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Therapeutic Drug Monitoring > TDM General Principles > Flashcards

TDM General Principles Flashcards

1
Q

Is TDM required for many drugs?

A

Most drugs do not require TDM, very few undergo clinical PK monitoring

  • Some drugs that should be monitored but aren’t cause they do not meet the criteria for monitoring
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2
Q

What can be used as an estimate of kidney function?

A

Creatinine

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3
Q

What drugs require TDM? Why?

A

Narrow therapeutic index drugs e.g. Digoxin

A lot of variability of PK parameters within a standard population

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4
Q

What is the relationship of the empiric dosing regimen and narrow therapeutic index drugs?

A

Hard to give empirical dose for NTD to ensure the drug leads to the appropriate clinical outcome

Empirical may be higher or lower than what is required

  • Need all the information; patient is overweight, drugs they are on
    –> All considerations for drug dosing
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5
Q

What is an issue with digoxin toxicity?

A

Digoxin toxicity looks like the condition it is trying to treat (AFIB)

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6
Q

Considerations for a pharmacist to consider when treating a patient? Examples?

A
  1. Patient Condition
    –> Physical characteristics
    –> Concurrent disease
    –> Lifestyle factors
    Concurrent medications
    –> Other factors

Particularly the kidney and liver altering the elimination of the drug effecting the MD of

  1. Therapeutic Objective
    - Css, ave within TR
    - Clinical Response

Not only the clinical response; two therapeutic outcomes, the second one is the drug concentration of the drug in the therapeutic range

  1. Selected Drug –> Formulation, route
  2. Dosage Regimen
    - LD and MD
    - Need to think about tau and dose
  3. Patient Monitoring
    - Drug Css,ave
    - Clinical parameters (Safety)
  4. Nature and severity of dx
  5. Correct diagnosis

People Take Drugs Routinely Monitor Nausea Diarrhea

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7
Q

Steady state of a drug is determined by….

A

The steady state concentration is at TROUGH levels

Right before the next dose (notthe number of doses)

MINIMUM STEADY STATE CONCENTRATIONS

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8
Q

Who chooses the target plasma concentration? What does it depend on?

A

Pharmacist chooses the target plasma concentration that lands in the TW

Depends on the disease and severity of the disease state

Give IV by antibiotic for someone with someone with sepsis; not oral)

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9
Q

TDM involves what types of monitoring?

A
  1. PK Monitoring - Measurement of drug concnetrations in the blood as example
  2. PD Monitoring - surrogate markers of effect as example
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10
Q

When does PK monitoring apply….Why?

A

Applies to narrow therapeutic index drugs

  • Can easily overdose or under dose a patient
  • Results in individualization of patient dosing regimen (and improved outcomes)
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11
Q

What are some examples of PD monitoring?

A

Blood glucose for antidiabetic drugs

Blood lipids for hypolipidemic drugs

Blood pressure for antihypertensive drugs

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12
Q

What are the two clinical outcomes of TDM?

A

Two clinical outcomes: Steady state trough and clinical response

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13
Q

Describe the process of TDM

A
  1. Diagnosis is made
    - Consider patients condition/complicating factors/otherdrugs
  2. Drug Selected/Therapeutic Objective Defined
  • Select target Css and clinical response
  • Use population based PK data to estimate patients PK
  • Modify with patient charcteristics
  • Choose dose, tau, route, formulation
  1. Drug Regimen designed to reach target Css and appropriate response
  2. Drug is adminstered
  3. Patient assesed and Css is measured
  4. Apply PK models and clincial judgement
  5. If dosage adjustment is necessary:
    - Use patient PK
    - Manipulate controllable variables (Dose and tau)
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14
Q

What is the goal of TDM?

A

Reach target Css

AND

Appropriate Clinical Response

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15
Q

Why is population PK estimates used in designing a DR?
Example?

