IntroductionTo Pharmacokinetics

Pharmacokinetics as a Tool

Review of CPS Monograph of Levaquin®Levofloxacin, Janssen-Ortho

Available on the web under Product Information Centrejanssen-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 functionStudy the drug Fate Distribution / location /penetration Clearance / organs Conc vs. responseCompare dosage formsQuantify interactionsInter-species scalingDefining dosage informationPopulation StudiesStudy designs

What is Biopharmaceutics?

How the pharmaceutical formulation variables affect drug performance

(absorption)in vivo

RouteIV

SolutionTabletMDI

Suppositoryetc.

Dosage Regimen

Concentration in Blood

An Overview of the Pharmacokinetics of

LevofloxacinBased on the CPS

Limited gram-negatives

Expanded gram-negatives

Expanded Gram-positive with

Gram negative and Atypical

Coverage

Above plus anaerobic coverage

Moxifloxacin po (2000)

Gatifloxacin iv/po (2001)

Moxifloxacin iv (June 2003)

Nalidixic Acid

Ciprofloxacin, Norfloxacin, Ofloxacin

Levofloxacin iv/po (1997)

Other Quinolones in Canada

An Overview of the

Pharmacokineticsof Levofloxacin

CPS 2004, pages 1067 – 71.Levaquin®; Levofloxacin, Janssen-Ortho Formulations: IR Tablets 250-mg, 500-mg & 750-mgIV 5mg/mL single use 20 mL vials

What aspects of the pharmacokinetics in this monograph need clarification?

Brand Name

Generic Name & salt

Drug ClassManufacturer

Brand Name

Generic Name & salt

Drug ClassManufacturer

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.

Brand Name

Generic Name & salt

Drug ClassManufacturer

Pharmacology usually presented first, often includes a mechanism of action.

Pharmacokinetics is a subsection of the Pharmacology Section

Statements under Pharmacokinetics

OralLevofloxacin 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

IVFollowing 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

DistributionThe 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

MetabolismLevofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug ( 87%) in the urine within 48 hours.

ExcretionThe 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.

RouteIV

SolutionTabletMDI

Suppositoryetc.

Dosage Regimen

Concentration in BloodDistribution

Elimination

Metabolites

Conc. – Response

Statements under Pharmacokinetics

Summary of PharmacokineticsThe 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.

CmaxTmaxAUCCl/FVd/FT½Cl

Statements under PharmacokineticsPage 2.

Factors Influencing Pharmacokinetics

ElderlyPediatricGenderRenal InsufficiencyClearance of levofloxacin is reduced and plasma elimination prolonged in this patient population.

Hepatic InsufficiencyBacterial Infection

RouteIV

SolutionTabletMDI

Suppositoryetc.

Dosage Regimen

Concentration in BloodDistribution

Elimination

Metabolites

FactorsGender

AgeWeightDisease

Other Drugs

Conc. – Response

Statements under DosagePage 4.

Renal InsufficiencyClearance 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?

RouteIV

SolutionTabletMDI

Suppositoryetc.

Dosage Regimen

How Much?How Often?

?

Concentration in Blood

Conc. – Response

Distribution

Elimination

Metabolites

EffectBeneficial or Adverse ?

FactorsGender

AgeWeightDisease

Other Drugs

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?