Asher Allyson A. Tulabut, PharmD.

How much? - Therapeutic and toxic response of the body

to a certain drug. (Dose)
How Often? - Importance of time in that the magnitude of
the effect eventually declines with time following a single
dose of a certain drug. (Frequency)
How long? - Recognizes the cost in terms of side effect, toxicity
also in economics incurred with drug administration. (Duration)
What Factors affect
the response?
Aminoglycoside antibiotic (10mg/kg) was infused
intravenously over 60 minutes to a 55 kg patient. Determine
the Vd if the plasma concentration (Cp) at zero time is 10
mg/L.

VD = DB0/Cp0
• DB0= dose given by IV bolus
• Cp0= extrapolated drug concentration at zero time

ANS = 55 Liters
1. Calculate how fast the drug appears in the blood.

2. Measure how much of the drug is in the blood.

3. Calculate how fast the drug disappears.

• D = Dose
• Vd = Volume of Distribution
• Ka/Ke = Absorption/Elimination rate constant
• F = Bioavailability
• Cl = Clearance
1. Pharmacokinetic Phase
2. Pharmacodynamic Phase
• Release of the drug from its dosage form.
• Excipient and Active drug
• Drug has entered the circulatory system.
• Into the site of absorption
• The fraction of drug absorbed into the systemic
circulation after extravascular administration is defined as?

BIOAVAILABILITY
• DISTRIBUTION
• From the circulatory system into the Target tissue or Peripheral
compartment
• METABOLISM
• First Pass Effect
• CYP450
• EXCRETION
• Intravascular administration – directly into the
bloodstream.

• Extravascular administration- must be absorbed 1st to

enter the bloodstream.
• CLINICAL PHARMACOKINETICS
• Application of pharmacokinetic principles to the safe & effective
therapeutic management of drugs in INDIVIDUAL patients.

Individualized Drug Therapy.

• Individualized drug therapy
• Drugs with narrow therapeutic index
• Therapeutic Drug Monitoring
• Used to identify the concentration of a drug in the
plasma.
• Interpret and apply these data to develop safe and
effective drug regimens.

• Therapeutic Range
• Antibiotics – AG and Vancomycin
• Theophylline
• Anti-epileptic drugs – Phenytoin, Valproic Acid
• Digoxin
• Immunosuppresant – Tacrolimus
• Fast achievement of therapeutic concentrations.

• Safer therapeutic concentrations compared to empiric

dose changes.
• There is no well-defined therapeutic plasma
concentration range.
• Presence of pharmacologically active metabolites which
complicates data.
• Toxic effects may occur at low doses.
• No significant consequences associated with too high or
too low levels.
Pharmacokinetics Principles
Asher Allyson A. Tulabut, PharmD.
 Case study
• A 74 year-old 60 kg male is started on
gentamicin IV in a dose of 80 mg every 8 hours.
However, his serum creatinine is raised at 220
umol/L and the physician is worried about
toxicity. He asks you what levels this dosage is
likely to produce.
 Case study
• Calculate the patients pharmacokinetic
parameters k, Vd & CL
• Predict the steady state peak and trough
levels likely to be achieved by this dosage
regimen
• What would your advice be to the doctor
based on predicted levels?
 Pharmacokinetics principle
• Absorption
• Volume of Distribution (Vd)
• First order and Zero order kinetics
• Elimination Rate Constant
• Half life (t1/2)
• Clearance (Cl)
• Area Under the Curve (AUC)
Absorption
 Absorption
q Entering the systemic circulation
q DEPENDS on route of administration
[Concentration] = Mass / Volume
If oral:
[Concentration] = Dose (oral) X F (bioavailability / Volume)
Blood volume = 5 L
Plasma volume = 2.5L (Blood – Cells)
 Sample problem
Patient A was recently admitted to your
institution with a diagnosis of Complicated UTI
then was prescribed with Ciprofloxacin 400mg IV
bolus every 12 hours. What is the plasma drug
concentration?
 Sample problem
A patient for discharged was prescribed with
Ciprofloxacin 500mg/tab every 12 hours (with a
bioavailability of 80%). What is the plasma drug
concentration?

