"Application of pharmacokinetics and bioavailability in clinical situations"

The success of drug therapy is highly dependent on the choice of the drug, the drug product, and the design of the dosage regimen. The choice of the drug is generally made by the physician after careful patient diagnosis and physical assessment. The choice of the drug product (eg, immediate release vs modified release) and dosage regimen is based on the patient’s individual characteristics and known pharmacokinetics.

1. Application of Pharmacokinetics and Bioavailability in Clinical Situations Faizan Akram The Certified Pharmacist

2. Contents Pharmacokinetics Clinical Pharmacokinetics Bioavailability Application of Pharmacokinetics and Bioavailability in Clinical Situations Individualization of drug dosage regimen Therapeutic drug monitoring Design of dosage regimen Conversion of intravenous infusion to oral dosing Determination of dose

3. PHARMACOKINETICS Pharmakon means drug Kinesis means motion, or change of rate “ The application of kinetics in study of absorption, metabolism and excretion of the drugs .”

4. CLINICAL PHARMACOKINETICS “The application of pharmacokinetics principles in clinical settings for safe and effective therapeutic management of individual patient .”

5. BIOAVAILABILITY “A measurement of the rate and extent to which therapeutically active moiety is absorbed from the drug product, reaches the systemic circulation and becomes available at the site of action .”

6. “Poisons and medicines are often times the same substance given in different intents”” Peter Latham (1789-1875) Therefore, the application of pharmacokinetics to dosage regimen design must be coordinated with proper clinical evaluation of the patient and monitoring.

7. Application of Pharmacokinetics and bioavailability in Clinical Situations Individualization of drug dosage regimen Therapeutic drug monitoring Design of dosage regimen. Conversion of intravenous infusion to oral dosing Determination of dose

8. Effect of changing dose and dosing interval on Cmax ∞, Cmin ∞, Cav ∞ Determination of frequency of drug administration Nomograms and tabulation in designing dosage regimens Determination of route of administration Dosing of drugs in infants and children Dosing of drugs in the elderly Dosing of drugs in obese patients Pharmacokinetics of drug interactions

9. 1. Design of Dosage Regimen Softwares available DataKinetic (ASHSP) Abbottbase Pharmacokinetic system

10. Methods Individualized Dosage Regimens Dosage Regimens Based on Population Averages Dosage Regimens Based on Partial Pharmacokinetic Parameters Empirical Dosage Regimens

11. 1) INDIVIDUALIZED DOSAGE REGIMEN Dosage regimen is decided on the basis of Not feasible for calculation of initial dose Pharmacokinetic parameters of the drug in the individual patient Patient’s age LBW Creatinine Clearance

12. 2) DOSAGE REGIMEN BASED ON POPULATION AVERAGES This method used avg. Pharmacokinetic parameter Based on

13. Fixed model Population average pharmacokinetic parameters Assumption: Drug follows the Pharmacokinetic of a One-compartment model. Pharmacokinetic parameters are remain constant.

14. Adaptive model Patient variables Assumption: Pharmacokinetic parameter does not change.

15. 3) Dosage regimen based on Partial Pharmacokinetic Parameters Some of assumptions will depend on F equal 1 or 100% the risk of undermedicated Safety Efficacy Therapeutic range

16. 4) Empirical Dosage Regimen

17. 2. INDIVIDUALIZATION OF DRUG DOSAGE REGIMEN "Adaptation of the dosage regimen in function of the clinical characteristics of the individual, aiming to achieve the best possible therapeutic efficiency at the lowest risk of unwanted effects."

18. OBJECTIVE To produce optimum therapeutic response with minimum adverse effects by maintaining serum drug concentration with in the therapeutic range.

