1. Pharmacokinetics as a Tool
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

2. Objectives for Today Review the Levofloxacin Monograph
Discover what we need to know
Integrate Kinetics with Response

3. 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.

4. 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

5. How the pharmaceutical formulation variables affect drug performance
What is Biopharmaceutics?
How the pharmaceutical formulation
variables affect drug performance
(absorption)
in vivo

6. Concentration in Blood
Route IV
Solution
Tablet
MDI Suppository
etc.
Dosage Regimen

7. An Overview of the Pharmacokinetics of Levofloxacin
Based on the CPS
Other Quinolones in Canada
Limited gram-negatives
Nalidixic Acid
Expanded gram-negatives
Ciprofloxacin, Norfloxacin, Ofloxacin
Expanded Gram-positive with Gram negative and Atypical Coverage
Levofloxacin iv/po (1997)
Moxifloxacin po (2000)
Gatifloxacin iv/po (2001)
Moxifloxacin iv (June 2003)
Above plus anaerobic coverage

8. 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?

9. Brand Name
Generic Name & salt
Drug Class
Manufacturer

10. presented first, often includes a mechanism of action.
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 anti-
bacterials involves the inhibition of bacterial topoisomerase II (DNA gyrase)
… vital for DNA replication, transcription, repair and recombination.

11. 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

12. 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.

13. 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.

14. 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.

15. Statements under PharmacokineticsIV
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.

16. Statements under PharmacokineticsIV
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.

17. Statements under PharmacokineticsIV
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).

18. 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.

19. 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.

20. Concentration in Blood
Conc. – Response
Distribution
Concentration in Blood
Elimination
Route IV
Solution
Tablet
MDI Suppository
etc.
Metabolites
Dosage Regimen

21. 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

22. 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

23. Concentration in Blood
Conc. – Response
Factors
Gender
Age
Weight
Disease
Other Drugs
Distribution
Concentration in Blood
Elimination
Route IV
Solution
Tablet
MDI Suppository
etc.
Metabolites
Dosage Regimen

24. 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?

25. Concentration in Blood
Conc. – Response
Factors
Gender
Age
Weight
Disease
Other Drugs
Effect
Beneficial or Adverse ?
Distribution
Concentration in Blood
Elimination
Route IV
Solution
Tablet
MDI Suppository
etc.
Metabolites
Dosage Regimen
How Much?
How Often? ?

26. Pharmacokinetic Questions:
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?