A

We know nothing about the drug; we do not know what there systemic clearance are

We have to resort to population based PK information to start

Example:

a) VD population estimate is 5 L/Kg, modify with weight

b) CYP 1A2 and Cls: Smoking induces 1A2, has to factor it in as the population standard estimate will not be appropriate for that smoker

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16
Q

Monitoring in TDM consists of…. What is a critical consideration?

A

a) Monitoring of patient response
b) Plasma levels of drug

We never use a drug level to treat a patient

A patient’s response can trump Css (This requires clinical judgment)

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17
Q

Why is getting a drug plasma level critical? (What does it allow us to do if we need to readjust DR)

A

Have pt’s blood level, gives you enough info to determine systemic clearance for that pt

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18
Q

When does a pharmacist request a drug plasma concentration?

A
  1. For TDM to individualize a patient’s dosage regimen
  2. Screen for potential toxic compound causing medical emergency (clinical toxicology)
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19
Q

Define Clinical Pharmacokinetics

A

Application of PK principles to the design of individualized dosage regimens that optimize therapeutic response and minimize chances of an adverse reaction

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20
Q

What are the ways of initiating drug therapy?

A
  1. Empirical Dose
  2. Individualized Dose
    a) Initial: Population mean PK parametrs
    b) Adjustment: Patients drug concentration
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21
Q

What is the goal of a DR?

A

Quickly attain and maintain serum drug concentrations within the TW

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22
Q

What type of kinetics do most drugs follow?

A

Linear Kinetics

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23
Q

Define Linear Kinetics

A

Predictable; proportional relationship between dose and concentration

  • Regardless of dose, CLs and Vd do not change as they are constants
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24
Q

Why is linear PK important?

A
  1. Allows us to use drug Cp,ss to:
    a) Asses response
    b) Compute individualized dosage regimens
  2. PK parameters are constants
    - Cls, Vd, t1/2, F
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25
Q

Half Life (t1/2) tells us about:

A

Time to steady state
Dosing Interval (Tau)

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26
Q

t1/2 Equation

A
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27
Q

Systemic Clerance teslls us about:

A

Maintenance Dose

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28
Q

Cls Equation

A
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29
Q

Vd informs us about:

A

Loading Dose

(Vd is not a real physiological parameter; allows us to describe why plasma concentrations are the way they are)

30
Q

Vd Equation

A
31
Q

Bioavilability (F) informs us about:

A

Loading Dose
Product Selection

32
Q

Bioavilability Equation

A
33
Q

Loading Dose Equation

A
34
Q

Maintenance Dose Equation

A
35
Q

Describe the relationship between Css,ave and response

A
36
Q

Briefly describe the relaionship between absorption and Css

A

Absorption dependent on bioavailability

Size of dose is also a second determinant of absorption

37
Q

Major assumption of PK. What happens when this assumption is not applicable?

A

PK processes act on the dose to determine the plasma level and therefore we assume a relationship with the concentration of drug at receptor site (drug must be within the unbound form)

If relationship is not good (plasma concnet. not correlating to clinical response), we cannot use plasma concentrations to determine and analyze drug monitoring

38
Q

Describe the therapeutic range of a drug. Downfall?

A

TDM promotes optimum drug therapy by maintaining CSS,ave in therapeutic range (TR)

A POPULATION BASED PARAMETER

There will be a window for the VAST MAJORITY that will produce a therapeutic response however, NOT EVERYONE

  • Captures only 60-70% of the population and using the TW to guide clinical decisions
  • Try to fit plasma concentration in TW, but only works for certain proportion of population

THEREFORE WHY NEED TO TAKE INTO ACCOUT PATIENT RESPONSE

39
Q

What is the goal of TDM?

A
  1. Css within the therapeutic range

Target Css approach
- TR is an initial guideline
Drug dose and Css individualized according to clinical response

  1. Appropriate clinical response

OPTIMIZE AND INDIVIDUALIZE PATIENT THERAPY

40
Q

Why are therapeutic ranges only ranges?

