Introduction
To Pharmacokinetics
Pharmacokinetics as a Tool
Review of CPS Monograph of Levaquin®
Levofloxacin, Janssen-Ortho
Available on the web under Product Information Centre
janssen-ortho.com
Objectives for Today
•Review the Levofloxacin Monograph
•Discover what we need to know
•Integrate Kinetics with Response
What is Pharmacokinetics?
The mathematical description
of drug absorption, distribution,
metabolism and excretion ….
As well as the quantitative description
of how these processes affect the
time course and intensity of response.
What is Pharmacokinetics?
Is a tool used to:
Study the body and its function

Phenotyping

Organ function
Study the drug

Fate

Distribution / location /penetration

Clearance / organs

Conc vs. response
Compare dosage forms
Quantify interactions
Inter-species scaling
Defining dosage information
Population Studies
Study designs
What is Biopharmaceutics?
How the pharmaceutical formulation
variables affect drug performance
(absorption)
in vivo
Concentration in Blood
Route
IV
Solution
Tablet
MDI
Suppository
etc.
Dosage Regimen
An Overview of the
Pharmacokinetics of
Levofloxacin
Other Quinolones in Canada
Based on the CPS
Limited gramnegatives
Nalidixic Acid
Expanded gramnegatives
Ciprofloxacin, Norfloxacin, Ofloxacin
Expanded Grampositive with
Gram negative
and Atypical
Coverage
Levofloxacin iv/po (1997)
Moxifloxacin po (2000)
Above plus
anaerobic
coverage
Gatifloxacin iv/po (2001)
Moxifloxacin iv (June 2003)
An Overview
of the
Pharmacokinetics
of Levofloxacin
CPS 2004, pages 1067 – 71.
Levaquin®;
Levofloxacin, Janssen-Ortho
Formulations:
IR Tablets
250-mg, 500-mg & 750-mg
IV 5mg/mL
single use 20 mL vials
What aspects of the pharmacokinetics
in this monograph need clarification?
Brand Name
Generic Name & salt
Drug Class
Manufacturer
Brand Name
Generic Name & salt
Drug Class
Manufacturer
Pharmacology usually
presented first, often
includes a mechanism of
action.
Pharmacology: Levofloxacin, a synthetic broad spectrum antibacterial
agent for oral and i.v. administration. Levofloxacin is the L-isomer of ofloxacin.
… The mechanism of action of levofloxacin and other quinolone antibacterials involves the inhibition of bacterial topoisomerase II (DNA gyrase)
… vital for DNA replication, transcription, repair and recombination.
Brand Name
Generic Name & salt
Drug Class
Manufacturer
Pharmacology usually
presented first, often
includes a mechanism of
action.
Pharmacokinetics is a
subsection of the
Pharmacology Section
Statements under Pharmacokinetics
Oral
Levofloxacin is rapidly and essentially
completely absorbed following oral
administration.
Peak plasma concentrations are
usually attained after 1-2 hours after
oral dosing.
The absolute bioavailability of a 500
mg tablet and a 750 mg tablet of
Levofloxacin is approximately 99%
in both cases, demonstrating complete
oral absorption of levofloxacin.
Statements under Pharmacokinetics
Oral
Levofloxacin pharmacokinetics are
linear and predictable after single
and multiple oral dosing regimens.
Steady-state conditions are reached
within 48 hours following a 500 mg
or 750 mg once-daily dosage regimen.
Statements under Pharmacokinetics
Oral
The peak and trough plasma
concentrations attained following
multiple once daily oral dosage
regimens were approximately
5.7 ug/mL and 0.5 ug/mL after the
500 mg doses and 8.6 ug/mL and
1.1 ug/mL after the 750 mg doses,
respectively.
There was no clinically significant effect of food on the extent
of absorption of levofloxacin. Oral administration with food slightly
prolongs the time to peak concentration by approximately 1 hour,
and slightly decreases the peak concentration by approximately 14%.
