Oncology + Obesity + Transplant + Dialysis

General Principles of Chemotherapy

1. Antineoplastics generally have ________ therapeutic ranges

2. The presence of tumor may _________ of drugs

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

4. Drug ______ are common

1. narrow

2. alter PK

3. drug conc where tumor is located

4. interxns

Chemo drugs

1. Unique AUC based dosing →

2. Therapeutic drug monitoring →

3. Clinical condition may affect PK of →

1. carboplatin

2. high dose MTX, 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

Cisplatin, Carboplatin

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

1. _____ BASED DOSING

2. Metabolism: ___________ metab to aquated & hydroxylated compounds

3. Excretion:

4. t1/2 NORMAL renal fx:

5. Protein binding:

6. Vd: 16L → penetrates … (4)

7. What does higher AUC mean?

1. AUC

2. minimal hepatic

3. urine (70% unchanged)

4. 2.6-5.9h, Pt 5+ days

5. carbo 0%, Pt yes

6. liver, kidney, skin, CNS

7. +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 mL/min

2. 300 mg (cap CrCL at 125)

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, PCNs, 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 → use 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? (5)

1. drug interxns

2. urine alkalinity + regular urine pH

3. adequate urine output

4. daily SCr/MTX

5. leucovorin

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 targets =

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

2. calc AUC/Css with ^

3. calc CL → CL = dose/AUC

4. calc dose → dose = CL x target AUC

5. Css 600-900, AUC 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 ______ 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. inc, 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? + calculate weight

3. 2.5 mg/kg/dose q 8-12h →

1. renal fx? comorbidities?

2. ABW = 87.4

3. ~220 mg

END STAGE KIDNEY DISEASE (ESRD) PK

1. Impair in gut wall barrier function →

2. +Vd →

3. __________ through kidneys

4. DIALYSIS → removes ______ _______ molecules in ______

1. +abs

2. excess fluid retention (affects hydrophilic drugs), hypoalbumin, -protein binding

3. -CL

4. small unbound, bloodstream (SMALL VD)

LIVER FAILURE PK

3 main factors affecting hepatic clearance

1. Hepatic blood flow →

2. Hepatocytes ability to metabolize a medication →

3. Fraction of unbound medication →

4. Also, ________ affecting the assessment of renal fx (SCr, CrCL)

1. +BA for meds w high 1st pass metab

2. -CYP450 fx

3. +free drug (-proteins like albumin, CFs)

4. low muscle mass

Goals of Organ Transplant

1. _______ “disease”

2. Improve patient and graft __________

3. Improve ________

1. replace

2. survival

3. quality of life

TRANSPLANT REJECTION: immune system activation

1. Signal 1:

2. Signal 2

3. Signal 3

1. antigen activation → antigen + MHC + TCR

2. COSTIM → CD80/86 + CD28

3. cytokine signaling → interleukins

INDUCTION immunosuppressants

1. “Depleting agents” → ________ → 2 agents

2. “Non depleting agents” → _________ → 1 agent

1. T cell lysis → thymoglobulin, alemtuzumab

2. inhib T cells → basiliximab

MAINTENANCE IMMUNOSUPPRESSION

1. primary immunosuppressants →

2. adjuvant agents →

1. CNI, antimetabolites, corticosteroids

2. mTORi, costim blocker

CALCINEURIN INHIBITORS

1. Agents = 2

2. MOA: Inhibit calcineurin, __________ is inhibited →

3. *Dose medications based on _________!

4. Very ______ therapeutic index

5. ______ levels are markers for AUC

1. tacrolimus, cyclosporine

2. inhib IL2 synth → inhib T cell proliferation

3. levels

4. narrow

5. TR

Which brand name of cyclosporine is the NON MODIFIED form and is NOT interchangeable?

Sandimmune

CALCINEURIN INHIBITORS ADES

1. Tacrolimus (3)

2. BOTH (4)

3. Cyclosporine (4)

1. hyperglycemia, alopecia, neurotox

2. NEPHROTOX, HTN, infxns, EL abnormalities

3. gingival hyperplasia, hyperlipidemia, hirsutism, gout

CALCINEURIN INHIBITORS

1. Absorption: BA ______ →

2. Distribution:

3. t1/2 _____ (2-36h)

4. Metabolism

1. variable → tacrolimus -abs w food, Sandimmune dependent on bile, diurnal variation

2. large Vd, highly protein bound

3. varies

4. CYP3A4, Pgp

Based on pharmacokinetic parameters, would dialysis impact tacrolimus levels?

