Geriatric,obese and pediatric patients Pharmacokinetics

1. Geriatric, obese, an pediatric
patients PK

2. • The biggest issue in PK/PD and drug therapy is
variability in response.
• Variability factors that affect pharmacokinetics
and pharmacodynamics influence clinical trials
and dose regimen designs.
• The term “population” pharmacokinetics is used
to emphasize that the PD response can be quite
different dependent on the demographic of the
subjects.

3. • A population approach refers to the many
factors that influence PK/PD as both
– intrinsic factors
• age, gender, race, weight, height, disease, genetic
polymorphism, and organ impairment
– extrinsic factors
• drugs (interaction), tobacco, alcohol, and food habits.

4. APPLICATION OF PHARMACOKINETICS
TO THE GERIATRIC PATIENTS
• Aging is a complex and multifactorial process that
is an outcome of the accumulation of various
functional deficits of multiorgan systems
occurring over time at varying rates.
• Due to the expected increase in the aging
population, it may be advisable to divide the
older population into 3 subgroups:
– young-old, age 65–75 years;
– old, age 75–85 years; and
– old-old, age ≥85 years,

5. • Drug therapy is an important medical intervention for the
care of older patients.
• Persons aged 65 and older are the most medicated group
of patients and receive the highest proportion of
medications
• Older patients usually have more disease burden and thus
take multiple drug therapies that result in polypharmacy.
• Polypharmacy can cause multiple drug interactions and
results in adverse drug events

6. • Understanding the effect of aging on
pharmacokinetics and pharmacodynamics is
important since it can help
– maximize the therapeutic effects and
– minimize the adverse effects of medications for
better care of older patients.

7. Effects of Age on Pharmacokinetics in
Older Adults
• Drug Absorption
• Gastrointestinal. The most common route of drug
administration is oral.
• Aging results in many physiological changes in the
gastrointestinal tract such as increased gastric pH, delayed
gastric emptying, decreased splanchnic blood flow,
decreased absorption surface, and decreased
gastrointestinal motility.
• Despite these changes, drug absorption upon oral
administration does not appear to alter in advancing age
especially for drugs that show passive diffusion-mediated
absorption

8. • Transdermal.
• Age-related changes in hydration and lipids result
in increased barrier function of the stratum
corneum for relatively hydrophilic compounds.
• Highly lipophilic chemicals may be able to
dissolve readily into the stratum corneum even
when the available lipid medium is reduced.

9. • Transdermal absorption of fentanyl was
suggested to be reduced in the older patients
resulting in dose adjustments, whereas
transdermal absorption of buprenorphine is
little affected because of age (Vadivelu and
Hines, 2008).

10. • Subcutaneous.
• Subcutaneous drug absorption is through the
vascular capillaries and lymphatic channels.
• The skin blood supply and lymphatic drainage
change with age (decrease)
• Thus, subcutaneous absorption of drugs may be
affected with aging and has clinical
consequences.

11. • Pulmonary.
• Lung anatomy and physiology change with age.
• Older individuals show
– a decrease of the alveolar surface,
– a variation of lung elasticity,
– a decrease of the alveolar capillary volume combined
– with a decline of the ventilation/perfusion ratio,
– decrease of the pulmonary diffusion capacity for carbon monoxide,
• Thus, age is an important parameter that affects the
pharmacokinetics of inhaled drugs

12. • the concentrations of isoflurane and
sevoflurane (inhalation anesthetic drugs)
necessary to maintain adequate depth of
anesthesia are less in older age
• There has been very little research for the
pharmacokinetic and pharmacodynamic
characteristics of new inhaled drugs in older
patients

13. • Drug Distribution
• Factors such as
– plasma protein concentration,
– body composition,
– blood flow,
– tissue-protein concentration, and
– tissue fluid pH are important for drug distribution.
• Of these factors, the changes in plasma protein
concentration and in body composition are the two
major factors of aging on drug distribution

