Introduction To Pharmacokinetics Pharmacokinetics as a Tool

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

6. Concentration in Blood Route IV Solution Tablet MDISuppository 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. 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 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.

16. 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.

17. 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).

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. Conc. – Response Distribution Concentration in Blood Elimination Route IV Solution Tablet MDISuppository 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. Conc. – Response Factors Gender Age Weight Disease Other Drugs Distribution Concentration in Blood Elimination Route IV Solution Tablet MDISuppository 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. Conc. – Response Factors Gender Age Weight Disease Other Drugs Effect Beneficial or Adverse ? Distribution Concentration in Blood Elimination Route IV Solution Tablet MDISuppository 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?