# Presentation: 698342

## Developmental Pharmacology

**Scaling adult doses to infants based on body weight or surface area does not account for developmental changes that affect drug disposition or tissue/organ sensitivity.**
**Frank Balis, M.D.**
**February 22, 2007**

**Notes:**
The safe and effective use of drugs in newborns, infants, and children, requires an understanding of the effects of normal growth and development on the pharmacokinetics and pharmacodynamics of the drugs being used. 
Pediatric drug dosage regimens should take into account the age or developmental state of the child and the disease state, rather than simply scaling an adult dose based on body weight or surface area.  Failure to take these factors into account may result in ineffective treatment or severe, unexpected toxicity.
Unfortunately, there are still large gaps in our understanding of how maturational changes influence the clinical pharmacology of most drugs,  but it does seem clear that most pharmacokinetic parameters change with age.

## Chloramphenicol

**Natural product of *****Streptomyces***** (1947)**
**Inhibits protein synthesis (bacteriostatic)**
**Eliminated by glucuronide conjugation (90%) and renal excretion (<10%)**
**Nursery infections treated with high doses**

**Notes:**
I will start with an example that illustrates the importance of accounting for age-dependent developmental changes when dosing children.
Chloramphenicol was the first broad spectrum antibiotic.
It was isolated in 1947 from a species of the soil-inhabiting micro-organism, streptomyces, and was introduced into clinical practice in 1948.
It is a bacteriostatic drug that works by inhibiting protein synthesis - specifically by binding to bacterial 50S ribosomal subunits and blocking peptide bond formation.
In adults, chloramphenicol is detoxified in the liver primarily through conjugation with glucuronide and a small fraction is excreted in the urine unchanged.
Because of its broad spectrum of activity, it quickly gained acceptance and was widely use to treat a variety of infections in the 1950s, including nursery infections.
In fact, because these nursery infections were with less sensitive hospital strains, doses that exceeded the adult recommended doses on a weight basis were used in premature and full-term infants.

## Chloramphenicol in Infants

**3320 gm infant, 44 week gestation**
**Meconium stained, foul smelling, timing of ROM unknown**
**Procaine penicillin (50,00 units) + chloramphenicol (250 mg) IM q8h - 230 mg/kg/day x 72 hr**
**Day 4, gray color & cold, moist skin**
**Died at 106 hr, 8 hr after onset of vascular collapse**

**Sutherland, Am J Dis Child 97:761-7, 1959**

**Notes:**
In 1959, 10 years after the introduction of chloramphenicol, Sutherland reported 3 infants that died during the first week of life of unexplained causes.
This is one of the case histories that Sutherland reported.
Sutherland noted that the 3 neonates had all received moderately high doses of chloramphenicol. The recommended dose in the 1950s was 100-150 mg/kg/day.  This dose was based on studies performed in adults.
He suggested that the deaths may have been caused by chloramphenicol and encouraged further studies be performed in this population.

## Chloramphenicol in Premature Infants

**Burns et al., NEJM 261:1318-21, 1959**

**Premature infants born ≥24 hrs after ROM**

**Notes:**
Shortly after these anecdotal reports of apparent deaths from chloramphenicol, a study was conducted in premature infants born more than 24 h after spontaneous rupture of membranes.
These infants were usually treated empirically with antibiotics, because of the presumed increased risk for infections.
This group of premature infants had a higher mortality rate and the case reports of chloramphenicol toxicity raised the question as to whether the antibiotic was contributing to the higher mortality rate.
Infants were assigned to one of 4 groups depending on the time they were admitted to the nursery:
No antibiotics
Procaine penicillin (150,000 to 600,000 units/day) and streptomycin (50 mg/kg/d)
Chloramphenicol (100-165 mg/kg/d IM), and 
All 3 antibiotics at the same doses
The mortality was strikingly higher in the groups given  chloramphenicol.  In the no antibiotic group and the group receiving pen and strep, the mortality was <20%, but with chloramphenicol, two thirds of the infants died.
In the infants weighing more than 2000 gms at birth (good prognostic group), 45% receiving chloramphenicol died compared with 2.5% in the other 2 groups.
Other than the antibiotic regimen, there were no other obvious differences among the infants assigned to each group, leading the authors to conclude that the high mortality was related to chloramphenicol.

