הוראה בנושאי טיפול תרופתי בסרטן

1. הוראה בנושאי טיפול תרופתי בסרטן פרמקוקינטיקה ומטבוליזם: עקרונות כלליים והדגמתם בתרופות לטיפול בסרטן ערך: פרופ' נ. חיים, מאי 2003, עודכן-ינואר 2005 n_haim@rambam.health.gov.il

2. Definitions (1) • Pharmacokinetics & pharmacodynamics…. • Drug disposition…. • Concentration-time curve…. • Compartment model…. • Distribution & elimination phases, terminal half-life…. • AUC….

3. Pharmacokinetics & Pharmacodynamics • Pharmacokinetics: the time-course of drugs and their metabolites in the body (“what the body does to the drug”). • Pharmacodynamics: the relationship between drug levels and the pharmacologic effects of drugs (“what the drug does to the body”). Holford NH & Sheiner LB. Clin Pharmacokinet 6: 429-53, 1981

4. Drug disposition ….the fate of the drug in the body: entry, distribution, metabolism, and elimination

5. Concentration (Plasma/blood level)-time curve y-axis=drug concentration x-axis=time • Increase in drug concentration: drug release & absorption (for oral administration), increase to steady state concentration (for IV continuous infusion). • Decrease in drug concentration: -distribution in tissues -elimination: excretion & metabolism • If drug concentration is expressed in a semilog plot, the curve will be a straight line (see “AUC” & “Serum MTX levels” slides)

6. Compartment model • The body can be represented as a series of compartments. A compartment does not need to be a real physiologic or anatomic site, but is considered as a tissue or group of different tissues which are similar in blood flow and affinity for a drug. • Drugs move dynamically, in and out of compartments. Central compartment The sum of all body regions (organs and tissues) in which the drug concentration is in instantaneous equilibrium with that in blood or plasma. Blood or plasma are always part of the central compartment. (The highly perfused tissues and blood make up the central compartment).

7. Distribution phase & Elimination phase • After IV injection, drug concentration in plasma declines rapidly due to distribution of the drug into more slowly perfused tissues (distribution phase of the curve). • After equilibrium is established, the loss of drug from the central compartment is due to the overall process of elimination of the drug from the body (elimination phase-slower than the distribution phase).

8. Terminal half-life • Half-life is the period of time required for the amount of plasma or blood drug concentration to decrease by one-half. • Following initial, phase with relatively short half-life (distribution phase), drug levels decrease according to longer t1/2 (s).The terminal half-life is the most clinically significant and represent the parent drug loss (elimination) from the body. • In general, drugs that are extensively distributed have a long t1/2.

9. Area under the curve (AUC) AUC is the area under the plasma (or blood) -time concentration curve. AUC=Drug level X Time (e.g. mg/ml x min)

10. Area under the curve (Cancer principles & practice of oncology. DeVita et al. 6th edition, chapter 19) .

11. Methotrexate pharmacokinetics • Concentration-time curve for HD-MTX • MTX & “third-space body fluids” • Prediction of decreased clearance/increased toxicity

12. Concentration-time curve for high-dose methotrexate (12 gram/m2) • note (in next slide): -Semilog plot of MTX serum levels; curve is straight line for each phase. -Toxicity can be predicted from serum levels. • DeVita….6th Edition :Methotrexate pharmacokinetics follows a 3 phase pattern: initial distribution phase which lasts few minutes, a second phase which lasts 12-24 hrs during which the drug is eliminated with half-life of 2-3 hrs, and a final phase with half-life of 8-10 hrs”. ….the second and final (=terminal) phases can be seen in next slide….

14. Methotrexate half-life & “third spaces” • Methotrexate distributes to “third spaces”(e.g. pleural effusion and ascites), resulting in increased terminal half-life. • Because methotrexate is highly schedule dependent, presence of “third spaces” has major clinical significance in patients treated with methotrexate.

15. Prediction of decreased clearance/increased toxicity according to half-life 24 שעות לאחר מתן מתוטרקסט במנה של 12 גרם/מ”ר: MTX plasma level= 5 X 10 -6 M Creatinine plasma level=1.0 mg/dl כעבור 24 שעות ירדה רמת התרופה ל- 3.5x10-6M האם רמת התרופה בנסיוב ירדה על פי הקצב הצפוי? מה המשמעות? תשובה בשקופית הבאה....