Ans = 160mg/L
Distribution
A. APPARENT VOLUME OF DISTRIBUTION

q Volume of body fluid in which drug is dissolved.

q NOT a true anatomic or physical volume.
q Plasma vs. Extravascular space
DB= VD x CP
Ø DB = Amount of drug in the body (Dose)
Ø CP = Plasma drug concentration
 A. Apparent Vd
q It can indicate the extent of drug distribution
and aid in determination of dose requirement.

Vd, the higher it distributes outside the plasma,

meaning, Larger dose must be given to achieve
a desired target concentration.
 A. Apparent Vd
q Drugs that stays in the plasma has a ____Vd.
q Drugs that are likely to stay in the
extravascular space has a ____ Vd.
q Hydrophilic drugs
q Lipophilic drugs
A. APPARENT VOLUME OF DISTRIBUTION

q VD after an IV bolus injection can be calculated using the

equation;
VD = DB0
Cp 0
Where;
DB0 = dose of the drug given by IV bolus
Cp0 = extrapolated drug concentration at zero time in the y
axis
B. Protein Binding
 Examples of drug
qWarfarin – 8.4 L
qDigoxin – 360 to 420 L
qChloroquine – 150,000 L

*this is for healthy 60kg

 C. P-Glycoprotein
qP-glycoprotein is also found in tumor cells,
resulting in the efflux of chemotherapeutic
agents out of the cell and, ultimately,
multidrug resistance.
qTolerance for opioids
 Sample Problem
1. A 40 year old female (45 kg) diagnosed with a Systemic infection and
was prescribed Amikacin with a target plasma concentration of 25
mg/L and a VD 0.25L/kg. Determine the IV dose.

Vd = 0.25L X 45 = 11.25 L
D = 11.25 L X 25mg/L

ANS = 281.25 mg
 Sample Problem
2. A patient for discharged was prescribed with
oral form of Drug A with a dose of 800mg with a
bioavailability of 55%, VD of 97.5L, calculate for
the desired plasma concentration.

ANS= 1.80mg/L
Metabolism : First Order and Zero
Order Kinetics
 FIRST ORDER ZERO ORDER
Elimination rate is Elimination rate saturates with
proportional to drug higher drug concentration
concentration
The higher the plasma conc., The higher the plasma conc., No
the higher the rate of change in the rate of metabolism
metabolism (Toxicity)

Linear kinetics Nonlinear kinetics

95 % of drugs ASA, Phenytoin and ethanol

 First-order Elimination
qThe rate of elimination is proportional to the
concentration.
qHalf-life is constant.
qThe Higher the plasma concentration 
Higher rate of metabolism
q95% of drugs
 Elimination Rate Constant (k)
q Represents a FRACTION of drug removed per
unit time and has units of reciprocal time (min-1,
hour-1 and day-1)
q First order
q Values for k uses absolute numbers.
q NOT affected by the route of administration.
Rather affected by physiologic or pathologic
condition. (e.g Age and Liver Failure)
Elimination Rate Constant (k)
*If two plasma drug
concentrations & their
corresponding time is known, K
can be calculated.

*If one plasma drug concentration

and K is known, then the plasma
concentration at any later time can
be calculated.
 Sample problem
A patient just received a dose of gentamycin.
Initial plasma concentration was 8mg/L and the
patient’s elimination rate constant is 0.25/hr.
what will the plasma concentration after 8H?

ANS = 1.1 mg/L

 Sample problem
A 50 kg woman was given a single IV dose of an
antibacterial drug at a dose level of 6 mg/kg.
Blood samples were taken at various time
intervals. The concentration of the drug (Cp) was
determined in the plasma fraction of each blood
sample and the following data were obtained:
 t (hr) Cp (ug/mL)
0.25 8.21
0.5 7.87
1.0 7.23
3.0 5.15
6.0 3.09
Calculate for the Elimination Rate constant.