## Gray Baby Syndrome

**% of Infants**

- Jaundice

- Vomiting

- Anorexia

- Resp. distress

- Abd. distention

- Cyanosis

- Green stools

- Lethargy

- Ashen color

- Death

**4**

**4.1**

**4.3**

**4.5**

**4.6**

**4.7**

**5**

**5.3**

**5.7**

**Burns et al., NEJM 261:1318-21, 1959**

**Notes:**
There was a  characteristic constellation of physical signs of chloramphenicol toxicity is called the gray baby syndrome.
The graph compares the incidence of this spectrum of physical signs in the group that received no antibiotics, the group treated with Pen + strep and the combined groups that received chloramphenicol.
Other than jaundice, these physical findings occurred at a much higher rate in infants treated with chloramphenicol.
The clinical course of the chloramphenicol babies who died were strikingly similar and the symptoms appeared in a typical order.
The column of numbers on the right list the average day of life that the sign appears.
Starting with vomiting, then refusal to feed
Respiratory distress, manifested by irregular rapid respirations
This is followed by abdominal distention, periods of cyanosis, and passage of loose, green stools.
24 hrs after the onset of symptoms these infants were seriously ill. They rapidly developed flaccidity, ashen color, hypothermia, vascular collapse, and death in the fifth day of life.
58% of the infants who received chloramphenicol and survived had similar signs, which completely resolved 24-36 hrs after stopping the drug.

## Chloramphenicol Blood Levels

**Chloramphenicol Blood Levels**

**Day of Life**

**Total Nitro Compounds [μg/ml]**

**Therapeutic range**

**Chloramphenicol doses**

**Burns et al., NEJM 261:1318-21, 1959**

**Notes:**
Chloramphenicol blood levels were measured in one of the infants who died using a non-specific colorimetric method that measures total aromatic nitro compounds (drug and metabolites).
Blood levels of chloramphenicol accumulated over time at the doses used.  At the time of this infants death, blood levels were 6-fold higher than the upper limit of the therapeutic range.
Remember that the drug is cleared in adults primarily by glucuronide conjugation and this metabolic pathway is not fully developed as evidenced by the deficient glucuronide conjugation of bilirubin in infants, which is responsible for the “physiologic jaundice” that commonly occurs.
Immature hepatic function, especially in the glucuronide conjugation system, as well as decreased renal function, allowed normally safe doses (as defined in adults) to accumulate to toxic levels

## Chloramphenicol Pharmacokinetics

**Weiss et al., NEJM 262:787-94, 1960**

**Time [hr]**

**Total Nitro Compounds [μg/ml]**

**4-5 yrs. (n=3)**

**1-2 days (n=5)**

**10-16 days (n=3)**

**Notes:**
After the reports of toxicity and deaths in newborns, attributed to the use of high doses of chloramphenicol, a number of investigators studied the pharmacokinetics of the drug in newborns and children.
These are data from studies performed by Parke Davis, the company that manufactured chloramphenicol.
The company had previously circulated a letter to all physicians recommending a maximum dose of 50 mg/kg/day for full term infants and 25 mg/kg/day for premature infants, based on the available clinical and pharmacological data. They also recommended routine therapeutic drug monitoring
This study was done using the non-specific colorimetric method, which measures both parent drug and metabolites.  In this case it may be more appropriate, because some of the metabolites may have contributed to the toxicity in neonates.
In fact when results are compared with a microbial assay, there was evidence that infants had a greater proportion of metabolites circulating than adults.
This study was performed with the water-soluble succinate ester of chloramphenicol which is administered parenterally.
Three age groups were studied: 3 children 4-5 yrs of age received 50 mg/kg S.C.; 3 infants 10-16 days of age received 25 mg/kg IM; and 5 newborns 1-2 days of age received 50 mg/kg IM.
The elimination was highly age-dependent. The half-life was 26 hrs in the newborns, 10 hours in the infants and 4 hours in the children.

## Repeated Administration

**Weiss et al., NEJM 262:787-94, 1960**

**Day of Life**

**Total Nitro Compounds [μg/ml]**

**Notes:**
The blood levels of chloramphenicol were studied infants of different age and followed with multiple samples over the course of treatment.
The circles in yellow represent multiple samples from 4 different infants who were started on chloramphenicol (25 mg/kg) on day 1 to 6 of life; and the green circles represent multiple blood levels in 3 different infants who were started on the same dose of chloramphenicol on days 14 to 23 of life.
There is considerable variability, but it is clear that newborn infants have considerable higher levels than older infants.
Blood levels drop off over the first 2 weeks of life, presumably as a result of upregulation of the metabolic pathways responsible for elimination of chloramphenicol.
This occurs very rapidly and it mirrors what happens with bilirubin in the newborn, which is also eliminated by conjugation with glucuronide.

## Drug Use in Infants and Children

**Scaling adult doses based on body weight or surface area does not account for developmental changes that affect drug disposition or tissue/organ sensitivity.**
**Pharmacologic impact of developmental changes are often discovered when unexpected or severe toxicity in infants and children leads to detailed pharmacologic studies.**
**Therapeutic tragedies could be avoided by performing pediatric pharmacologic studies during the drug development process (before wide-spread use of agents in infants and children).**

**Notes:**
This therapeutic tragedy with chloramphenicol was not an isolated incident although it was one of the most severe.
It illustrates several important points;
Simply scaling adult doses based on body weight or surface area to treat children does not account for developmental changes that affect drug disposition or tissue/organ sensitivity.
Pharmacologic impact of developmental changes are often discovered when unexpected or severe toxicity in infants and children leads to detailed pharmacologic studies.
Therapeutic tragedies could be avoided by performing pediatric pharmacologic studies during the drug development process (before wide-spread use of agents in infants and children).

