This document discusses dosing considerations for various patient populations including infants, children, elderly patients, obese patients, and patients with renal impairment. It notes that infants and children require different dosing than adults due to differences in body composition, organ maturity, and pharmacokinetic parameters. The elderly also have altered pharmacokinetics due to changes in organ function, body composition, and drug absorption, distribution, metabolism, and excretion. Obese patients require dosing based on ideal body weight rather than actual weight. Patients with renal impairment require dose adjustments based on creatinine clearance to maintain therapeutic drug levels. Common methods for estimating creatinine clearance and adjusting doses based on clearance or elimination rate constant are presented.

1. 1
Application of Pharmacokinetics to
Clinical Situations:
Dosing in infant, children and
elderly

2. Dosing of Drugs in Infants &
Children
 Preterm newborn infant,
 Newborn infant (0-28 days),
 Infant (28 days-23 months),
 Young child (2-5 yrs),
 Older child (6-11 yrs),
 Adolescent (12-18 yrs), &
the adult
 Unfortunately, the phk & phd
of most drugs are not well
known in children ˂12 yrs of
age.
 With age there is differences
in PhK due to
 The variation in body
composition &
 the maturity of liver & kidney
function
2
Infants & children have different dosing requirements than adults.
 Here for convenience, "infants'' are children 0-2 yrs of age.
 However, special consideration is necessary for infants ˂ 4 wks,
 because their ability to handle drugs often differs from that of more mature
infants.

3. 3
Pharmacokinetic in infants
 Distribution
 many drugs exhibit reduced binding to plasma
albumin.
 Metabolism
 Complete hepatic function is not attained until the 3rd
wk.
 Oxidative processes are fairly well developed in
infants, but there is a deficiency of conjugative
enzymes.
 Renal excretion
 Newborns show only 30–50% of the renal activity of
adults

4. Comparison of Newborn & Adult Renal Clearances
4
Parameters Average
Infant
Average Adult
Body weight kg 3.5kg 70kg
Body water Percen
t
77% 58%
volume 2.7L 41L
Inulin
clearance
Cl  3ml/min 130ml/min
k 0.0011 min– 1 0.0032 min– 1
t1/2 630 min 220 min
PAH
clearance
Cl 12 mL/min 650 mL/min
k 0.0043 min– 1 0.016 min– 1
t1/2 160min 43min
Inulin (*K) PAH (*K)
 Infant k(min– 1)= 3/2700 = 0.0011 12/2700 = 0.0043
 Adult k(min– 1)= 130/41,000 = 0.0032 650/41000= 0.016

5. 5
Elimination Half-Lives of Drugs in Infants and
Adults
Drug Half-Life in
Neonatesa (hr)
Half-Life in
Adults (hr)
Penicillin G 3.2 0.5
Ampicillin 4 1–1.5
Methicillin 3.3/1.3 0.5
Carbenicillin 5–6 1–1.5
Kanamycin 5–5.7 3–5
Gentamicin 5 2–3
a0–7 days old

6. Practice Problem
6
 The elimination half-life of penicillin G is 0.5 hour in adults
and 3.2 hours in neonates (0 to 7 days old). Assuming that
the normal adult dose of penicillin G is 4 mg/kg every 4
hours, calculate the dose of penicillin G for an 11-pound
infant.
 Solution
 Therefore, this infant may be given the following dose:
Dose = 4mg/kg = 11Lb/2.2Lb/kg = 20 mg every 24 hr
 Alternatively, 10 mg every 12 hours would achieve the same
C ∞
av.

7. Dosing of Drugs in the
Elderly
7
 Defining "elderly'' is difficult.
 The geriatric population is often older than 65yrs
 "older elderly'' population are often ˃85yrs
 Chronologically, the elderly have been classified
as
 The young old (ages 65–75 years),
 the old (ages 75–85 years), and
 the old old (age > 85 years)
 The aging process is more often associated with
physiologic changes during aging rather than

8. Changes in old age
8
Physiology
 Decreased in physiologic function complicates DR
 Renal plasma flow, GFR, cardiac output, & breathing
capacity can drop from 10% to 30% compared to
those at age 30.
Pharmacodynamic
 Alterations in target drug receptors,
 Quantitatively, the number of receptors decline with
age
 Qualitatively, a change in the affinity for the drug

9. 9
Alterations in drug absorption
  in the splanchnic blood flow, altered GI motility,
  in gastric pH, and alteration in the GI
absorptive surface.
Alteration of distribution
 Changes in plasma albumin & 1-acid
glycoprotein
  drug protein binding in the plasma as a result
of  in the albumin conc.
 Vd may change due to a  in muscle mass and
an  in body fat.