ANS = 0.1699 hr
 Half Life (t½)
qTime required to decrease the initial dose of
drug by 50%
q96% of drug is decreased after 4 half lives.
qUnit of measurement = time (sec, min, hr)
 Importance of Half-life
qDetermining the dosing interval
qPredict how long will the drug reach steady
state (In general, 3-5 half lives. For IV infusion,
4-5 half lives)
qPredict the accumulation of a drug in the
body for a specific dosing interval
Steady state
How do we calculate for Half Life (t½)?
t½ = 0.693
k
qDetermine if two plasma concentration are
given. Then,
qCalculate for the Elimination rate constant (K)
qUse the formula of half-life

*This is for first order kinetics

 Sample problem
• A dose of gentamycin is administered and a peak
plasma concentration of 6mg/L was observed. 4
hours later, the plasma concentration was
observed to be 1.5mg/L. What would be the
dosing interval for this medication?

ANS= 2 Hours
 Drug X was administered as an IV bolus.

Time Plasma concentration

0 sec 50 mg/L
10 sec 25mg/L
15 sec 15mg/L
20 sec 10mg/L
25 sec 5mg/L

Calculate for K from time 0 to 25 sec. and determine

the t1/2
Clearance and AUC
 Clearance (Cl)
q Term used to evaluate *Do not indicate amount of
efficiency of drug drug being removed.
removal from the body.
q Describes the removal of
drug from a volume of *Indicates the volume of
plasma in a given unit of plasma from which the drug
time is completely removed in a
given period of time.
q Clearance is a first-order
process, the amount of
drug removed depends
on the concentration
(volume/time).
 Clearance (Cl)
qTotal Body Clearance
qClearance per organ (liver, renal, inhalational)

Cl = (Vd)(k)
 Importance of Clearance
qComputation of the maintenance dose.
qDetermine or predict the duration of action of
a drug.
 Area under the Curve
qThe rate and extent of drug absorption.
qProportion to amount of drug absorbed.

qUnits = μg.hr/mL
How do we compute for the AUC?
q Trapezoidal method
q AUC from time 0 to the last blood level point
determined is composed of trapezoids
 Area under the Curve
AUC 0-tx = {[ C1 +2 C2 (t2–t1)] + [ C2 +2 C3 ](t3–t2)] + [ C3 +2Cx (tx–t3)]}, etc.

AUC tx - ∞ = Cx / k

AUC 0 -∞ = AUC 0 – tx + AUC tx - ∞

 An 100mg dose of drug X is administered as an intravenous bolus
and the ff plasma concentrations result:
Time After Dose (hours) Plasma Concentration (mg/L)
0 6.7
0.5 6.0
1 5.3
2 4.2
4 2.6
Answers:
1. Compute for Vd, K, and T1/2 1.
2. Compute for Clearance 2.
3. Compute for AUC 0 - ∞ 3.
ABSORPTION OF ORAL DOSAGE FORM
AND NONVASCULAR PARENTERAL
FORMULATION
AAAT, PharmD., RPh.
Absorption (enteral route)
Most of the drug are administered extravascularly.
For IV administration, it is always 100% absorbed
Weak acids are absorbed more rapidly from the stomach
at pH 1.0 than at pH 8.0
Routes of Administration

Enteral routes- sublingual, buccal, oral, rectal

Parenteral routes- intravenous, intra-arterial, intrathecal,

intramuscular, Subcut, inhalational

Topical
Important determinants

Surface area
 Permeability
 Perfusion rate-limited absorption
 Blood flow
Small Intestine
 Accounts to drug absorption in the GI
 pH 6 to 7.5
 Surface area of 200m2
 Microvilli
 Estimated of 1 liter/min of blood passes
 Gastric emptying
Factors to consider in Absorption of enteral
drugs:
A. Gastric Emptying
B. Low Oral Bioavailability
C. Insufficient time of Absorption
D. Competing reactions
A. Gastric Emptying
 Food specially fats, slows gastric emptying which
explains why drugs are frequently recommended to be
taken on an empty stomach when a rapid onset of action
is desired.
A. Gastric Emptying
 Drugs that affect gastric emptying may also affect
absorption of other drugs (ex. Taking metoclopramide and
Digoxin at the same time)
C. Insufficient time for Absorption
Depending on the permeability of drugs
Some Polar drugs have poor permeability (not all)