16. Prediction of decreased clearance/increased toxicity according to half-life (contd) קצב הירידה ברמת התרופה הוא לפי זמן מחצית ארוך מהמצופה (למעלה מ-24 שעות במקרה זה). אפשרות סבירה היא, כי החולה פתח רעילות כלייתית משנית לטיפול.

17. Clinical significance of half-life of anti-cancer drugs • Mouth & scalp cooling for prevention of stomatitis & alopecia…. • Frequency/timing of drug administration….

18. קירור רקמות בריאות למניעת רעילות של תרופה-המשמעות של זמן מחצית חיים ניתן להפחית את הרעילות לרירית הפה, הנגרמת ע”י 5 פלואורואורציל, שניתן בבולוס, ע”י קירור רירית הפה במשך כ- 30 דקות החל מזמן קצר לפני תחילת הטיפול. 1.מה הבסיס הפרמקולוגי?, 2. האם ניתן להשיג אפקט דומה של קירור רירית הפה במניעת סטומטיטיס כתוצאה ממתוטרקסט? ,מאדריאמיצין?, 3. האם סביר להניח, כי קירור אצבעות הידיים יפחית פגיעה בציפורניים בעקבות טקסוטר?, 4. האם סביר להניח, כי קירור הקרקפת (כובע קרח) יפחית נשירת שיער בעקבות CMF ?, בעקבות CAF ? • תשובה בשקופית הבאה...

19. קירור רקמות בריאות למניעת רעילות של תרופה-המשמעות של זמן מחצית חיים Terminal half-life: 5-Fluorouracil=approx. 10 min (6-20 min) Methotrexate=8-10 hrs Doxorubicin (Adriamycin)=25-28 hrs Docetaxel (Taxotere)=12 hrs Cyclophosphamide=4-6.5 hrs מטרת הקירור: להפחית זרימת הדם (וחשיפת הרקמה הבריאה לתרופה).משך הקירור צריך להיות בסדר גודל של זמן מחצית חיים. לכן- מבין האפשרויות, שצוינו בשקופית הקודמת, רק מניעת סטומטיטיס של 5-פלואורואורציל בבולוס היא מעשית.

20. Half-life & Frequency/timing of drug administration • Rational for administration of Tamoxifen as single daily dose • Rational for administration of Leucovorin in 4 divided daily doses • תשובה בשקופית הבאה...

21. Half-life & Frequency/timing of drug administration Terminal half-life: Tamoxifen=4 -11 days (לכן- אין הגיון לחלק את המנה היומית למספר מנות). Leucovorin=approx. 0.5 hr for l -LV (active isomer) and 6-8 hrs for d -LV (Bleyer WA. Cancer 63:995-1007,1989) (הטיפול בלויקובורין אמור לכסות (ברמות פרמקולוגיות) את מתוטרקסט, שזמן ממחצית החיים שלה=8-10 שעות).

22. Half-life & Frequency/timing of drug administration • Rational for administration of trastuzumab every 3 weeks: • תשובה בשקופית הבאה...

23. Half-life & Frequency/timing of drug administration The estimated half-life of trastuzumab is 18-27 days (initially it was estimated to be 8.3 days). -Cobleigh M and Frame D. J Clin Oncol 21: 3900-1, 2003 (editorial) -Leyland-Jones B et al. J Clin Oncol 21: 3965-71, 2003

24. Half-life & Frequency/timing of drug administration ASCO recommendations for Mesna administration(Schuchter LM et al. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 20: 2895-2903, 2002): • IV short infusion………. • IV continuous infusion……

25. Half-life & Frequency/timing of drug administration According to ASCO recommendations: IV administration(when the ifosfamide dose is less than 2.5 g/m2 administered as short infusion): 20% of the total daily ifosfamide dose (20% weight/weight) given (as bolus) 15 min before and 4 and 8 hours after ifosfamide infusion for a total of 60% weight/weight dose of ifosfamide. Rational: The mean terminal half-life of mesna is 0.4 hours, and the half-life of dimesna is 1.2 hour (the half-life of ifosfamide is longer).