## Zidovudine

**Synthetic nucleoside analog**
**Inhibits HIV reverse transcriptase**
**Eliminated by glucuronide conjugation (67%) and renal excretion (33%)**
**Perinatal therapy to prevent HIV transmission**

**Notes:**
The development of zidovudine for use in infants is an example of how drugs should be studied prior to widespread use in this population.
Zidovudine is a dideoxynucleoside that was discovered on a shelf at BW
It blocks HIV replication by inhibiting reverse transcriptase.
Like chloramphenicol, it is eliminated primarily by glucuronide conjugation, so there was concern about administering this agent to newborns.
The primary indication for administration to infants was the prevention of vertical transmission of HIV.

## Zidovudine in the Newborn

**Age [weeks]**

**ZDV AUC [μg•hr/ml]**

**Boucher et al., J Pediatr 122:137-44, 1993**

**Notes:**
Prior to routine administration of zidovudine to newborns and infants born to HIV-infected mothers, the pharmacology and safety were carefully studied in:
Newborns born to mothers who had received ZDV prenatally
In 32 full term newborns treated with low, escalating doses of ZDV (phase I trial).  Low doses were used in these trials (1/3rd doses used in children)
Pharmacokinetics were also measured separately in 15 preterm newborns
In the term infants this graph shows the AUC after oral doses at varying ages. Serum concentration come down over the first 3 weeks of life. (Age is a log scale).
This drop reflects primarily an increase in drug clearance.

## Zidovudine in Newborns

**Boucher et al., J Pediatr 125:642-9, 1994**
**Mirochnick et al., Antimicrob Agents Chemother 42:808-12, 1998**

**Balis et al., J Pediatr 114:880-4, 1989**
**Klecker et al., Clin Pharmacol Ther 41: 407-12, 1987**

**Notes:**
These are the pharmacokinetics of ZDV in preterm and full term infants
The dose in the preterm infants was 1.5 to 2.0 mg/kg and in the term infants it was 2 to 4 mg/kg.
The clearance in preterm infants is slower than full term infants and the clearance increases rapidly - doubling in 2 weeks in both term and preterm infants.
CLICK. These are the PK parameters of ZDV in children over 1 yr and adults.  By 2 weeks clearance of ZDV approaches values in adults and older children.
The bioavailability in newborns is higher, presumably because of the lower level of first-pass metabolism.
Based on these PK studies + the safety at the doses administered a safe and potentially effective dose was defined for term and preterm newborns.

## Prevention of HIV Transmission

**Connor et al., NEJM 331:1173-80, 1994**

**Notes:**
Once the pharmacology and safety of zidovudine had been studied in the prenatal, perinatal setting in pregnant women and in infants, a placebo controlled, double-blind, randomized trial of ZDV conducted in HIV-infected pregnant women to determine if ZDV could block maternal-infant transmission of HIV
Mothers received 100 mg of ZDV antepartum  orally, 5 times daily, and then were started on a continuous infusion of ZDV at an infusion rate of 1 mg/kg/hr when they were admitted in labor and continuing through delivery.
Infants were treated with 2 mg/kg of ZDV orally every 6 hours for 6 weeks, beginning 8-12 hours after birth.
The Table on the left summarizes the results.  Infants were defined as being HIV-infected if they had at least 2 positive cultures.
The transmission rate from mother to child was significant reduced by administering ZDV before, during and after the delivery.
Equally important was that there were no substantial adverse events from this regimen.  In the placebo group 3/4 of the patients were not infected, so 3/4 of the infants receiving ZDV, received it unnecessarily.
The bar graph shows the mean hemoglobin level in the ZDV-treated and placebo control groups of infants.  The Hgb was lower in the treated group, but only slightly lower and by 12 weeks (6 weeks after the completion of therapy), the Hgb level was the same.
By carefully studying the safety and pharmacokinetics of this agent in infants, prior to the large randomized trial, a safe and effective dose was identified which led to a positive outcome.

## Ontogeny and Pharmacology

**Excretory organ (liver and kidneys) development has the greatest impact on drug disposition (pharmacokinetics)**
**The most dramatic changes occur during the first days to months of life**
**Anticipate age-related differences in drug disposition based on knowledge of ontogeny**
**Effect of ontogeny on tissue/organ sensitivity to drugs (pharmacodynamics) is poorly studied**
**Disease states may alter a drug’s PK/PD**

**Notes:**
Difficult to make generalizations about the effect of development on the pharmacology of drugs used in newborns, infants and children.