 Ranitidine, a polar stable compound almost totally excreted

unchanged when given in IV. 60% is absorbed orally but all within
the first 3 to 4 hours after administration; the rest is recovered
unchanged in feces.
B. Low oral bioavailability
 Oral drug must pass Ff = fraction neither lost in
sequentially from the GI the feces nor decomposed
lumen through the GUT on the lumen
wall, and through the liver
before entering the Fg= reducing the fraction of
general circulation. dose reaching the portal
vein to Ff

F = Ff X Fg X Fh
Fh = reaching the liver
escapes extraction there
D. Competing Reactions
• Any reaction that 1. Complexation – Ca, Al,
Fe vs. Tetracycline,
competes with Fluoroquinolones
absorption may
2. Decarboxylation-
decrease the oral Levodopa – loss of
bioavailability of a activity
drug. 3. Hydrolysis – ACID (Pen
G, Erythromycin,
Digoxn), Enzymatic
(ASA, Insulin)
Rectal Administration
Define advantage over oral route for drugs destroyed
by gastric acidity or by enzymes in the intestinal wall
and microflora
May also reduce first pass effect (bypass hepatic
circulation)
 Inferior hemmorrhoidal vein
 Middle hemmorrhoidal vein
Examples of drugs with low oral bioavailability
due to extensive first pass effect
A. Doxorubicin, 5-FU, Cytarabine
B. Hydralazine, ISDN, Metoprolol, Nifedipine,
Nitroglycerin, Propranolol, Labetalol, Diltiazem
C. Naloxone, Nalbuphine, Ketamine, Morphine
NONVASCULAR
PARENTERAL ROUTES
Nonvascular Parenteral Routes
• Perfusion-rate limited
Intramuscular • Increase in blood flow, increase
in absorption
Subcutaneous • Nature of barrier (Capillary
wall)
• Site of Injection (Interstitial fluid
Intraperitoneal and blood

• Macromolecular and
Lymphatic Transport
• The larger the molecule, the
difficult it is to be transported
How does Nonvascular parenteral route
reaches the Systemic circulation?
• Diffusion through the interstitial fluid
A. Penetrations in the linings of the vascular capillaries –
molecular size , ex. For drugs with 5000g/mole primarily pass
through capillary pathway
B. Convective flow of the interstitial fluid through lymphatic
channels – slower, ex. >20,000 g/mole are less able to
traverse the capillary wall so they primarily enter the blood
through lympathic pathway.
Advantage of NPR
1. Offer the advantage or providing prolonged input for
short half-life protein drugs.
2. Allow for less frequent drug administration than IV
route.
Absorption Kinetics of NPRs
 Site of Injection
 Temperature
 Degree of rubbing at the injection site
PHARMACOKINETICS IN
DISEASE STATES
AAAT
Disease States

■ Hepatic disorders– Cirrhosis (ex. Theophylline)

■ Circulatory disorders–CHF (ex. Lidocaine)
■ Renal Disease – Uremia (ex. Gentamicin)
Hepatic Disorders

■ Major site of Drug metabolism.

■ In average, Hepatic clearance of drugs in Cirrhosis on
average is decreased.
■ Prolongation of half life with reduced hepatic drug
metabolizing activity.
■ Depressed synthesis of albumin= decreased plasma
binding, resulting in increase in VD
Hepatic Disorders

■ Fall in hepatic enzymes due to decreased

hepatocytes.
■ Oral bioavailability in hepatic disorders is increased.
– Diminished first-pass hepatic loss due to
decreased hepatocytes
– Cirrhotic patients develop portal bypass (>200%)
Dosing in Hepatic Disorders

■ Drug dosage may need to be reduced in

patients with hepatic function impairment as
a result of both decreased clearance and
increased oral bioavailability.
Exceptions in Hepatic Disorders

■ Due to numerous drug metabolism pathway (Phase I and

Phase II), not ALL drugs may undergo all of the
pharmacokinetic adjustments in hepatic disfunction.