19. WHY DO WE REQUIRE INDIVIDUALIZATION OF DOSAGE REGIMEN? "The right medicine for the right person at the right dosage regimen"

20. Factors Gender, age, weight, BSA... etc . Deficient liver- and kidney function or other diseases Severity of side effects and patient’s ability to tolerate the drug Genetic factors  

21. Clinical laboratory analyses Plasma drug concentration For drugs with a narrow therapeutic window For drugs that follow nonlinear pharmacokinetics For some drugs that have large inter- and intra-subject variability in its pharmacokinetics

22. Individualized drug therapy with Feedback Control Technology & starting information Internet General patient database General drug database Software applications Aids for compliance, monitoring and feedback control

23. Treatment methods Patient specific data Assessments Individualized treatments Compliance, monitoring and feedback control

24. Example; Patient specific data

25. Assessments Pathology data influencing pharmacokinetics Treatment evaluation Drug effects Side effects Drug dosage regimen Compliance Drug Interactions

26. Individualized Treatments Individual parameters Population parameters Treatment targets Treatment suggestions with outcome prediction

27. Compliance, monitoring and feedback control Aids for compliance, monitoring and feedback control E-packages Mobile phones PDA´s Traditional Diary

28. 3. Conversion from I.V. infusion to oral dosing Objective: To calculate the appropriate oral dosage regimen for a patient whose condition has been stabilized by an I.V drug infusion .

29. Time( in hr) Plasma conc.(µg/ml) MEC MTC Therapeutic range Plot showing conversion from IV infusion to oral dosing C SS IV infusion Oral dose

30. Method: Css after IV infusion is identical to the desired C∞av after multiple oral doses. Equation: C ∞av = FSD o /kV D τ

31. 4.Determination of Dose Objective: To deliver a target therapeutic level of the drug in the body.

32. Total dose = Loading dose + Maintenance dose Loading dose (D L ) D L = C P V D /F Maintenance dose (D o ) D o = C ∞av V D τ / 1.44t 1/2 F

33. Dosing interval in hr Plasma Drug Conc. MEC MTC Loading dose D0 D0 Do Do D0 Maintenance Doses D0

34. Principle of Superposition Assumption: Early doses don't affect the pharmacokinetics of subsequent doses. When the dose & dosing interval kept constant. The extent of accumulation of drug in the body depend upon dosing interval.

35. Factors: During Multiple dosing, concentration of drug in the body depend upon Persistence factor Elimination factor Accumulation factor

36. 5. THERAPEUTIC DRUG MONITORING “The monitoring of drug concentration for optimal drug therapy.” It involves measuring drug concentration in blood. Alternative to blood Saliva Tears

37. Objective To attain rapid and safe concentration of drug in plasma with in the therapeutic range in order to provide the safest approach to optimal drug therapy. Minimum therapeutic concentration Maximum therapeutic concentration Sub-therapeutic Level Toxic Level Therapeutic Range Plasma drug concentration Time

38. Therapeutic range of commonly monitored drugs Drugs Therapeutic range Digoxin 1-2 ng / mL Gentamycin 5-10 µg/ mL Pheytoin 10-20 µg/ mL Theophyline 10-20 µg/ mL Amikacin 20-30 µg/ mL

39. TARGET CONCENTRATION INTERVENTION “Drug concentrations need to be interpreted in the context of individual patient without rigid adherence to a target range” ( Aust Prescr 2008; 31:42-4)

40. Prerequisites for use of serum drug concentration in tdm Drug response Concentration of free drug Concentration in serum Concentration of free drug Degree of serum protein & tissue binding

41. Target Concentration Rational Therapeutics Pharmacokinetics Dose Effect Pharmacodynamics Variables affecting the target concentration

42. Do all drugs need TDM?

43. Drugs that do not need TDM Drug whose serum concentrations do not correlate with therapeutic or toxic effects Drugs with less complicated pharmacokinetics Some drugs have a broad range of effective and safe dosage regimens Drugs that used for treating diseases of which their clinical end point can be easily be monitored

44. Indications for TDM Drugs with Narrow therapeutic range Drugs with non-linear pharmacokinetics Drugs which exhibit relatively wide inter-individual variation in the rate of metabolism