Tacrolimus = High Vd, highly protein bound

A. Yes

B. No

B (small Vd, unbound are affected by dialysis)

CNI DRUG INTERXNS:

1. CYP3A4 inhibitors = (6)

2. Effect?

1. clarithro/erythromycin, azole, nondihydro CCB, protease inhib (-navir), grapefruit juice, CBD prod

2. +

CNI DRUG INTERXNS:

1. CYP3A4 inducers / Pgp inducers = 4

2. Effect?

1. rifampin, phenytoin, St john wort, carbamazepine

2. -

CNI DRUG INTERXNS:

1. Pgp inhibitors = 7

2. Effect?

1. amiodarone, dronedarone, propafenone, carvedilol, clarithro/erythromycin, azole, verapamil

2. +

ANTIMETABOLITES

inhib cell cycle proliferation

1. Agents 1 + moa

2. Agent 2 + moa

3. *Dose based on ________!, NOT levels

1. mycophenolate → inhib IMPDH

2. azathioprine → inhib purine synth

3. side effects

ANTIMETABOLITES

1. Abs

2. Distribution

3. Metabolism

4. Excretion

1. good abs

2. large Vd

3. hepatic → MPA to MPAG (inactive) back to MPA, azathioprine prodrug to 6MP

4. urine as metabs

MYCOPHENOLATE metabolism

1. undergoes _____________

2. DDI → Inhibited by ________

3. DDI → ______ inhibit glucuronidase activity of gut flora → -enterohepatic recirculation → -[MPA]

4. ADEs → 5

5. Major DDI

1. enterohepatic recirculation

2. cyclosporine

3. ABs

4. GI, leukopenia, anemia, TC, teratogenic

5. birth control

AZATHIOPRINE metabolism

1. Recommended to test for _________ prior to allopurinol initiation

2. Xanthine Oxidase inhibitors lead to ________ and _________

3. ADEs (6)

4. Major DDI

1. TPMT deficiency

2. MS, hepatotox

3. leukopenia, anemia, TC, pancreatitis, hepatotox, squamous skin cell CA

4. XO inhib

CORTICOSTEROIDS

1. MOA:

2. ________ at high doses

1. -IL2 prod

2. cytotoxic to T cells

mTOR INHIBITORS

Inhibits cell cycle in all rapidly dividing cells

1. Agents = 2

2. MOA: inhib a protein kinase mTOR, _____________

3. *Dose medications based on __________

1. sirolimus, everolimus

2. mammalian target of rapamycin

3. TR levels

mTOR INHIBITORS

1. Abs

2. Distribution

3. Metabolism

4. Half life

5. Excretion

1. BA 30%, -abs w fatty meals

2. large Vd

3. CYP3A4, Pgp

4. prolonged (adjust doses slowly)

5. feces

mTOR INHIBITORS

Sirolimus, Everolimus

1. ADEs → 6

2. BBW →

   ^ DONT use within 1st month of tx, consider alternative prior to surgery

1. TC, anemia, proteinuria, hyperlipidemia, -wound healing, peripheral edema

2. +risk hepatic/renal artery thrombosis in first 30 days post tx

COSTIMULATION BLOCKER

1. Agent =

2. MOA =

3. May be used in ________ patients ONLY!

4. BBW →

1. Belatacept

2. bind CD80/86

3. EBV+

4. lymphomas, malignancies, other infxns

COMMON MAINTENANCE IMMUNOSUPPRESSION REGIMEN =

1. -

2. -

3. -

4. ____ tablets/capsules per day

1. tacrolimus → goal FK 8-10

2. mycophenolate

3. prednisone

4. 15

Someone calls you in the pharmacy to tell you a tacrolimus level returned at 15 and asks what they need to do.

What is your response? (5)

1. is this a true TR?

2. What is the goal level is the transplant team going for?

3. Any recent rejections? infections?

4. Liver fx?

5. When was their transplant?

Kidney transplant recipient presents to your pharmacy with a prescription for Paxlovid (nirmatrelvir and ritonavir) for recent diagnosis of COVID.

What do you do?

patient should call txp center → RITONAVIR CYP INHIBITOR

You are reviewing a patient’s medication list and notice an interaction between sirolimus and diltiazem.

What do you do?