14. • the blood albumin concentration is about 10% lower in
older people
• but α1-acid glycoprotein is higher in older people
(McLean and Le Couteur, 2004)
• Also these changes in plasma proteins may not affect
the clinical exposure of a patient to a drug. Thus, no
adjustments in dosing regimens may be necessary in
general except in rare case of a drug with a high
extraction ratio and narrow therapeutic index such as
such as intravenous dosing of lidocaine

15. • With advancing age, the decrease in lean body
mass includes a decrease in total body water.
The total body water for an 80-year-old is
10%–20% lower than a 20-year-old (Vestal,
1997; Beaufrère and Morio, 2000).
• Thus, the distribution volume of hydrophilic
drugs such as digoxin, theophylline, and
aminoglycosides will decrease with aging

16. • With advancing age, in contrast, body fat is
18%–36% higher in men and 33%–45% higher
in women (Vestal, 1997; Beaufrère and Morio,
2000).
• This increase in body fat may provide partial
explanation for the increase in volume of
distribution for lipophilic drugs such as
benzodiazepines (Greenblatt et al, 1991).

17. • Drug Metabolism
• Phase I metabolism is primarily catalyzed by
enzymes of the cytochrome P450
monoxygenase system (CYP450), and the key
members in this family of drug-metabolizing
isozymes are CYP3A, CYP2D6, CYP2C9,
CYP2C19, CYP1A2, CYP2B6, and CYP2E1.

18. • Hepatic drug clearance via CYP metabolism
that is studied for many drugs in older
individuals is either unchanged or modestly
decreased with reductions in clearance
reported to be in the range of 10%–40%.

19. • The clearance of two CYP3A substrates,
amlodipine and erythromycin, was evaluated in
the old and old-old frail as well as nursing home
patients and was not changed compared to
younger individuals in these patient groups (Kang
et al, 2006; Schwartz, 2006).
• However, a study of old-old patients and nursing
home residents showed that the oral clearance of
atorvastatin, a CYP3A substrate, decreased in
men (Schwartz and Verotta, 2009).

20. • Phase II drug metabolism does not seem to
change with age based on the following
studied reactions and prototype substrates
(Benedetti et al, 2007):
• Glucuronidation—lorazepam, oxazepam, and
acetaminophen
• Sulfation—acetaminophen
• Acetylation—isoniazid and procainamide

21. • The liver undergoes many changes with aging that includes
– reduction in blood flow and size of the liver.
• The reduction in blood flow suggests a reduction in
clearance of high extraction ratio or nonrestrictively cleared
drugs.
• It is more difficult to interpret the effect of changes in liver
size on drug clearance (McLean and Le Couteur, 2004).
• In general, the reduction of drug metabolism with
advancing age appears modest.

22. • Drug Excretion
• Renal drug clearance is the most consistent and predictable age-
related change in pharmacokinetics.
• Renal function including
– renal blood flow,
– glomerular filtration rate (GFR; measured as mean inulin clearance
decreased
– active renal tubular secretory processes,
• all decline with increasing age
• Renal tubular reabsorption also decreases, at least measured as
glucose reabsorption,

23. • The Cockcroft–Gault (CG) equation for
creatinine clearance as GFR estimate
(Cockcroft and Gault, 1976):

24. • Serum creatinine concentration is a common
endogenous glomerular filtration marker in
clinical practice.
• Lean muscle mass declines at a rate of about
1% a year after 30 years of age with multiple
causes

25. • For renally impaired patients, the age-associated
decrease in creatinine production may
significantly blunt an increase of serum creatinine
concentration despite a marked decrease in the
GFR and creatinine clearance.
• Thus, serum creatinine concentration alone may
lead to serious errors in assessing the severity of
renal disease in the older population.