26. Half-life & Frequency/timing of drug administration According to ASCO recommendations: IV administration(when the ifosfamide dose is less than 2.5 g/m2 administered as continuous infusion): as a bolus dose equal to 20% of the total daily ifosfamide dose (20% weight/weight) followed by a continuous infusion of mesna equal to 40% of the ifosfamide dose, continuing for 12 to 24 hours after completion of the ifosfamide infusion. Rational: The mean terminal half-life of mesna is 0.4 hours, and the half-life of dimesna is 1.2 hour (the half-life of ifosfamide is longer).

27. Examples for correlation between P/K parameters & and pharmacodynamics of anti-cancer drugs • Peak plasma levels of doxorubicin: -continuous infusion…., -weekly administration…., -pegylated liposomal…. • AUC ( carboplatin)…. • Duration of concentrations above a certain threshold ( methotrexate)….

28. Schedule of doxorubicin & cardiac toxicity higher peak plasma doxorubicin levels are associated with higher risk of cardiotoxicity; therefore, continuous infusion(24, 48, or 96 hrs) causes less cardiotoxicity. Legha SS et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96: 133-9, 1982(University of Texax, M.D.Anderson) (with 48 hr infusion 600-650 mg/m2 can be given, and with 96 hr infusion-800 to 1000 mg/m2).

29. Schedule of doxorubicin & cardiac toxicity Higher peak plasma doxorubicin levels are associated with higher risk of cardiotoxicity; therefore, weekly (bolus) administration is associated with less cardiotoxicity than the standard schedule I.e. IV bolus every 3-4 weeks). (In a study ,in which cardiac biopsies were done, (Torti F et al. Ann Intern Med 99: 745-49, 1983 ),it was estimated the weekly administration allowed 168 mg/m2 additional doxorubicin….According to Perry MC…3rd Edition:approximately additional 200 mg/ m2).

30. Cardiotoxicity of pegylated liposomal doxorubicin (Doxil) • Lower peak doxorubicin plasma levels (than with non encapsulated doxorubicin), and therefore, less cardiotoxicity. • “The cardiac risk and its risk compared to conventional doxorubicin formulations have not been adequately evaluated” (manufacturer).

31. Carboplatin & AUC • מניחים, כי קיים קשר ישיר בין האפקט הציטוטוקסי של קרבופלטין (פרמקודינמיקה) ובין AUC (פרמקוקינטיקה). • הנחה זאת מהווה בסיס לחשוב מנת קרבופלטין לפי נוסחת Calvert(ראה בהמשך מצגת זאת).

32. Relationship between duration of exposure and MTX cytotoxicity • MTX is most active against rapidly proliferating cells, as its cytotoxicity effects occur primarily during the S phase. During longer periods of drug exposure, a higher fraction of cells enter the S phase. • In addition, MTX polyglutamate formation is enhanced with longer exposure. (The cytotoxic effect of MTX also depends on drug concentration) • “For bone marrow and GIT epithelium, the plasma concentration and the time-threshold appear to be 2x10-8 molar and about 42 hrs.” Bleyer WA. The clinical pharmacology of methotrexate. Cancer 41: 36-51, 1978

33. Definitions (2) & examples from cancer chemotherapy • Steady-state…. • Bioavailability…. • volume of distribution…. • Protein binding….

34. Steady state concentration (Css) following IV infusion at a constant rate • Css is the plateau level. • Time to reach 90% of Css=3.32 half-lives • Time to reach 95% of Css=4.32 half-lives • Time to reach 99% of Css=6.65 half-lives Therefore, Css is almost completely reached after 4 to 5 half-life.The time required to reach Css is independent of the infusion rate.

35. Time required to achieve steady state concentrations (Css) following continuous infusion • For 5-fluorouracil (terminal half-life approximately 10 min): about 50 min • For bleomycin (terminal half-life approx.2.2 hrs): about 12 hrs

36. Bioavailability • of the oral dose which reaches the general circulation. • Factors that determine bioavailability: - drug characteristics - drug dose - first-pass - factors affecting absorption (e.g. food, GIT surgery, malabsorption, interaction with other drugs given orally)

37. Estramustine phosphate (EP) &food-effect on bioavailability Coadministration of food or dairy products impairs the absorption of EP. Calcium rich foods lead to formation of poorly absorbable calcium complex. Therefore, fasting and avoidance of calcium-rich foods and calcium antacids is recommended before oral EP administration.