If it is new or +dose, they should call txp center

Mneumonic for need of DIALYSIS

1. A acidosis

2. E EL abnormalities

3. I intoxication

4. O overload

5. U uremia

Most common types of dialysis

1. Inpatient/outpatient

2. exclusively INPATIENT (ICU, etc)

1. iHD, PD

2. CVVH, CVVHD

IRRT vs CRRT

(intermed renal replacement therapy vs continuous)

1. IRRT advantages

2. IRRT disadvantages

3. CRRT advantages

4. CRRT disadvantages

1. rapid removal, simpler, no anticoagulation

2. hypotension, rapid V/EL changes

3. hemodynamics, adjustable

4. complex, anticoagulation, hypothermia, limited evidence on med dosing

DRUG CHARACTERISTICS THAT IMPACT DIALYSIS REMOVAL

1. Molecular weight

2. Vd

3. Protein binding

4. Renal vs nonrenal clearance → if drug _____ renal CL, then kidney failure unlikely to have much impact

1. relative to pore size of filter → small <500, mod 500-1000, large >1000

2. small Vd removed (ex AGs, theophylline)

3. unbound

4. <25%

Factors impacting FREE FRACTION of drug (4)

1. critical illness

2. drug interxns

3. uremia

4. pH

DIALYSIS CHARACTERISTICS that effect drug removal

1. __________ of filter/semipermeable membrane

2. __________ of semipermeable membrane

3. ______ of dialysis

1. pore size

2. surface area

3. type

DIALYSIS MEMBRANES

1. Low vs high flux membranes

2. Diffusion → used by …

   +MW, -CL

3. Dialysis saturation (capacity of drug to diffuse)

1. low = smaller pores, high = large

2. iHD, CVVHD, PIRRT

3. conc in dialysate / plasma conc

CONVECTION / HEMOFILTRATION

pumped through a filter

1. Used by _______

2. Better removal of _____ solutes

3. *Sieving coefficient =

4. Dependent on _________ and ______

1. CVVH

2. large

3. drug conc in ultrafiltrate / drug plasma conc

4. age of memb, filtration fraction

FDA requires drug manufacturers to complete __________ for renally eliminated drugs in patients on chronic hemodialysis

PK studies

Which medication may have decreased dialysis clearance due to increased protein binding?

A. Cefepime

B. Vancomycin

C. Tobramycin

D. Phenytoin

D (95% protein bound)

Which medication may have increased dialysis clearance due to its Vd?

A. Cefepime

B. Vancomycin

C. Tobramycin

D. Phenytoin

C (small Vd)

Which medication may have decreased dialysis clearance due to its molecular weight?

A. Cefepime

B. Vancomycin

C. Tobramycin

D. Phenytoin

B (large Mw)

DIALYSIS THERAPEUTIC DRUG MONITORING

1. ____________ is helpful/necessary

2. Ensure sufficient time has lapsed after HD is complete to allow for _____ to occur before drawing levels

1. serum conc

2. rebound

TACROLIMUS Goal TR levels

Days post-transplant (UAMS Kidney transplant protocol)

1. 1-90

2. 90-365

3. >365

1. 8-10

2. 6-8

3. 5-7

Recall: Dosing based on …

1. CNIs (tacrolimus, cyclosporine)

2. Antimetabolites (MPA, azathioprine)

3. mTOR inhibitors (sirolimus, everolimus)

1. levels

2. side effects

3. TR levels

Which transplant meds are CYP3A4 + Pgp substrates?

1. CNIs

2. mTORi

Order of efficient drug removal via dialysis

CVVHDF > CVVHD > CVVH > PIRRT >/= iHD

Drug characteristics that impact dialysis removal (4)

1. mw

2. Vd

3. Protein binding

4. Renal vs non renal CL

PERITONEAL DIALYSIS

1. _____ efficient at drug removal

2. ______ need replacement or increased doses

3. May add _____ to dialysate

1. Less

2. Rarely

3. Meds

If the half-life of sirolimus is 60 hours, when should you plan to get a steady state TR level after starting the medication or switching doses?

A. 1 day after starting sirolimus

B. 10 days after starting sirolimus

C. Before the 4th dose of sirolimus

D. Sirolimus is not dosed based on TR levels

B (steady state 3-5 half lives)

Which statement is true comparing the PK/PD differences between an 80 yo grandmother GM (5’4” and 200 lbs) and her 7 yo grand daughter GD if giving phenytoin to both patients?

A. Based on age GM would require a larger dose than GD due to faster metabolism

B. Based on age GM will have decreased muscle mass requiring a larger dose than GD

C. Both can be treated the same

D. Based on age GD would require a larger dose than GM based on better renal function

E. Based on age GD will have more albumin and will require a larger dose than GM

E