26. • Drugs that are eliminated primarily via glomerular
filtration, including aminoglycoside antibiotics, lithium,
and digoxin, have an elimination clearance that
decreases with age in parallel with the decline in
measured or calculated creatinine clearance
• The renal clearance of drugs undergoing active renal
tubular secretion also decreases with aging. For
example, the decrease in renal tubular secretion of
cimetidine parallels the decrease in creatinine
clearance in older patients

27. • studies showed that aging itself may have a
minor effect on kidney function but the
confounding factors such as hypertension and
chronic heart diseases account for the decline
of kidney function

28. APPLICATION OF PHARMACOKINETICS
TO THE OBESE PATIENTS
• Obesity, defined as body mass index (BMI) of
30 or higher, has been recognized as a
“disease” in 2013 by the American Medical
Association, requiring a range of medical
interventions to advance treatment and
prevention

29. Pharmacokinetic Changes in Obesity
• Absorption
• Information currently available on the
absorption and bioavailability of medications
in the obese population is scarce and
inconclusive.

30. • Distribution
• Drug distribution, measured as volume of
distribution (VD), is influenced by
– the size of the tissue,
– tissue perfusion,
– plasma protein binding,
– tissue membrane permeability, etc (Rowland and
Tozer, 2011).
• Thus, the volume of distribution for many drugs
may be increased in the obese population.

31. • Renal Elimination
• The size of the kidney,
• renal plasma flow, and
• urine flow rate
• may influence the function of the kidney.

32. • Renal clearance is increased in the obese
patients due to increased glomerular filtration
and tubular secretion.
• vancomycin (Bauer et al, 1998), daptomycin
(Dvorchik and Damphousse, 2005), and
enoxaparin
• procainamide, ciprofloxacin, and cisplatin

33. Dosing Considerations in the Obese
Patients
• based on the findings from the
pharmacokinetic studies, principles of drug
dosing for the obese patients may be adopted
to calculate loading dose and maintenance
dose.

34. • A. Loading dose
• The loading dose is primarily based on VD.
• In general, the weight used to calculate the loading dose depends
on how the drug is distributed in the lean and fat tissues in the
body.
• If the drug is primarily distributed into the lean mass, IBW will be
used to calculate the loading dose.
• In contrast, if the drug is largely distributed into the fat tissues, TBW
will be used.

35. • B. Maintenance dose
• The maintenance dose primarily depends on drug clearance (Cl).
• equations to estimate glomerular filtration rate (GFR) are
Cockcroft–Gault (CG) equation
• To estimate Clcr by the CG equation, it is recommended to use
– TBW in underweight patients,
– IBW in patients with normal weight, and
– adjusted body weight for overweight, obese, and morbidly obese
patients

36. Example Estimating Creatinine
Clearance in Obesity
• A 50-year-old female, BT, was admitted to the
hospital with sepsis. Her height is 5 feet and 5
inches, and weight was 350 lb. Her serum
creatinine is 1.2 mg/dL. The team has decided
to start BT on an antibiotic regimen.

37. • Her TBW in kilogram = 350 (lb)/2.2 (lb/kg), which
is 159.1 kg
• Her height in centimeter (cm) = 65 (inches) × 2.54
(cm/inch), which is 165.1 cm
• Her BMI = 58.4 kg/m2 (She is morbidly obese)
• It is recommended to use adjusted body weight
to estimate Clcr from the CG equation for
patients who are overweight, obese, or morbidly
obese.

38. • In order to calculate Adj. BW, IBW needs to be
calculated first,
• IBW = 45.5 + 2.3 × [Height (inches) – 60] kg
• Her IBW = 57 kg
• Adj. BW = IBW + 0.4 × (TBW – IBW) kg
• Her Adj. BW = 97.8 kg
• Clcr (mL/min) = [(140-age) × (Weight in kg)]/[72 ×
serum creatinine] × 0.85
• Her estimated Clcr = 87 mL/min

39. APPLICATION OF PHARMACOKINETICS
TO THE PEDIATRIC PATIENTS
• Pediatric subjects are not miniature adults,
• nor belong to a homogeneous population as their
anatomical development and physiological
functions vary depending on their age brackets.
• Therefore, the pharmacokinetic characteristics of
medications differ among pediatric
subpopulations.