## Glomerular filtration rate
Low at birth
Full term newborn - 10-15 ml/min/m2
Premature - 5-10 ml/min/m2
GFR doubles by 1 week of age
Adult values by 6-12 months of age
Tubular function
Secretory function impaired at birth
Glomerulotubular imbalance
Adult values by 1 year of age

**Low at birth**
- Full term newborn - 10-15 ml/min/m2
- Premature - 5-10 ml/min/m2
**GFR doubles by 1 week of age**
**Adult values by 6-12 months of age**
**Tubular function**
**Secretory function impaired at birth**
**Glomerulotubular imbalance**
**Adult values by 1 year of age**

**Renal Ontogeny**

**Notes:**
At birth renal function is limited, because the kidney is anatomically and functionally immature.
Renal blood flow in newborns is approximately 40 ml/min/kg in newborns which is about 16% of cardiac output.  Within hours after birth there is a dramatic decrease in renal vasculature resistance and an increase in RBF.  Adult values are reached by 1 year of age.
GFR is also low at birth and the level of function is related to the post-conception age, so GFR is significantly lower in preterm infants:
Full term newborn - 10-15 ml/min/m2
Premature - 5-10 ml/min/m2
GFR doubles by 1 week of age related to the rapid decrease in renal vasculature resistance.
Adult values achieved by 1 year of age.
Tubular secretory function is also depressed at birth and there is a glomerulotubular imbalance, because of the greater maturity of glomerular function.
As a general rule, after 8 months of age, the renal excretion of drugs is comparable with that observed in older children and adults.

## Glomerular Filtration Rate

**GFR [ml/min/1.73 m****2****]**

**Age [months]**

**Aperia, Acta Pædiatr Scand 64:393-8, 1975**

**Notes:**
This is an early study that demonstrates the rapid development of renal function after birth in full term newborns.  GFR was estimated in this study using inulin clearance.
There is a steep increase during the first 2 months of life and adult levels are achieved within the first year of life.

## GFR in Infants

**GFR in Infants**

**GFR [ml/min/1.73 m****2****]**

**Age [days]**

**Guignard, J Pediatr 87:268-72, 1975**

**Notes:**
This is a similar study performed in newborns by measuring inulin clearance.  GFR approximately doubles in the first 2-4 weeks of life.
The rapid increase in GFR in early life is probably related to profound renal hemodynamic changes.

## Gentamicin in the Newborn

**Gentamicin Clearance [ml/kg•hr]**

**Creatinine Clearance [ml/kg•hr]**

**15 full term**
**23 premature**

**Koren et al., Clin Pharmacol Ther 38:680-5, 1985**

**Notes:**
For drugs such as gentamycin that are eliminated primarily by renal excretion the clearance of the drug can be correlated with renal clearance - measured using creatinine clearance in this study of 38 premature and full term newborns.
Dosing of this potentially toxic drug in premature and full term infants must be adjusted to account for the initial lower levels of renal function, but must also be adjusted to account for the rapid increase in function during the first 1-2 weeks of life.

## Gentamicin Clearance

**Gentamicin Clearance**

**Postnatal Age**

**Gentamicin Clearance [L/kg•hr]**

**Premature (<37 weeks)**

**Full term**

**Pons, Ther Drug Monit 10:421-7, 1988**

**Notes:**
This graph shows gentamycin clearance broken down by post-natal age
Just as we saw for GFR, the clearance of gentamycin is significantly lower in premature newborns than in full term babies and drug clearance increases by 50% to 100% in the first week of life.

## Phase 1 (oxidation, hydrolysis, reduction, demethylation)
Activity low at birth
Mature at variable rates
Oxidative metabolism increases rapidly after birth
Alcohol dehydrogenase reaches adult levels at 5 yrs
Activity in young children exceeds adult levels
Phase 2 (conjugation, acetylation, methylation)
Conjugation:
Glucuronidation at birth
Sulfatation  at birth
Acetylation  at birth, “fast” or “slow” phenotype by 12-15 mo.