10. 10
Alteration of elimination
 There is gradual reduction in the kidney size & function.
  Renal excretion as a result of  in GFR &/or active secretion.
 Both penicillin & kanamycin show  t1/2 in the aged patient
  Hepatic drug clearance due to activity of the enzymes
Changes in Renal Function with Age
 In general GFR decline with age.
 GFR decreases at a mean rate of 1%/yr after 40 yrs of age.
 Since muscle mass & urinary CrCl decrease at nearly the
same rate in the elderly, mean serum conc. may stay
relatively constant.
 CrCl measured by serum Cr conc. only may yield
inaccurate GFR function if urinary CrCl is not measured.

11. Practice Problems
11
1. An aminoglycoside has a normal t1/2 of 107 min in
young adults. In patients 70 to 90 yrs old, its t1/2 is 282
min. The normal dose of the aminoglycoside is 15 mg/kg
per day divided into two doses. What is the dose for a
75-year-old patient, assuming that the Vd per body
weight is not changed by the patient's age?
Solution
 The t1/2 in old patient is due to a  in renal function.
 There is a good inverse correlation b/n t1/2 &
clearance.
 To maintain the same average conc. of the
aminoglycoside in the elderly as in young adults, the
dose may be reduced

12. 12
Therefore, the same dose of the aminoglycoside may be
administered every 32 h without affecting the average Css of
the aminoglycoside.
Keeping the dose constant,
DN = Do, where DN is new dose & Do is the old dose

13. 13
2. The clearance (Cl) of lithium was determined to
be 41.5 mL/min in a group of patients with an
average age of 25 yrs. In a group of elderly patients
with an average age of 63 years, the Cl of lithium
was 7.7 mL/min. What percentage of the normal
dose of lithium should be given to a 65-year-old
patient?
Solution: The dose should be proportional to
clearance; therefore,
 The dose of lithium may be reduced to about 20%
of the regular dose in the 65-year-old patient
without affecting the steady-state blood level.

14. 14
Application of Pharmacokinetics
to Clinical Situations:
Obese Patient

15. Dosing of Drugs in the Obese
Patient
15
 A patient is considered obese if actual body weight
exceeds ideal or desirable body weight by 20%.
 Obesity often is defined by body mass index (BMI), a
value that normalizes body weight based on height.
 BMI is expressed as body weight (kg) divided by the
square of the person's height (meters) or kg/m2.

16. Dosing of Drugs in the Obese
Patient
16
The obese patient (BMI > 30): total body water
vs Vd
 has a greater accumulation of fat (Adipose) tissue
 Water of fat tissue < muscle tissue. Thus,
 Total body water (TBW) of obese pt ˂ TBW of pt of
ideal body weight (IBW), which could affect Vd of the
drug.
 For example, Vd of antipyrine in obese patients is
(0.46 L/kg) whereas IBW patients is (0.62 L/kg)
 Ideal body weight (IBW) refers to the normal
weight for a male or female based on age, height
& weight

17. 17
The obese patient (BMI > 30): Body fat vs PhK
 There is distributional changes in the drug's phks
due to partitioning of the drug b/n lipid & aqueous
env’t.
 E.g. Very polar Drugs such as digoxin and gentamicin
tend to distribute into water rather than into fat tissue.
 lipophilic drugs are associated with larger Vd in obese
patients compared to hydrophilic drugs
Other pharmacokinetic parameters altered
 as a result of physiologic alterations, such as
 fatty infiltration of the liver affecting biotransformation
&
 cardiovascular changes that may affect renal blood

18. 18
 Dosing by actual body weight may result in
overdosing of drugs such as aminoglycosides
(eg, gentamicin), which are very polar and are
distributed in ECF.
 Dosing of these drugs is based on ideal body
weight.
 Lean body weight (LBW) has been estimated
by several empirical equations based on the
patient's height and actual (total) body weight.

19. 19
The following equations have been used for
estimating lean body weight, particularly for
adjustment of dosage in renally impaired patients:
Example
 Calculate the lean body weight for an adult male
patient who is 5 ft 9 in (175.3 cm) tall and weighs 264
lb (120 kg).
Solution

20. Application of
Pharmacokinetics to Clinical
Situations:
Dose adjustment in renal
failure

21. Introduction
 Role of kidney
 regulating body fluids, electrolyte balance,
 removal of metabolic waste, and drug excretion
from the body.
 Impairment/degeneration of its function affects
the phk of drugs.
 Some of the causes of its failure include disease,
injury, and drug intoxication.