41. • When dosage guidelines are not available for a drug,
empirical dose adjustment methods are often used.
• Dosage normalized based on the child’s age or body
weight from adult drug dosages was used through the
Young’s rule
• [Adult Dose × (Age ÷ (Age + 12)) = Child’s Dose]
• and Clark’s rule
• [Adult Dose × (Weight ÷ 150) = Child’s Dose],
respectively.

42. • However, these dosages are rough estimates and often
inadequate to reflect the developmental and
physiological differences that lead to pharmacokinetic
consequences among the pediatric subpopulations, as
well as between pediatric and adult populations.
• Therefore, pediatric subjects should not be considered
as small adults in the aspect of pharmacokinetics.
Pediatric drug use information should be consulted in
the product label’s Use in Specific Populations
subsection.

43. Absorption
• In neonates, the gastric pH is >4, and gastric emptying and
intestinal transit are faster and irregular with immature
biliary function (Murphy, 2012).
• In infants, the pH is 2–4 with increasing emptying and
transit time, but biliary function is near the adult pattern.
• In children, the emptying and transit time is still increasing
up to 4 years of age to mature, but pH and biliary function
are similar to those of adults (Kearns et al, 2003).

44. • As a consequence, the higher pH in neonates
and infants result in higher bioavailability (F)
of acid-labile drugs, such as penicillin G,
ampicillin, and nafcillin,
• but lower F of phenobarbital (weak acid) that
may require a higher dose as compared to
those for children and adults (O’Connor et al,
1965; Sliverio and Poole, 1973; Morselli,
1977).

45. • The fast GI transit reduces the rate and extent
of absorption in neonates, infants, and young
children.
• The neonates are difficult to absorb fat-
soluble vitamins compared to infants and
children due to the immature biliary function
(Heubi et al, 1982).

46. Drug Distribution
• changes in
• (a) plasma protein concentration,
• (b) total body fat, as well as
• (c) total body water and extracellular water
• are the three major factors exerting significant
effects on drug distribution in pediatric
population (Murphy, 2012).

47. • The total body water is high, constituting 75%–
90% of total body weight in neonates and infants
up to the first 6 months of life,
• compared to about 60% in children and adults
(O’Connor et al, 1965).
• As a result, the apparent volume of distribution
(V) of hydrophilic drugs is age dependent,

48. • The extracellular fluid (ECF) is high in neonates, 45%, as
compared to 25%–26% in adults, but approaching adult
value in one year of life.
• The total body fat is less, 12% in neonates and infants,
• but peaks at 30% in one year,
• then decreasing gradually to adult value of 18%.
• Therefore, when we dose on a weight (kg) basis, lower
plasma concentrations for hydrophilic drugs are expected in
neonates and young infants, due to their higher percentage
of total body water and ECF for drug distribution out of
blood circulation.

50. • The protein concentrations are low in the neonates and infants up
to one year old.
• The changes in circulating plasma proteins, albumin and α-acid
glycoprotein, affect the distribution of highly bound drugs.
• In neonates and young infants, phenytoin has a higher unbound
fraction of the drug in circulation to exert activity (MacKichan,
1992).
• The competitive binding of bilirubin on albumin is also a relevant
issue in neonates, in that a higher unbound fraction of a drug will
be resulted from the displacement by bilirubin in binding of the
drug to albumin (Allegaert et al, 2008).