**Activity low at birth**
**Mature at variable rates**
- Oxidative metabolism increases rapidly after birth
- Alcohol dehydrogenase reaches adult levels at 5 yrs
**Activity in young children exceeds adult levels**
**Phase 2**** ****(conjugation, acetylation, methylation)**
**Conjugation:**
- Glucuronidation at birth
- Sulfatation  at birth
**Acetylation ******** at birth, “fast” or “slow” phenotype by 12-15 mo.**

**Hepatic Ontogeny**

**Notes:**
Drug metabolizing enzymes are divided into 2 broad categories:
Phase 1 reactions are non-synthetic alterations to the drug such as oxidation, hydrolysis, reduction, demethylation.  These reactions usually reduce the activity of the drug, although active metabolites may also be formed
Phase 2 reactions are synthetic reactions such as conjugation with glucuronide, sulfate or glycine, acetylation, methylation.  These reactions almost always inactivate the drug.
The activity of most phase 1 drug metabolizing enzymes is low at birth
These enzymes systems mature at variable rates postnatally and the rate of maturation can be influenced by drug exposure in utero or after birth.
Oxidative metabolism increases rapidly after birth
Alcohol dehydrogenase reaches adult levels at age 5 years of age
After infancy phase I enzyme activity in young children can actually exceed adult levels, and drug clearance may also be more rapid in children than adults.
For phase 2 reactions, conjugation is the most important metabolic pathway:
Glucuronidation at birth
Sulfatation  at birth
Therefore, although the overall clearance rate may be similar in infants and adults, the metabolites that are formed may differ.
Acetylation  at birth, “fast” or “slow” phenotype by 12-15 mo.

## Cytochrome P450 (CYP) Enzymes

**Superfamily of Phase 1 enzymes (oxidation, demethylation)**
**Nomenclature:**
**17 Families and 39 subfamilies in humans**
**CYP1, CYP2, CYP3 are primary drug metabolizing enzymes**
**Half of all drugs metabolized by CYP3A subfamily**
**CYP3A4 is most abundant hepatic P450 enzyme and metabolizes at least 50 drugs**

**CYP3A4**

**Family (>40%)**

**Subfamily (>55%)**

**Isoform**

**Notes:**
The Cytochrome P450 superfamily of enzymes are the most important group of phase I enzymes

## CYP Ontogeny

**CYP Ontogeny**

**Kearns GL et al. NEJM 349: 1157, 2003**

## CYP2E1 Ontogeny

**Notes:**
CYP2E1 content was determined in human hepatic microsomes from samples spanning fetal (n   73, 8–37 weeks) and postnatal (n   165, 1 day–18 years) ages.
CYP2E1 in neonatal samples was low and less than that of infants 31 to 90 days of age, which was less than that of older infants, children, and young adults.
Among those older than 90 days of age, CYP2E1 content was similar.
CYP2E1 was clearly expressed in human fetal liver. Furthermore, the postnatal data suggest that infants less than 90 days old would have decreased clearance of CYP2E1 substrates compared with older infants, children, and adults.

## CYP3A Ontogeny

- <30w

- >30w

- <24h

- 1-7d

- 8-28d

- 1-3mo

- 3-12mo

- >1yr

- Adult

**Fetus**

**Postnatal Age**

**CYP3A7 Activity**

**CYP3A4 Activity**

**LaCroix D et al. Eur J Biochem 247:625, 1997**

**Notes:**
Developmentally regulated expression
16 hydroxylation of dehydroepiendrosterone used to measure CYP3A7 activity and conversion of testosterone to its 6 derivative used to measure CYP3A4 activity in fetal and neonatal livers from a liver bank.
CYP3A7 most active form of CYP3A in the fetus and peaked during first week of life before progressively declining to very low levels of activity in the adults liver.
CYP3A4 very low in fetus.  Reached 30-40% of adult levels by 1 month of age.
Using a substrate catalyzed by both enzymes (pentoxyresorufin), overall CYP3A activity remains nearly constant.

## Acetaminophen Metabolism

**Acetaminophen Metabolism**

**Miller et al., Clin Pharmacol Ther 19:284-94, 1976**

**% of Dose**

**Notes:**
Oral dose of 10 mg/kg
70 to 80% of the dose was recovered as drug or metabolite in the urine
<4% of the dose was excreted as unchanged drug
There were significant age-related differences in the amounts of two conjugated metabolites.  A higher proportion of the dose was excreted as the sulfate conjugate in newborns and to a lesser extent in young children.
In adults the glucuronide conjugate is the primary urinary metabolite.
Despite these quantitative differences in the metabolic pathways used to inactivate the drug, the overall elimination rate constants for the parent drug did not show any significant age-related differences.
Therefore in this case sulfate formation compensated for the deficiency in glucuronide conjugation.

## Theophylline Urinary Metabolites

**% Recovered in Urine**

**Post-conception Age**

**Age Range**

**Notes:**
Theophylline passes through age-dependent routes of metabolism in children.
In premature neonates, over 50% of the drug is excreted unchanged in the urine.
Theophylline is also N-methylated to caffeine in infants and in adults, but the elimination of caffeine is delayed in newborns (t1/2 of 100 hr vs. 4 hr in adults).  Therefore, caffeine is detectable in the serum and urine in newborns, but by 6 months to 1 year of age caffeine is metabolized more rapidly and is no longer measurable.
The metabolism of theophylline in the liver by P450 enzymes increases during infancy.
By 2-3 years of age the fraction of theophylline excreted unchanged in the urine has dropped to 15%.
CLICK. This is the overall clearance of theophylline (renal + metabolic).  It is markedly delayed in newborns and children have a clearance that is 40% higher than adults when normalized to body weight.