22. Introduction…
Common Assumptions in Dosing Renal-Impaired Patients

CrCL accurately measures the degree of renal impairment

Drug follows dose-independent pharmacokinetics

Nonrenal drug elimination remains constant

Drug absorption remains constant

Drug clearance, Clu, declines linearly with creatinine
clearance, ClCr

Unaltered drug protein binding

Target drug concentration remains constant

23. Introduction…
Group Description Estimated CrCl
(mL/min)
1 Normal renal function >80 mL/min
2 Mild renal impairment 50–80 mL/min
3 Moderate renal impairment 30–50 mL/min
4 Severe renal impairment <30 mL/min
5 ESRD-end-stage renal
disease
Requires dialysis
Renal Impairment and Creatinine clearance ClCr

24. Determination of Creatinine clearance
 ClCr is most often estimated from the patient's
Serum Cr conc, CCr , due to the difficulty of
collecting 24 hr urine
 The most methods are based on the patient's age,
height, weight, and gender.
1. Cockcroft and Gault formula:
Adults
 For males,
 For females, use 85% of the ClCr value obtained in
males

25. Example: What is ClCr for a 25-year-old male patient (5 ft, 4
inches in height & weighs 103 kg) with a CCr of 1 mg/dL?
Solution
 The patient is obese and the ClCr calculation should be
based on ideal body weight.
 LBW (males) = 50kg + 2.3kg for each inch over 5 ft
= 50kg + 2.3kg x 4
= 59.2kg
 Using the Cockcroft and Gault method, the ClCr is

26. Example:
 Bon Josh is a 43 year-old, 50 kg male. The
following serum creatinine measurement was
returned from the clinical laboratory: SrCr =
1.5 mg/dL.
 Estimate Creatinine clearance for B.J.

27. 2. The nomogram
method
 Siersback-Nielsen et
al (1971) estimates
ClCr on the basis of
 age,
 weight, &
 Serum CCr

28. How to use nomogram?
Steps
 Join the points at age (yrs) & weight with a ruler-let the line
intersect line R.
 Connect the intersection point at line R with the CCr point, and
extend the line to intersect the "clearance line."
 The extended line will intersect the clearance line giving the
ClCr.
Example. What is the ClCr for a 25-year-old male pt with CCr of 1
mg/dL & a body weight of 80 kg?
 Solution
 join the points at 25 years (male) & 80 kg with a ruler-let the line
intersect line R.
 Connect the intersection point at line R with the CCr point of 1 mg/dL,
and extend the line to intersect the "clearance line."
 The extended line will intersect the clearance line at 110 mL/min,
giving the ClCr for the patient.

29. Children
 There are a number of methods for calculation
of ClCr in children, based on body length and
serum creatinine conc.
 where ClCr is given in mL/min/1.73 m2.

30. General Approaches for Dose Adjustment in
Renal Disease
 Several approaches are available for
estimating the appropriate DR. Most of these
methods assume that
 Plasma [drug]uremic = Plasma [drug] normal
renal
 Uremic patients are
 maintained on the same C∞
av after multiple oral
doses or IV bolus injections.
 For IV infusions, the same C SS is maintained.

31. 1. Dose Adjustment Based on Drug
Clearance
A) C∞
av after multiple oral doses or IV bolus injection is
 Where ClT is Normal total body Cl is
 Therefore, to maintain the same desired C∞
av,
 the dose, Do, must be changed to a uremic dose, Du
0 or
 the dosage interval, , must be changed to u,
 where the superscripts N and u represent normal and uremic
conditions, respectively. Total body clearance of the uremic
patient is Clu
T.

32.  Rearranging Equation
and solving for Du
0.
 If  is kept constant,
then the uremic dose
Du
0 = fraction (Clu
T/ClN
T)
of DN
0
B) For IV infusions the
CSS uremic pt = CSS
normal renal pt
 The rate of infusion, R,
must be changed to a
new value, Ru, for the
uremic patient,

33. 2. Dose Adjustment Based on Changes
in the Elimination Rate Constant, K
 The overall K for many drugs  in the uremic pt.
 A DR may be designed for the uremic patient
either
 by  Do of the drug and keeping  constant, or
 by   and keeping the Do constant.
 Assuming the VD is constant, then Du
0 is a
fraction (ku/kN) of the DN
0 :

34. Dose Adjustment Based on K…
Nomograms
 Are charts used in estimating DR in uremic
patients.
 Are based on serum Cr conc., patient data
(height, weight, age, gender), & the phk of the
drug.
 Provides an estimate of the ratio of uremic ku
to normal (kN) on the basis of creatinine

37. Dose Adjustment Based on K…
 Uremic dose ( is kept constant) can be
estimated according to Equation
Uremic dose = ku/kN x Normal dose
Du
0 = DN
0 (ku/kN)
Dosage interval  in Uremia (dose is kept
constant)
u = ku/kN x N
 Where N is the dosage interval in normal renal
function.

