Body Surface Area and Chemotherapy

1. Body Surface Area and Chemotherapy ???

3. Inter-ethnic differences in the myelotoxicity for adjuvant breast cancer AC: doxorubicin: 60mg/m2 cyclophosphamide: 600mg/m2 Proc Am Soc Clin Oncol 21: 2002 (abstr 252)

4. From dosage to survival

5. Outline Calculation of BSA Chemotherapy dose based on BSA Adjustment of the dosage

6. Calculation of BSA

7. In 1890s, for animal, BSA = aW3/2 In order to calculate the metabolic rate of animals and persons The metabolic rate of a species in proportional to its surface area (??????)

10. Formula of BSA Du Bois formula Only 9 patients were studied Linear measurement of total surface area: ranging from 0.8-1.8 m2 The principles geometrically similarity ; BSA=weight(Kg)0.425*Height(cm)0.725*0.007184 Tight underwaer for measurement of BSA Geometric method Shape remanins constant as body size changesTight underwaer for measurement of BSA Geometric method Shape remanins constant as body size changes

11. Other formulas of BSA BSA = aWb BSA = a(W+H) BSA = a WbHc BSA = W.5378xH.3964x0.24265 Geometric method

12. Rationales of formulas Bilaterally symmetrical body type No physical abnormalities Physiologically normal

13. Difference between formulas No formula is correct No formula is incorrect All formulas have their confident interval, limit, and error No one formula is better than another

14. Chemotherapy dosage based on BSA

15. BSA and metabolic rate Rubner in 1883 reported small animals utilized more oxygen and produce more heat than large animals Kleiber in 1932 reported the �mouse-elephant� curve 1. Due to small animals having reatively larger BSA than larger animals1. Due to small animals having reatively larger BSA than larger animals

16. Foundation of BSA-based chemotherapy dosage Pinkel in 1958 reported a retrospective study about 5 cytotoxic drugs (BSA-based) in human ( adult and child) and different animals

17. From preclinical to clinical study The starting C/T doase in phase I clinical trial is from the preclinical animal study By the interspecies scaling and possible dirrefent PK/PD in different species, the starting dose is LD10 of sensitive aninal

18. Shortcome of BSA-based dosage Variation of clinical toxicities and response under the same dosage/M2 The correlation of BSA and liver function was not fully established the measure of drug PK/PD was common now Although BSA is related to renal and cardiac output, the drug metabolism is more complexAlthough BSA is related to renal and cardiac output, the drug metabolism is more complex

19. BSA and Chemotherapy ? Adults with normal liver and renal function r>0.707 Is betterAdults with normal liver and renal function r>0.707 Is better

20. BSA and Cisplatin Dosing

23. Alternative proposals to BSA Age Median ratio of child to adult per m2 is 1.5 Functional difference between the young and elderly Fixed dosing PK-guided dose calculation Therapeutic drug monitoring and pharmacologic adaptive control PMT dosing

24. Pharmacokinetically Guided Dose Adaptation AUC: area under curve Css: concentration at steady state Cmax: peak plasma concentration Pharmacodynamics: response/Toxicities Palliative or curative treatment

25. From dosage to survival

26. Take home message Chemotherapy dosage basing on BSA shouldn�t be over-emphasized There is much errors logically, but we have few other choices ????!!

27. Therapeutic Drug Monitoring and Pharmacologic Adaptive Control Using PK parameters to adjust subsequent doses Shortage : Drug-tumor interactions; Combination therapy; Financial cost and inconvenience Cellular PK instead of serum drug PK? Etopsie ; SuraminEtopsie ; Suramin

28. Body shape vs body size Errors of measuring weight and height Ideal body weight / real body weight / lean body mass?

29. The Correct Use of BSA Mostly confined to blood compartment A high affinity to serum serum protein Drugs eliminated by process taking place in the central compartment Primarily eliminated by the kidney (replaced by drug clearance or AUC)

30. BSA and BMR The ration of blood volume to BSA was constant in rabbits, guinea, pigs and mice Human cardiac output and renal function was correlated to BSA, reported by Grollman in 1929 and Smith in 1951

31. Histological Backgroun Body size and BMR ( basic metabolic rate) Quantitative interspecies dose of antineoplastic drugs

33. BSA and Chemotherapy Drug clearance was calculated by compartmental or non-compartmental analysis Criteria: 1. a linear regression coefficient R>0.5 2.P<0.01 3.a relative reduction of clearance >15%Drug clearance was calculated by compartmental or non-compartmental analysis Criteria: 1. a linear regression coefficient R>0.5 2.P<0.01 3.a relative reduction of clearance >15%

34. For example, we found that body surface area was highly correlated with temozolomide clearance (R .88, P<.001) and was associated with 35% of the variation in temozolomide clearance among patients. Temozolomide is an alkylating agent that undergoes pH-dependent breakdown to the active moiety 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide immediately following drug administration and is virtually isolated to the central compartment. Interpatient variability in DHA�paclitaxel clearance was reduced by 26% when the dose of that agent was normalized to body surface area. DHA� paclitaxel has a low clearance (~0.11 L/h), has a small volume of distribution (~4 L), and is extensively (>99.6%) but nonspecifically bound to alpha1- acid glycoprotein and albumin (76). Cremophor EL For example, we found that body surface area was highly correlated with temozolomide clearance (R .88, P<.001) and was associated with 35% of the variation in temozolomide clearance among patients. Temozolomide is an alkylating agent that undergoes pH-dependent breakdown to the active moiety 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide immediately following drug administration and is virtually isolated to the central compartment. Interpatient variability in DHA�paclitaxel clearance was reduced by 26% when the dose of that agent was normalized to body surface area. DHA� paclitaxel has a low clearance (~0.11 L/h), has a small volume of distribution (~4 L), and is extensively (>99.6%) but nonspecifically bound to alpha1- acid glycoprotein and albumin (76). Cremophor EL