## Factors Affecting Drug Distribution

**Physicochemical properties of the drug**
**Cardiac output/Regional blood flow**
**Degree of protein/tissue binding**
**Body composition**
**Extracellular water**
**Adipose tissue**

**Notes:**
Factors that affect drug distribution include:
Physicochemical properties of the drug - lipid vs. water solubility
Cardiac output/Regional blood flow - only an issue during the first hours of life
Degree of protein/tissue binding - determines the concentration of free drug
Body composition
Extracellular water
Adipose tissue

## Ontogeny of Body Composition

**Ontogeny of Body Composition**

**% of Total Body Weight**

**EC H****2****O**

**IC H****2****O**

**Protein**

**Other**

**Fat**

**Kaufman, Pediatric Pharmacology (Yaffe & Aranda, eds) pp. 212-9, 1992**

**Notes:**
The relative and absolute amount of body water and fat have been studied in different age groups and is summarized in this graph.
In the fetus and premature infant, water makes up 85-90% of body weight and 60% of body weight is extracellular fluid.  <5% of the body is fat.
In a full term infant water makes up 75% of body weight and fat is 15%.  With the rapid weight gain that occurs during the first year, the fat fraction increases to 25%, but falls thereafter when infants start walking and become more active.
Total body water reaches adult levels by 6 months of age, but there is a more gradual shift of water from the extracellular to intracellular compartment.  ECF reaches the adult value of 20% of body weight by puberty.
Developmental changes in the relative size of body water and fat compartments will affect the volume of distribution of drugs, depending on whether the drug is water soluble or lipophilic.  Water soluble drugs will have a larger volume of distribution in infants when normalized to body weight.
In order to achieve comparable plasma and tissue concentrations of drugs distributing into the extracellular fluid, higher doses per kilogram of body weight must be given to infants and children compared to adults.

## Volume of Distribution of Sulfa

**Volume of Distribution [L/kg]**

**Routledge, J Antimicrob Chemother 34 Suppl A:19-24, 1994**

**Notes:**
Water soluble antibiotics, like sulfisoxazole have a larger volume of distribution because of the greater proportion of the body that is water in the newborn and infant.

## Tissue and Organ Weight

**Notes:**
This table breaks down body composition by organ or tissue - relating the fraction of body weight that each comprises in the fetus, newborn and adult. 
The excretory organs (liver and kidney) are relatively larger in the infant, but the most striking difference is the size of the brain, which is disproportionately larger by a factor of about 5-fold in the newborn, compared to the adult.
With a specific form of regional therapy - the direct injection of drug into the intrathecal space - this disproportionate size in CNS compartment had a quantifiable affect on drug concentrations achieved in the CSF.

## Plasma Proteins

**Notes:**
Consequences of protein binding of drugs
The degree of drug binding to plasma proteins is inversely related to the Vd (keeps drugs in the vascular compartment)
Affects the rate of renal clearance (only free drug is filtered)
Affects the amount of drug reaching the target site (proportional to the free drug concentration)
Plasma proteins which bind drugs are low at birth compared to adults, but reach adult levels by the 3rd year of life for acidic drugs, but not until the 5th-7th year of life for basic drugs because of lower globulin levels.
Acidic drugs are usually bound to albumin, whereas basic drugs bind to 1-acid glycoprotein or globulins
The binding properties of fetal albumin are similar to those of the adult form.
Higher levels of free fatty acid and bilirubin (bound to albumin) in newborns can also lower the fraction of drug that is bound to plasma proteins.

## Protein Binding in Cord and Adult Plasma

**Kurz et al., Europ J Clin Pharmacol II:463-7, 1977**

**Notes:**
Because of the lower levels of most proteins, protein binding of most categories of drugs is reduced in the newborn compared to adults.
Although the absolute differences in the fraction of drug bound may be only 10-20%, for highly bound drugs this could make a substantial difference in the concentration of free drug in plasma.
CLICK. For example the free fraction of promethazine is 2-fold higher in cord blood.
The differences in binding also influences our interpretation of plasma or serum drug levels.  When we perform therapeutic drug monitoring we usually measure total serum or plasma drug concentration, but if the free drug concentration is higher in newborns, the therapeutic and toxic levels must be proportionally lower.

## CSF MTX and Age

**Time [days]**

**CSF Methotrexate [μM]**

**Bleyer, Cancer Treat Rep 61:1419-25, 1977**

**Notes:**
Dr Bleyer measured CSF MTX levels at varying times after an intrathecal dose of 12 mg/m2, which was the standard method of calculating the dose.
When these levels are plotted relative to age, which is shown on this graph, a dose based on surface area (12 mg/m2), high levels tended to occur in adults (white), intermediate levels in adolescents (yellow), and low levels in children (green).