51. Metabolism
• In neonates, Phase I enzymes of CYPs 3A4, 2D6, 2C9,
and 2C19 are all reduced, with 20%–40% of adult
activities
• In infants, CYP2D6 remains reduced, but reaches adult
pattern by the age of 1 year (Mortimer et al, 1990).
• Other CYP enzymes, CYP3A4, -2C9, and -2C19,
– reach adult levels by 6 months of life,
– peak in young children at ages of 3–10 years,
– and decline to adult levels at puberty

52. • The hepatic metabolism of carbamazepine
(substrate of CYP3A4) is increased in infants and
children as compared to neonates and adults
(Korinthenberg et al, 1994).
• With diazepam (substrate of CYP2C19), the age-
dependent changes in oxidative metabolism
result in the shortest half-life in children, 7–37
hours, as compared to those of 25–100 hours in
neonates and infants, and 20–50 hours in adults
(Morselli et al, 1973).

53. • Clinical observations are consistent that hepatic
metabolism is age dependent in pediatric patients.
• Hepatic metabolism in children of 3–10 years of age is
greater than that of adults.
• The greater hepatic clearance in this subpopulation
remains significant even after the correction for the
age-dependent liver weight (Murry et al, 1995).
Therefore, the doses required for this subpopulation of
children are often higher on the body weight basis, as
compared to adolescents and adults.

54. Excretion
• The rates of glomerular filtration, tubular
secretion, and tubular reabsorption are slower at
birth, but rapidly rise to adult levels in 8–12
months of age (van den Anker, 1995).
• Therefore, drugs of high fe (fraction excreted in
urine unchanged) require longer dosing intervals
to accommodate the slower drug renal clearance.

55. • As a result, similar systemic drug
concentrations can be maintained as to those
with more mature renal function.
• For example, the dosing interval of
aminoglycoside is suitable as 24 hours for
term newborns, but is required to be 36–48
hours for preterm newborn (Schwartz et al,
1987; Brion et al, 1991).

56. Examples of altered PK
• For example, the F of nelfinavir (a weak acid
drug) in newborns and infants <2 years of age
is lower than those in older children, due to
the food effect, higher gastric pH or both (Hirt
et al, 2006).

57. • Decreased albumin contents in newborns and
neonates cause increases in the unbound
fraction of highly protein-bound anti-HIV
drugs, such as enfuvirtide (>90% bound), that
result in increased efficacy and toxicity
(Bellibas et al, 2004).

58. Clinical Example of Rational Dosing in
Pediatric Patients
Drug clearance based dosing of
busulfan
• Bsusulfan success depends on reaching target
AUC of 900–1500 microMol•min, and adverse
effect is observed when AUC is >1500
microMol•min.

59. • With the IV Busulfex, the age-dependent
clearance is characterized based on 5 body
weight strata
Total dose (mg/kg) = Cltot × (Target AUC)

62. • Temozolomide (Temodar®) is an antineoplastic
alkylating agent, indicated for refractory (first relapse)
anaplastic astrocytoma. The recommended treatment
protocol is oral doses of 200 mg/m2/day for 5 days and
repeated every 28 days. The F of temozolomide is 0.98
with an empty stomach and 0.6 when the drug is taken
with fatty food. The Cl and t1/2 of the drug are 100
mL/min/m2 and 1.8 hours, respectively. The available
capsule strengths are 5, 20, 100, and 250 mg.
• CB is a 15-month-old patient of 7-kg body weight (0.3
m2). (a) What is the Cl of temozolomide in CB?
• (b) Recommend a regimen for CB, which F is to be
used?
• (c) Predict the Css,ave.

63. • WS, an 8-year-old, 25-kg male, is receiving a 250-mg
capsule of valproic acid (VA) q12h for the treatment of
seizures.
• The Cls of VA are 13 mL/kg/h for children and 8 mL/kg/h for
adults. The V and F of VA are 0.14 L/kg and 1, respectively.
The therapeutic plasma VA concentrations are 50–100
mg/L. The toxicity is observed as >200 mg/L.
• WS has normal hepatic and renal functions.
• (a) Predict the steady state trough concentration (Css,min)
for WS, and
• (b) comment on the adequacy of his current regimen, using
a 1-compartment intravenous bolus model.