A

Not everyone reacts the same as receptors are different

Substanial interindividual PD variability at given Css, ave

So a range is considered rather than a single value

PHARMACODYNAMIC

41
Q

What is the rationale behind TDM?

A

Based on the assumption that plasma drug Css,ave are proportional to response

Css,ave allows us to determine the contribution of PK (ADME) variability to dose requirements

Dose is then modified to attain therapeutic Css, ave

42
Q

What are the drug characteristics that make a drug applicable for TDM?

A

Css is the intermediate endpoint (no quantifiable therapeutic enpoint or pharmacological effect)

Predictable Css vs response relationship

Narrow range of safe and effective Css

Wide interpatien variation in PK parameters

Toxicity/lack of effect puts patient at grave risk

Drug effect persists for relatively long time

Availability of validated drug analytical assay

Population PK parameters and TR known

CanPeople Notice Wh That East Amzing Pe

43
Q

What are some drug classes and examples that require TDM?

A

Antibiotics → aminoglycosides, chloramphenicol, vancomycin

Cardiac agents → digoxin, amiodarone, procainamide, lidocaine, quinidine

Antiepileptics → phenytoin, valproic acid, carbamazepine, barbiturates

Psychotherapeutics → lithium, tricyclic antidepressants (imipramine, amitriptyline)

Miscellaneous → cylcosporine, methotrexate, theophylline

44
Q

When should a pharmacist request a drug level?

A

Toxicity suspected

Need to asess compliance

Lack of response

Change in clincial state of patient (In partciular, kidney and liver. Can be stable in people witha condition; however, if state changes then need a new level)

Potential drug interaction

Symptoms of toxicity = symptom of disease state

Assess therapy following initiation or change in dosing regimen

45
Q

For a pharmacist to be capable of interpreting a plasma concentration, it is pertinent to know what information?

A

Concurrent Drug TX
- Interacting drugs
- Analytical assay interference

Analytical Assay
- Possible lab error

Population PK Parameters
- Cls, Vd

Laboratory Data
- Renal function
- Hepatic function
- Albumin

Clinical Status of the patient
- Weight, age, gender, sex, condition being treated, concurrent disease states, race

Previous Cp

Time of blood sample relative to dose administration

History of drug administration
- Drug, dose, dosage form, route, time of administration, compliance

46
Q

How can one use TDM to design an individualized DR?

A
  1. Compute initial dose (LD and MD)
    - Use 1-comp’t/steady state equations
    - Identify ‘target CSS’ within TR (use severity of dx, condition, lifestyle, etc.)
    - Use population PK parameter estimates modified by patient characteristics
  2. Take a blood sample from patient to determine drug concentration at steady state levels (CSS,ave)
    - Cp is taken at Css,min
    -Loading doseas are not steady state concentrations - wait 3-5 half-lives as it is closer to the therapeutic value you want to achieve
    - Take blood sample dose close to the next dose (30-60 mins before next dose)
  3. Use patient CSS,ave and clinical response to determine need for dosage adjustment
    - If Css,min outisde TR but clinical response appropriate, may not need to adjust MD
    - If Css,min outisde TR and clinical response not appropriate, use patient Css,ave to calculate patient’s own PK characteristics ad recalculate MD
47
Q

Steps for Initial Dosing

A

Design doasgae regimen based on target Css (Population Characteristics)

Consider how patient charcteristics alter ‘average’ population PK parameter estimates
- Smoking - Induces CYP 1A2- 60% increase in Cls

Determine if patient is is obese
- Compare IBW with ABW
- If ABW is >25% of IBW; use IBW for dose calculations

Calculate Loading Dose

Calculate MD

48
Q

Steps for Assesment After Initial Dosing

A

Assess patient response and drug plasma CSS
–> Take a blood sample at predicted steady state (CSS,min)