## CNS Growth and Development

**Age [yrs]**

**Adult Value [%]**

**CNS Volume**

**Body Surface Area**

**Bleyer, Cancer Treat Rep 61:1419-25, 1977**

**Notes:**
The physiologic reason for this age discrepancy relates to the differences in the rate of growth of the brain relative the rest of the body.
Intrathecally administered drug is distributed in the CSF - this reaches 80% of the adult volume by 3 years of age, while the BSA increase at a slower rate.
Young children receive a lower dose relative to their CNS volume when dose is calculated from body surface area. In adults we continue to increase dose as their surface area increases despite the fact that their CNS volume reached a maximum years before.

## Adaptive IT MTX Dosing Regimen

**Bleyer, Cancer Treat Rep 61:1419-25, 1977**

**Notes:**
A new pharmacokinetically guided, age-based dosing schedule was devised to account for inability of body surface area to correlate with CNS volume. All patients 3 years of age and older receive the same dose 12 mg. When this schedule was instituted the CSF MTX levels were much less variable.

## Dose Change with Adaptive Regimen

**Age [yrs]**

**% Change in Dose**

**Adaptive dose**

**12 mg/m****2**** dose**

**X 100**

**Bleyer, J Clin Oncol 1:317-25, 1983**

**Notes:**
This graph depicts the change in dose using the new adaptive dosing schedule vs. the old 12 mg/m2 schedule. The dose is increased in young children- in some by 50%. and is lower in patients older than 10 years.

## Effect of Adaptive IT Dosing on Outcome

**Incidence of**
**CNS Relapse**
**[%]**

**MTX Dose Based on BSA**

**MTX Dose Based on Age**

**Age [months]**

**Concurrent**

**Isolated**

**0**

**10**

**0**

**10**

**20**

**<18**

**18-35**

**36-83**

**84-119**

**≥****12**

**Bleyer, J Clin Oncol 1:317-25, 1983**

**Notes:**
The new dosing regimen was instituted in the CCG 160’s series of leukemia studies. After the completion of these trials the CNS relapse rates were compared with those from prior trials which used the old dosing method  (based on BSA).
CNS relapse rate is presented in these graphs divided into age groups from the 160’s studies and the prior set of studies.
As can be seen on the prior study the relapse rate was age dependent and higher in the lower age groups. With the new schedule the overall relapse rate was significantly lower and the age-relationship was gone. The new regimen had a significant impact on the efficacy of intrathecal MTX.

## Dosing Based on Body Surface Area

**BSA = 2-dimensional surface area of the skin**
**Estimated from formulas using weight & height**
**Correlation between BSA and kidney/liver function is weak**
**BSA dosing evolved from scaling doses from animals to humans (toxicology)**

| Species | Wt [kg] | BSA [m2] | Dose [mg] | Dose [mg/kg] | Dose [mg/m2] |
| --- | --- | --- | --- | --- | --- |
| Mouse | 0.018 | 0.0075 | 0.027 | 1.5 | 3.6 |
| Rat | 0.25 | 0.045 | 0.125 | 0.5 | 2.8 |
| Infant | 8 | 0.4 | 1.25 | 0.15 | 3.1 |
| Child | 20 | 0.8 | 2.5 | 0.12 | 3.1 |
| Adult | 70 | 1.85 | 5.0 | 0.07 | 2.7 |

**Pinkel, Cancer Res 18:853, 1958**

**Notes:**
Table is MTX dosing. Doses are from the literature for animals and”generally accepted” for humans
Also looked at MP, mechlorethamine, actinomycin D and thiotepa.
Dose more uniform across species and sizes of humans when normalized to BSA than per kg.
The PETA principle (rat is a boy is a dog)
Use of BSA to scale the dose is based on the belief that physiologic parameters relevant to drug metabolism and elimination, such as the basal metabolic rate, renal and hepatic function and cardiac output, scaled among individuals according to surface area.

