Oncology + Obesity

General Principles of Chemotherapy

1. Antineoplastics generally have ________ therapeutic ranges

2. The presence of ______ may ALTER PK of drugs

3. Must know …. → blood/serum conc not always same as conc in tissues

4. Drug ______ are common

1. narrow

2. tumor

3. drug conc where tumor is located

4. interxns

1. Unique AUC based dosing →

2. Therapeutic drug monitoring →

3. Clinical condition may affect PK of →

1. carboplatin

2. high dose MTX and busulfan

3. third space MTX

Pharmacogenomic Considerations

1. Dihydropyrimidine dehydrogenase deficiency →

2. UGT1A1*28 homozygosity →

3. Thiopurine S-methyltransferase deficiency →

4. CYP2D6 alterations/drug interxns →

1. fluorouracil

2. irinotecan

3. 6MP, 6-thioguanine

4. tamoxifen

PLATINUM COORDINATION COMPLEXES

1. Platinum-based _________ agents

2. _______ binds DNA → produce _____ DNA cross links

3. Targets which phase of CC?

1. alkylating

2. covalently, interstrand

3. Mitosis

CARBOPLATIN

AUC BASED DOSING

1. Metabolism: ___________ metab to aquated & hydroxylated compounds

2. Excretion:

3. t1/2 NORMAL renal fx:

4. Protein binding:

5. Vd: 16L → penetrates …

6. What does higher AUC mean?

1. minimal hepatic

2. urine (70% unchanged)

3. 2.6-5.9h, Pt 5+ days

4. carbo 0%, Pt yes

5. liver, kidney, skin, CNS

6. +TC

1. CARBOPLATIN: Calvert Formula

2. Cap CrCL at ______

3. If SCr …

4. Weight consideration

1. Dose (mg) = target AUC x (GFR + 25)

2. 125 mL/min

3. <0.7 → round to 0.7

4. use TBW, if 20-30%>IBW use ABW

1. CrCL =

2. Dose =

1. 63 mL/min

2. 440 mg

1. CrCL =

2. Dose =

1. 168.8 mL/min

2. ~388 mg

METHOTREXATE

1. MOA:

2. Oral abs:

3. Distribution: penetrates _______ fluids and exits them slowly

4. Excretion

1. inhib DHFR → prevent tetrahydrofolate FH4 to dihydrofolate FH2

2. variable, -abs w HIGHER doses → use IV

3. third space

4. 80-90% urine, <10% feces (unchanged)

THIRD SPACING OF MTX

1. ________ clearance of MTX

2. ^ extends t1/2 by ____ times

3. Must __________________ prior to MTX infusion

1. prolongs

2. 3

3. drain third space fluids

HIGH-DOSE METHOTREXATE

1. Dose _______ gram/m² IV

2. Used for (3)

3. Why high dose? → allows MTX to enter cell by _____________ rather than through RFC

4. Required hospital admission and ____________

5. ^ Purpose:

6. *Rescue/reversal agent REQUIRED FOR ALL PTS RECEIVING HD-MTX + site of action

7. Agent 2 + site of action (really expensive!!!)

1. >/= 0.5

2. leukemia, lymphoma, osteosarcoma

3. passive diffusion

4. monitoring of levels

5. predict/minimize toxicity

6. leucovorin/folinic acid → intracell → does NOT -MTX

7. Glucarpidase → extracell → use when kidney injury → will -MTX, given w leucovorin+hydration

PRIOR TO MTX INFUSION

1. Check for drug interxns: 7 examples

2. Give ________ to achieve adequate urine output to promote excretion of drug

3. Use ____________-based IV fluids to ensure alkalinization of urine BEFORE infusion → why?

4. Ensure _______

5. When to start leucovorin? + typical starting dose

6. ^ dosage form?

7. ^ Monitoring → 2

8. Continue IV fluids + leucovorin until MTX level is ____ micromolar (~3-4 days)

1. PPIs, NSAIDs, penicillins, phenytoin, cipro, amiodarone, probenecid

2. IV fluids

3. sodium bicarb → prevent precipitation

4. no third spacing

5. ~24h after inf complete → 25-50 mg q 6h

6. oral saturable → IV >25 mg

7. daily serum MTX + SCr

8. <0.1

What monitoring and supportive care is required for this patient’s high dose
methotrexate?

1. drug interxns

2. urine alkalinity + regular urine pH

3. adequate urine output

4. daily SCr/MTX

BUSULFAN

1. Alkylating agent that reacts with ___________ and interferes w DNA rep + RNA transcription

2. Oral abs →

3. Distribution

4. Metabolism

5. Excretion

6. HIGH DOSE BUSULFAN USE →

7. Goals of busulfan therapeutic drug monitoring →

1. N7 pos of guanine

2. rapid + complete

3. plasma = CSF (readily crosses BBB)

4. HEPATIC → glutathione then oxidation

5. 25-60% urine as METABs, <2% unchanged

6. stem cell txp

7. minimize tox AND maximize efficacy

HIGH DOSE BUSULFAN : IV busulfan PK procedures

1. Step 1: After 1st dose, draw levels at …

2. Step 2:

3. Step 3:

4. Step 4:

5. Typical Css target =

6. Typical AUC target =

1. at end, 15 min, 2h, 3h, 4h, 6h after EOI

2. calc AUC or Css w above values

3. calc CL → CL = dose/AUC

4. calc dose → dose = CL x target AUC

5. 600-900

6. 900-1500

Obese classification

1. underweight

2. normal

3. overweight

4. pre-obese

5. Obese

6. obese class I

7. obese class II / severely

8. obese class III / morbidly

9. super obese

10. super super obese

1. <18.5

2. 18.5-25

3. 25+

4. 25-30

5. 30+

6. 30-35

7. 35-40

8. 40+

9. 50+

10. 60+

PK CHANGES IN OBESITY: Absorption

1. -

2. -

3. IM injections may inadvertently be administered as ______

4. High Vd drug → tissues → which weight dosing?

5. Low Vd drug → plasma → which weight dosing?

6. Factors that impact drug distribution → 3

1. delayed GE → lower Cmax (peak)

2. +abs of some oral meds w fatty meal → higher Cmax

3. deep SQ → unknown impact on abs

4. lipophilic → TBW

5. hydrophilic → IBW/ABW

6. hydro/lipophilicity, plasma protein binding, Mw

PK CHANGES IN OBESITY: Metabolism

1. largely ________

2. hepatic volume increases but most likely due to _________ rather than +metabolic activity

3. SOME data show +CYP2E1, 1A2, 2C9 and decreased _____

4. ELIMINATION → Bi directional, generally +CL but higher incidence of renal dysfx w _____ or _____

1. unknown

2. fatty infiltration

3. 3A4

4. HTN, diabetes

1. What is the most accurate (but most expensive) CrCL equation for obesity?

2. Can also use Cockroft & Gault using _____

1. 24h urine collection + measured CrCL eqn

2. LBW

AMINOGLYCOSIDES ADME

1. A - poor PO

2. D - small

3. E - renal

VANCOMYCIN ADME

1. A - poor PO

2. D - large

3. E - renal

100 kg 5’4” female patient

1. BMI

2. IBW

3. ABW

1. 38

2. 55

3. 73

32 yo female, 270 lbs, 5’8, needs to be initiated on Tobramycin for pneumonia. CrCl is approx. 100 ml/min/m²

Assume traditional dosing

1. What questions would you ask?

2. Which body weight to use?

3. 2.5 mg/kg/dose q 8-12h →

1. renal fx? comorbidities?

2. ABW