■ Glucuronyltransferase (Phase II) – not affected by hepatic

disease
– Oxazepam (Benzodiazepine) – mainly eliminated by
glucuronidation (phase II) is not affected by hepatic
disfunction.
Circulatory Disorders

■ Blood flow may influence drug absorption,

distribution, and elimination.
■ Shock, Malignant Hypertension, Congestive Heart
Failure
■ Diminished vascular perfusion to one or more
parts of the body.
Circulatory Disorders

■ Diminished perfusion may lead to reduced blood flow

to other organs.
– Hepatic blood flow
– Renal blood flow
■ Diminished perfusion of absorption sites – seen in
patient with depressed CV states.
– Gastrointestinal tract and muscle
– *Brain and Myocardium are exemptions
Renal Impairment

■ Urinary excretion of drugs is diminished.

■ The degree of reduction in renal elimination
depends on the reduction in renal function.
■ Drug accumulation occur in patients with renal
impairment.
■ Creatinine Clearance
– Cockcrauft and Gault
– CKD-EPI Creatinine 2009 Equation (eGFR)
Renal Impairment

■ Altered kinetic parameters in renal impairment

– Oral Bioavailability
– Volume of distribution (depends on protein
binding)
– Half life
Renal Impairment

■ Acute diseases or trauma to the kidney can cause

Uremia – leading to accumulation of excessive
fluid and blood nitrogen products in the body.

■ Uremia reduces GFR = Decrease renal drug

excretion = LONGER elimination half life of the
drug.
Renal Impairment

■ Oral bioavailability of a drug in severe uremia is

decreased.
– Changes in stomach pH due to N and V
– Changes in GI motility
– Mesenteric blood flow is altered (Intestine)
Renal Impairment

■ Impaired renal function is also associated with

important changes in the binding of drugs to plasma
proteins
– Reduction of serum albumin
– Structural changes in binding sites
– Displacement of drug from albumin binding sites
by organic molecules that accumulate in uremia
Dosing adjustment in renal disease

■ Renal clearance and elimination rate are reduced.

■ Elimination Half life is increased and Vd is altered.
■ Creatinine clearance of <50-60mL/min may be
considered for dose adjustment.
■ *Some antimicrobials may benefit if given with
long infusion time
Dosing adjustment in renal disease

■ Some antimicrobials may benefit if given with long

infusion time
■ Depending on the stability of antimicrobial.
Cefepime
Minimum Stability 37⁰C 8 hours
25⁰C 24 hours
4⁰C 24 hours

Recommended Dose by CrCl > 60ml/min 6 grams infused over 24

Continuous Infusion hours daily
CrCl 30-60 ml/min 4 grams infused over 24
hours daily
CrCl 11-29 ml/min 2 grams infused over 24
hours daily

*Sanford guide to antimicrobial

Meropenem
Minimum Stability 37⁰C < 4 hours
25⁰C 4 hours
4⁰C 24 hours

Recommended Dose by CrCl > 50ml/min 2 grams infused over 3

Continuous Infusion hours every 8 hours
CrCl 30-49 ml/min 1 gram infused over 3
hours every 8 hours
CrCl 11-29 ml/min 1 gram infused over 3
hours every 12 hours

*Sanford guide to antimicrobial

Piperacillin + Tazobactam
Minimum Stability 37⁰C 24 hours
25⁰C 24 hours
4⁰C ND

Recommended Dose by CrCl > 20ml/min 3.375g infused over 4

Continuous Infusion hours every 8 hours
CrCl <20 ml/min 3.375g infused over 4
hours every 12 hours

*Sanford guide to antimicrobial