0.47
(0.33-0.72) 5.7
(2.9-8.3) 65
(32-131)

Gentamicin Vc CL (ml/min/1.73 m2)

Preterm infants and full-term infants 0.48 5.7 21.0

Infants and children 0.28 1.4 130

Adults 0.21 2.1 95

Chloramphenicol Vd CL (ml/hr/kg)

Infants (11-56 d) 10

Infants (1-12 mo) 0.90 5.5 50-400

Children (1-11 yr) 0.90 4.4 100-400

Adults 0.4-0.9 2-5 100-300

Table 24.3.3 Pharmacokinetic Parameter Values for Infants and Children compared with Adult values (Miles 1983)
Age group	Volume term (L/kg)	Half-life (hr)	Total body clearance (ml/min/kg)
Theophylline
Premature neonates	0.62 (0.19-1.0)	26.9 (14.4-57.7)	19 (6.3-29.9)
Infants	0.44 (0.16-0.83)	4.6 (0.8-8.6)	76 (28-156)
Children	0.44 (0.20-0.68)	3.4 (1.9-8.5)	95 (60-221)
Adults	0.47 (0.33-0.72)	5.7 (2.9-8.3)	65 (32-131)
Gentamicin	Vc		CL (ml/min/1.73 m2)
Preterm infants and full-term infants	0.48	5.7	21.0
Infants and children	0.28	1.4	130
Adults	0.21	2.1	95
Chloramphenicol	Vd		CL (ml/hr/kg)
Infants (11-56 d)		10
Infants (1-12 mo)	0.90	5.5	50-400
Children (1-11 yr)	0.90	4.4	100-400
Adults	0.4-0.9	2-5	100-300

Dosing recommendations

For some drugs detailed pharmacokinetics development of dosage regimens for pediatric patients is not practical. Either there isn't enough good data to make an accurate estimate of dose regimen or there is too much intra- patient variability in parameter values. Alternately, dosage regimens can be determined from various reference texts such the Pediatric Dosage Book. For very young infants and neonates the primary literature should be consulted.

For older children minimal adjustments can be based on weight, surface body area, or age.

Dosing based on weight, e.g. per mg doses or Clark's rule

Equation 24.3.1 Clarks' Rule
Dosing based on surface area, e.g. per m²
Dosing based on age, e.g. Young's rule for children older than 2 years

Equation 24.3.2 Young's Rule

References

Morseli, P.L. 1976 Clinical pharmacokinetics in neonates, Clin. Pharmacokin., 1, 81-98
Rane, A., and Wilson, J.T. 1976 Clinical pharmacokinetics in infants and children. Clin. Pharmacokin., 1, 2-24
Shirkey, H.C. 1973 Pediatric Dosage Handbook, Amer. Pharm. Assoc., Washington, DC
Hilligoss, D.M. 1980 Chapter 5 "Neonatal Pharmacokinetics" in Applied Pharmacokinetics, Evans, W.E., Schentag, J.J., and Jusko, W.J. ed., Applied Therapeutics, San Francisco, CA Table 1, p 88
Miles, M.V. 1983 "Pediatric Pharmacokinetics" in Applied Clinical Pharmacokinetics, ed Mungall, D.R., Raven Press, New York, NY, pp 367-388
Taketomo, C.K., Hodding, J.H. and Kraus, D.M. 2004 Lexi-Comp's Pediatric Dosage Handbook, 11th ed., Lexi-Comp., Hudson, OH
Hale, T.W. 2004 Medications and Mother's Milk, 11th ed., Pharmasoft Publishing, Amarillo, TX

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