Is dosage adjustment necessary

Adjust dose using patient PK parameters

Calculate a new MD with patient PK estimates
–> Administer as constant IV infusion and continue to monitor patient
–> Take new CSS level and reassess patient

49
Q

BSA Methods

A

Dubois/Dubois Method
Mosteller Method

50
Q

Creatinine Clearance Methods

A

eGFR: CKD-EPI (NKF recommended)
Cockcroft-Gault Equation
MDRD Equation
Salazar-Corcoran Equation (Obese)
Schwartz Equation (Pediatrics)

51
Q

IBW Method

A

Devine Method

Actual body weight might not be appropriate for emaciated or obese patients

52
Q

Dubois/Dubois Can be used for…..

A

Average and obese patients

53
Q

Monstellor can be used for…

A

Average patients

54
Q

IBW can be used for….

A

Average/Obese, Renally Impaired Patients

55
Q

BSA is necessary for:

A

Dosing of some drugs (e.g. cancer chemotherapy)
Assessment of severity of burn injury
Calculation of cardiac index and other indices of organ function

56
Q

Limitation of BSA

A

Many equations which give highly divergent results – creates a challenge in the clinical context

BSA used in dose calculations – variances in BSA calculations can result in over- or under-dosing

57
Q

What is the Clr equation and why is it important?

A

Assessment of renal function important for appropriate dosage regimen design

Impaired renal function
↓ClR
Alteration in MD

58
Q

Why is Crcl used?

A

Estimates glomerular filtration rate (GFR) and, hence, ClGFR

GFR is best overall index of renal function
Varies with age, sex, body size

59
Q

Describe creatinine clearance physiologically?

A
60
Q

Describe the intact nephron hypothesis

A
61
Q

Reductions in GFR result in…..

A

Increases in SCr

62
Q

What is eGFR?

A

Estimates how well kidneys are filtering blood

Simple blood test is needed

Calculation to estimate kidney filtering function is based on measurement of creatinine and cystatin C (a protein that slows down the breakdown of other protein cells)

63
Q

Caveats of eGFR

A

–> Possible inaccurate estimates with early stage kidney disease
–> Can miss early acute GFR changes

64
Q

Why is a correction factor applied in females when using the Cockcroft-Gault equation?

A

Females have smaller muscle mass, so SCR is lower and correction factor applied

65
Q

Assumptions for Cockcroft-Gault

A
66
Q

When do the assumptions for Cockcroft Gault Breakdown

A
67
Q

Salazar-Corcoran Equation Use

A

Use in obese patients (patients not within 30% of their ideal body weight)

Height is in m2; Weight is in kg; SCR is in mg/dL

To convert SCR in SI units (μmol/L) to traditional units (mg/dL) multiply SI value by conversion factor (0.0113); Plug SCr in mg/dL into S-C equation

68
Q

MDRD Variables

A

Most common formula is the “4-variable MDRD”
–> Variables are serum creatinine, age, ethnicity, gender

Equation validated in patients with chronic kidney disease
–> Underestimates GFR in healthy patients

Not validated in children, elderly, pregnant mothers, normal individuals, body mass extremes

69
Q

CKD-EPI

A

More accurate than MDRD particularly when GFR > 60 mL/min for GFR estimation in adults

Also recommends increased use of Cystatin C

Good for chronic kidney disease as combination of filtration markers – creatinine and cystatin C – is more accurate

Estimates GFR with consideration of age, sex, and race

70
Q

Standardized Creatinine CL

A

An indexed eGFR is standardized a a body surface area of 1.732 meaning that eGFR is given in units of mL/min/1.73 m2

–> CKD staging and progression assessed with indexed eGFR value

Drug dosing decisions generally based on non-indexed eGFR value except obese patients where this can overestimate the measured GFR and therefore cause overdosing.

For some TDM durgs if ClCR is not standardized (or indexed to standardized BSA), need to normalize ClCR to BSA of 1.73 m2

Therapeutic Drug Monitoring (4 decks)

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