45. Indications for TDM Drugs whose sign of toxicity are difficult to recognize clinically Check patient compliance When the patients are receiving multiple drug therapy with potential risk of drug interaction

46. Indications for TDM Therapeutic failure Drugs which exhibit poor and erratic absorption. Concomitant disease Individualization of dose

47. Candidates for TDM: Antibiotics Antiepileptics Cardiac agents Antiarrythmics Psychotherapeutics Miscellaneous agents

48. 51 Functions of TDM

49. Initiation and management of drug therapy

50. PROCESS OF TDM

51. TDM TDM involves NOT only Measuring drug concentration But Interpretation of result This requires: Knowledge of the pharmacokinetics Sampling time Drug knowledge Patient’s clinical condition

52. Gentamicin Very poorly absorbed orally Renally cleared

53. Gentamicin

54. Example: Gentamicin Multiple daily dosing: 1 - 2 mg/kg 8 - 12 hourly Once daily dosing 5 - 7 mg/kg once daily

55. The following formula can be used to calculate creatinine clearance in order to determine the doses and dosing interval when prescribing gentamicin . Where N = 150 for female patients; 160 for male patients >70 years,170 for male patients <70 years Normal creatinine clearance Male range 97 – 137ml/min Female range 88 – 128 ml/min

56. Gentamicin TDM Once daily dosing Sampling: Every 3–5 days in clinically stable patients Daily if patient clinical state is unstable Methods: Graphical method Trough concentrations Target AUC

57. 1) Graphical method Using nomograms Sample collection (6 and 14 hours) after completion of dosing If level is normal line

58. If concentration is the maximum line - Reduce dose - Extend dose interval to 36 or 48 hours

59. 2) Trough concentrations Do not indicate whether dosage is adequate To avoid drug accumulation and risk of toxicity Measure plasma concentration 24 hours after administration of initial dose

60. 3) AUC Target AUC ( 72 - 101 mg.h /L ) Requires 2 samples First sample ½-1 hr after completing the infusion/injection The second at a specific time depending on renal function and technique of assay used

61. Gentamicin TDM Multiple daily dosing Dosing every 8–12 hours Usually monitored by measuring Peak concentration (taken 30 min after infusion) Peak concentration is 5-8 mg/L Trough concentration (taken before next dose) Trough concentration is <2 mg/L

62. Factors Affecting TDM Factors related to drug administration or blood drawing Factors related to pharmacokinetic principles Factors related to laboratory

63. Factors: Drug Administration or Blood Drawing Wrong dose administered Dose skipped Dose given at wrong time, blood drawn as ordered Dose given at right time, blood not drawn at right time Infusion time too fast or too slow Infusion hold prior to draw Blood drawn form same vein into which drug infused

64. Factors: Pharmacokinetics Levels obtained not at steady state Levels obtained without respect to dosing time Active metabolites not taken into account Poor absorption due to any reasons Drawing levels before distribution to site of action is complete

65. Fluid status changes Inappropriate weight use Significant changes in liver or renal function Significant changes in percent of bound and free drug Changes in metabolizing enzyme saturation threshold Drug interactions

66. Factors: Laboratory Improper performance of assay Active metabolites not measured Assay interference Improper specimen collection or storage

67. Clinical Usefulness of TDM Maximum efficacy of drug Avoiding toxicity Identify factors regarding individual variation Facilitating dose adjustment Greater insight into the factors determining the patients response to drug therapy.

68. References Shargel Leon, Andrew Yu B.C., “Applied Biopharmaceutics and pharmacokinetics”, Page no. 185,207, 613-625. P.L. Madan , “ Biopharmaceutics and Practical Pharmacokinetics” Page no. 399-455. Gibaldi M., “ Biopharmaceutics And Clinical Pharmacokinetics” Page no.345. Malcolm Rowland, Thomas N. Tozer “Clinical Pharmacokinetics Concepts & Application” Page no.53-83, 203-290.

69. Thank You