38. Bioavailability of anticancer drugs • Leucovorin: almost 100% for the active isomer (l); much less for the d isomer • Mesna (standard dose): 50%-75% • Etoposide (VP-16) 50mg/m2: about 50% • Vinorelbine (soft gel capsules): about 40%; PO 60 mg/m2 corresponds to IV 25mg/m2, and PO 80 mg/m2 corresponds to IV 30mg/m2. • 5FU: erratic

39. Bioavailability and oral administration: mesna ASCO recommendations for oral Mesna administration:…….. • Schuchter LM et al. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 20: 2895-2903, 2002 • 2. Hensley ML et al. (ASCO Special Article). American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17: 3333-3355, 1999

40. Bioavailability and oral administration ASCO recommendations for oral Mesna administration: Oral administration of mesna is an cceptable alternative when the total daily ifosfamide dose is less than 2.0 g/m2. The first dose is given IV at a dose equal to 20% of the total ifosfamide dose. The next 2 doses (40% w/w of the ifosfamide dose) are given orally at 2 and 6 hours. Rational: Bioavailability of mesna is 50-75%. The mean terminal half-life of mesna is 0.4 hrs, and the half-life of dimesna is 1.2 hrs.

41. Volume of distribution (Vd) • Is the hypothetical volume of body fluid that would be required to dissolve the total amount of drug at the same concentration as that found in blood or plasma (i.e. parameter that relates the plasma concentration to the amount of the drug in the body). (Vd=dose/serum (or plasma) drug level) • High Vd reflects extensive extravascular distribution and avid binding to extra vascular tissues.

42. Volume of distribution (Vd) Explain: “The Volume of Distribution of methotrexate approaches that of total body water”…. • הסבר בשקופית הבאה

43. Fluid compartment in the body Water compartmentpercent of body weight plasma 4.5 total extracellular water 27.0 total intracellular water 33.0 total body water 60.0

44. Volume of distribution (Vd) Explain: “for doxorubicin Volume of distribution= 214-690 L/m2”…. • הנפח הגדול, שאינו מתאים לשום יחידה אנטומית או פיזיולוגית, מעיד על קשירה חזקה של התרופה מחוץ לפלזמה.

45. Protein-binding • Drug combines with plasma protein to form a reversible complex. The major component of plasma protein responsible for drug binding is albumin. • Only the free (unbound) drug can pass through cellular membranes, reach the drug receptors or become eliminated. • Protein-binding is of clinical significance when it exceeds 80-90%. • The drug can be displaced from protein binding by other compounds with higher affinity for the protein-binding sites.

46. Interaction between methotrexate to sulphonamides, andphenytoin due to protein binding Increased toxicity of MTX due to protein-binding displacement by these drugs.

47. Etoposide & hypoalbuminemia Dose reduction is needed due to increased unbound plasma concentrations…. Joel SP et al. J Clin Oncol 14: 257-67, 1996 Perdaems N et al. Eur J Clin Pharmacol 54:677-83, 1998

48. Etoposide-hyperbilirubinemia-and protein binding • More than 90% (about 95%) of etoposide is protein bound (mainly to albumin). • Bilirubin displaces etoposide from albumin and , therefore, the unbound drug fraction increases. • Patients with increased bilirubin do not have lower total systemic clearance of etoposide, but have higher exposure to unbound etoposide (which explain the trend toward higher total clearance in these patients). Arbuck SG et al. J Clin Oncol 4:1690-5, 1986 Stewart CF et al. J Clin Oncol 8: 1874-9, 1990 Stewart CF et al. Cancer Res 50: 6854-6, 1990 (About 30%- 50% of etoposide clearance is renal.; non-renal clearance is not fully understood).

49. Clearance • Definition…. • Renal…. • MTX clearance….

50. Clearance • Clearance =dose/AUC or (if determined by continuous infusion): Clearance=infusion rate/Css • units=volume/time (e.g. ml plasma cleared from the drug per minute) • clearance does not depend on dose (unless the drug has non linear pharmacokinetics).