Therefore, levofloxacin can be administered without regard to food.
Statements under Pharmacokinetics
IV
Following a single intravenous dose
of levofloxacin to health volunteers,
the mean peak plasma concentration
attained was 6.2 ug/mL after a 500
mg dose infused over 60 minutes,
and 7.99 ug/mL after a 750 mg dose
infused over 90 minutes.
Levofloxacin pharmacokinetics are
linear and predictable after single
and multiple IV dosing regimens.
Statements under Pharmacokinetics
IV
Steady state conditions are reached
within 48 hours following a 500 mg
or 750 mg once-daily IV regimens.
The peak and trough plasma
concentrations following multiple
once-daily i.v. regimens were
approximately 6.4ug/mLand
0.6 ug/mL after 500 mg doses and
7.92 ug/mL and 0.85 ug/mL
after 750 mg doses, respectively.
Statements under Pharmacokinetics
IV
The plasma concentration profile
of levofloxacin after IV
administration is similar and
comparable in extent of exposure
(AUC) to that observed for
levofloxacin tablets when equal
doses (mg/mg) are administered.
Therefore, the oral and IV routes
of administration can be considered
interchangeable (see figure).
Statements under Pharmacokinetics
Distribution
The mean volume of distribution of
levofloxacin generally ranges from
74 to 112L after single and multiple
a 500 mg or 750 mg doses,
indicating widespread distribution
to body tissues.
Levofloxacin reaches its peak levels
in skin tissue (11.7 ug/g for a
750 mg dose) and in blister fluid
(4.33 ug/g for a 500 mg dose)
at approximately 3-4 hours
after dosing.
Statements under Pharmacokinetics
Metabolism
Levofloxacin undergoes limited
metabolism in humans and is
primarily excreted as unchanged
drug ( 87%) in the urine within
48 hours.
Excretion
The major route of elimination of
levofloxacin in humans is as
unchanged drug in the urine. The
mean terminal plasma elimination
half-life of levofloxacin ranges from
6 to 8 hours following single or
multiple doses of levofloxacin given
orally or intravenously.
Conc. – Response
Distribution
Concentration in Blood
Elimination
Route
IV
Solution
Tablet
MDI
Suppository
etc.
Metabolites
Dosage Regimen
Statements under Pharmacokinetics
Summary of Pharmacokinetics
The mean pharmacokinetic
parameters of levofloxacin
determined under single and steady
state conditions following oral (po)
or intravenous (IV) doses of
levofloxacin are summarized in the
following table.
Cmax
Tmax
AUC
Cl/F
Vd/F
T½
Cl
Statements under Pharmacokinetics
Page 2.
Factors Influencing Pharmacokinetics
Elderly
Pediatric
Gender
Renal Insufficiency
Clearance of levofloxacin is reduced
and plasma elimination prolonged
in this patient population.
Hepatic Insufficiency
Bacterial Infection
Conc. – Response
Factors
Gender
Age
Weight
Disease
Other Drugs
Distribution
Concentration in Blood
Elimination
Route
IV
Solution
Tablet
MDI
Suppository
etc.
Metabolites
Dosage Regimen
Statements under Dosage
Page 4.
Renal Insufficiency
Clearance of levofloxacin is reduced
and plasma elimination prolonged
in this patient population.
For patients with altered renal
function, CrCl < 80 mL/min
… Table 4
Why is there an initial dose
and then a subsequent dose?
Conc. – Response
Factors
Effect
Gender
Age
Weight
Disease
Other Drugs
Beneficial or Adverse ?
Distribution
Concentration in Blood
Elimination
Route
IV
Solution
Tablet
MDI
Suppository
etc.
Metabolites
Dosage Regimen
How Much?
How Often?
?
Pharmacokinetic Questions:
1.
•
•
•
•
•
•
Kinetic Variables:Cmax, Tmax, AUC, Clearance, F, Vd, T½
Dosing Frequency; Role of clearance, half-life…
Steady-State??? Time to Steady State?
Interactions? Predicted from PCK?
Terminal elimination phase????
Dosage Form; Interchangeable… rationale??
How do you make dosing adjustments?