38. Practice Problem
Lincomycin is given at 500 mg every 6 hours to a 75-kg
normal patient.
 What doses would be used (a) in complete renal shutdown
(ClCr = 0) and (b) when ClCr = 10 mL/min?
Solution
 To use the nomogram method, follow the steps below:
 1. Locate the group to which the drug belongs in the
nomogram.
 2. Find k u/k N at the point corresponding to the Cl Cr of the
patient.
 3. Determine ku for the patient.
 4. Make the dose adjustment in accordance with
pharmacokinetic principles.

41. 41
Application of Pharmacokinetics
to Clinical Situations:
Therapeutic Drug Monitoring

42. 1. Introduction…
42
What is Therapeutic drug monitoring?
 Individualization of dosage by maintaining Cp within a
target range
 optimize patient management & improve clinical
outcomes
It involves
Measuring [drug] in plasma &
interpreting these conc. in terms of
relevant clinical parameters.
3/11/2023
TDM

43. 1. Introduction…
43
Why therapeutic drug monitoring?
 TDM can guide the clinician to provide effective and
safe drug therapy ¡n the individual patient using serum
drug concentration
Goals of TDM
 Ensure that a given drug dosage produces
 Maximal therapeutic benefit
 Minimal toxic adverse effects
 Drug must have an appropriate conc. at site of
action that produces benefits
3/11/2023
TDM

44. 1. Introduction…
Therapeutic range for commonly monitored
drugs
44
Amikacin 20–30 g/mL
Carbamazepine 4–12 g/mL
Digoxin 1–2 ng/mL
Gentamicin 5–10 g/mL
Lidocaine 1–5 g/mL
Lithium 0.6–1.2 mEq/L
Phenytoin 10–20 g/mL
Procainamide 4–10 g/mL
Quinidine 1–4 g/mL
Theophylline 10–20 g/mL
Tobramycin 5–10 g/mL
Valproic acid 50–100 g/mL
3/11/2023
TDM

45. 3. CRITERIA FOR TDM
45
1. Drugs having narrow therapeutic range
2. Therapeutic effect cannot be readily
assessed by
clinical observation
3. If a direct relationship exists b/n the drug or
drug
metabolite levels in plasma & the
pharmacological or toxic effects.
4. Large inter-individual variability ¡n plasma
conc.
5. Drug follow non-linear Pharmacokinetics
6. Drugs used for treating life threatening
3/11/2023
TDM

46. Drugs which do not need TDM
46
1. Drugs with wide therapeutic range
2. Pharmacological effects can be clinically
quantified/ monitored by clinical end points, e.g.,
BP, HR, cardiac rhythm, blood sugar, blood
cholesterol, etc.
3. Drugs whose serum concentrations do not
correlate with therapeutic or toxic effects.
4. Drugs used to treat less complicated or non life
threatening diseases
5. Drug following linear kinetics (less complicated
Phk)
6. Hit and run drugs e.g. omeprazole
3/11/2023
TDM

47. 4. FUNCTIONS OF A TDM
SERVICE
47
 Select drug.
 Design dosage regimen.
 Evaluate patient response.
 Determine need for measuring
Cp
 Assay for [drug] in biological
fluids.
 Perform phk evaluation of [drug]
 Readjust dosage regimen. 3/11/2023
TDM

48. 5. TDM: Common drugs
1. Cardio active drugs:
 amiodarone, digoxin,
digitoxin,
disopyramide,
propranolol and
quinidine
2. Antibiotics:
 gentamycin, amikacin
and tobramycin
3. Antidepressants:
 lithium and tricyclic
antidepressants
4. Antiepileptic drugs:
 Phenytoin, Valproic
acid phenobarbitone,
benzodiazepines,
carbamazepine, and
ethosuximide
5. Bronchodilators:
 theophylline
6. Cancer
chemotherapy:
 Methotrexate
7.
Immunosuppressives:
 Cyclosporine
48
3/11/2023
TDM

49. 49 3/11/2023
TDM