## Liver Function (Children)

**Murry et al. Drug Metab Disp 23:1110, 1995**

**BSA [m****2****]**

**Liver Vol [ml]**

**r****2****=0.75**

**AP CL [ml/min]**

**r****2****=0.04**

**Notes:**
Antipyrine clearanceby oxidative metabolism (up to 6 CYP enzymes involved).

## Excretory Organ Growth

**Age [yr]**

**Liver [g]**

**Kidney [g/m****2****]**

**Kidney [g/kg]**

**Kidney [g]**

**Liver [g/m****2****]**

**Liver [g/kg]**

**Notes:**
Generated from growth charts and normal organ weights from autopsy series.

## Body Weight :Surface Area

**Age [yrs]**

**Weight**
**BSA**

**Adult**
**1 mg/kg = 40 mg/m****2**
**Dose = 70 mg**

**1 y.o.**
**1 mg/kg = 10 mg**
**40 mg/m****2**** = 18 mg**

**Notes:**
This graph depicts the relationship between weight and BSA - the ratio of Weight to BSA.
Body surface area is greater relative to weight in small individuals. With growth, weight increases at a more rapid rate than the BSA in children.
Many physiologic parameters such as cardiac output, respiratory metabolism, blood volume, ECF volume, GFR, and RBF are better correlated with BSA than weight.
Clinical experience has shown that dosing according to BSA results in more uniform serum drug concentration across a broad age range.
Doses developed in adults or older children that are normalized to weight will result in a lower absolute dose in infants than doses normalized to BSA.

## Anticancer Drug Clearance

**McLeod et al., Br J Cancer 66 (Suppl. 18):S23-S29, 1992**

## Vincristine Clearance

**Vincristine Clearance [ml/min/****m****2****]**

**Vincristine Clearance [ml/min/****kg****]**

**Crom et al., J Pediatr 125:642-9, 1994**

**Notes:**
Dose based on BSA may not be the best method for every drug.
Vincristine is an anticancer drug that produces peripheral neuropathy as its primary dose-limiting toxicity.
In clinical trials the youngest patients appeared to be more susceptible to this toxicity.
The clearance of this drug in infants is compared to older children in these 2 graphs - normalized to BSA on the left and to body weight on the right.
In this case, the clearance based on BSA was lower in infants so dose based on BSA would result in higher plasma concentrations which would in turn explain the greater toxicity.
Infants are now routinely dosed based on body weight, which results in a lower dose  and they tolerate the drug better.

## Etoposide Clearance

**Etoposide**
**Clearance**
**[ml/min/****m****2****]**

**Etoposide**
**Clearance**
**[ml/min/****kg****]**

## Doxorubicin Clearance

**Doxorubicin**
**Clearance**
**[ml/min/****m****2****]**

**Doxorubicin**
**Clearance**
**[ml/min/****kg****]**

## Oral Busulfan (16-30 mg/kg)

**Engraftment**

**Graft rejection**

**Age [yrs]**

**Busulfan C****ss**** [ng/ml]**

**Slattery et al., ****Bone Marrow Transplant 16:31, 1995**

**Notes:**
Dose 16 to 30 mg/kg
Circles grade 0 toxicity, squares grade 1, diamonds grade 2, upright triangles grade 3, and upside down triangles grade 4 regimen related toxicity.
Age-dependent clearance of busulfan also has a direct impact on clinical outcome for this anticancer drug.  Orally administered busulfan is a bifunctional alkylating agent that is an important component of bone marrow transplant preparative regimens.
In children <5 years of age, the apparent clearance of busulfan is 2-3 fold higher than it is in adults, due to enhanced glutathione conjugation (primary route of elimination) in children . 
As a result, the steady state plasma concentrations of busulfan are lower in young children, and the incidence and severity of busulfan-related toxicity was also lower, but the graft rejection rate was significantly higher.
Glutathione conjugation is primary elimination route

## Drug Clearance in Cystic Fibrosis

**Clearance [ml/min•m****2****]**

**Renal**

**Hepatic**

**Rey, Clin Pharmacokinet 35:313-29, 1998**

**Cystic Fibrosis**

**Controls**

**Notes:**
Cystic fibrosis is a multisystem inherited disorder that can effect major organs associated with drug disposition, including the GI track, pancreas, heart, liver and kidney.
The PK of many drugs are altered in patients with CF, and, surprisingly, plasma concentrations are usually lower.
Increased rates of clearance for a variety of drugs - both renally excreted and hepatically metabolized.
The precise mechanism has not been identified
The studies have resulted in dose recommendations in CF patients:
20-30% higher doses of beta-lactams and dose adjustments of aminoglycosides based on TDM.

## Retinoids

|  | ≤12 Yr. | >12 Yr | Adult |
| --- | --- | --- | --- |
| ATRA |  |  |  |
| MTD | 60 mg/m2/d | 90 mg/m2/d | 150 mg/m2/d |
| DLT | Pseudotumor cerebri | HA and PC | Dermatologic |
| 9-cis-RA |  |  |  |
| MTD | 35 mg/m2/d | 85 mg/m2/d | 140 mg/m2/d |
| DLT | Pseudotumor cerebri | HA and PC | HA, diarrhea, dermatologic |

## Conclusions

**Infants (esp. newborns) may have reduced capacity to eliminate drugs**
**Anticipate the effects of ontogeny on drug disposition based on route of elimination**
**More systematic pharmacokinetic studies of drugs in infants are needed**
**Tissue sensitivity to the toxic effects of drugs may be age-dependent**