TDM General Principles Flashcards
Is TDM required for many drugs?
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
What can be used as an estimate of kidney function?
Creatinine
What drugs require TDM? Why?
Narrow therapeutic index drugs e.g. Digoxin
A lot of variability of PK parameters within a standard population
What is the relationship of the empiric dosing regimen and narrow therapeutic index drugs?
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
What is an issue with digoxin toxicity?
Digoxin toxicity looks like the condition it is trying to treat (AFIB)
Considerations for a pharmacist to consider when treating a patient? Examples?
- 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
- 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
- Selected Drug –> Formulation, route
- Dosage Regimen
- LD and MD
- Need to think about tau and dose - Patient Monitoring
- Drug Css,ave
- Clinical parameters (Safety) - Nature and severity of dx
- Correct diagnosis
People Take Drugs Routinely Monitor Nausea Diarrhea
Steady state of a drug is determined by….
The steady state concentration is at TROUGH levels
Right before the next dose (notthe number of doses)
MINIMUM STEADY STATE CONCENTRATIONS
Who chooses the target plasma concentration? What does it depend on?
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)
TDM involves what types of monitoring?
- PK Monitoring - Measurement of drug concnetrations in the blood as example
- PD Monitoring - surrogate markers of effect as example
When does PK monitoring apply….Why?
Applies to narrow therapeutic index drugs
- Can easily overdose or under dose a patient
- Results in individualization of patient dosing regimen (and improved outcomes)
What are some examples of PD monitoring?
Blood glucose for antidiabetic drugs
Blood lipids for hypolipidemic drugs
Blood pressure for antihypertensive drugs
What are the two clinical outcomes of TDM?
Two clinical outcomes: Steady state trough and clinical response
Describe the process of TDM
- Diagnosis is made
- Consider patients condition/complicating factors/otherdrugs - 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
- Drug Regimen designed to reach target Css and appropriate response
- Drug is adminstered
- Patient assesed and Css is measured
- Apply PK models and clincial judgement
- If dosage adjustment is necessary:
- Use patient PK
- Manipulate controllable variables (Dose and tau)
What is the goal of TDM?
Reach target Css
AND
Appropriate Clinical Response
Why is population PK estimates used in designing a DR?
Example?
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
Monitoring in TDM consists of…. What is a critical consideration?
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)
Why is getting a drug plasma level critical? (What does it allow us to do if we need to readjust DR)
Have pt’s blood level, gives you enough info to determine systemic clearance for that pt
When does a pharmacist request a drug plasma concentration?
- For TDM to individualize a patient’s dosage regimen
- Screen for potential toxic compound causing medical emergency (clinical toxicology)
Define Clinical Pharmacokinetics
Application of PK principles to the design of individualized dosage regimens that optimize therapeutic response and minimize chances of an adverse reaction
What are the ways of initiating drug therapy?
- Empirical Dose
- Individualized Dose
a) Initial: Population mean PK parametrs
b) Adjustment: Patients drug concentration
What is the goal of a DR?
Quickly attain and maintain serum drug concentrations within the TW
What type of kinetics do most drugs follow?
Linear Kinetics
Define Linear Kinetics
Predictable; proportional relationship between dose and concentration
- Regardless of dose, CLs and Vd do not change as they are constants
Why is linear PK important?
- Allows us to use drug Cp,ss to:
a) Asses response
b) Compute individualized dosage regimens - PK parameters are constants
- Cls, Vd, t1/2, F
Half Life (t1/2) tells us about:
Time to steady state
Dosing Interval (Tau)
t1/2 Equation
Systemic Clerance teslls us about:
Maintenance Dose
Cls Equation
Vd informs us about:
Loading Dose
(Vd is not a real physiological parameter; allows us to describe why plasma concentrations are the way they are)
Vd Equation
Bioavilability (F) informs us about:
Loading Dose
Product Selection
Bioavilability Equation
Loading Dose Equation
Maintenance Dose Equation
Describe the relationship between Css,ave and response
Briefly describe the relaionship between absorption and Css
Absorption dependent on bioavailability
Size of dose is also a second determinant of absorption
Major assumption of PK. What happens when this assumption is not applicable?
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
Describe the therapeutic range of a drug. Downfall?
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
What is the goal of TDM?
- Css within the therapeutic range
Target Css approach
- TR is an initial guideline
Drug dose and Css individualized according to clinical response
- Appropriate clinical response
OPTIMIZE AND INDIVIDUALIZE PATIENT THERAPY
Why are therapeutic ranges only ranges?
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
What is the rationale behind TDM?
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
What are the drug characteristics that make a drug applicable for TDM?
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
What are some drug classes and examples that require TDM?
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
When should a pharmacist request a drug level?
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
For a pharmacist to be capable of interpreting a plasma concentration, it is pertinent to know what information?
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
How can one use TDM to design an individualized DR?
- 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 - 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) - 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
Steps for Initial Dosing
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
Steps for Assesment After Initial Dosing
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
BSA Methods
Dubois/Dubois Method
Mosteller Method
Creatinine Clearance Methods
eGFR: CKD-EPI (NKF recommended)
Cockcroft-Gault Equation
MDRD Equation
Salazar-Corcoran Equation (Obese)
Schwartz Equation (Pediatrics)
IBW Method
Devine Method
Actual body weight might not be appropriate for emaciated or obese patients
Dubois/Dubois Can be used for…..
Average and obese patients
Monstellor can be used for…
Average patients
IBW can be used for….
Average/Obese, Renally Impaired Patients
BSA is necessary for:
Dosing of some drugs (e.g. cancer chemotherapy)
Assessment of severity of burn injury
Calculation of cardiac index and other indices of organ function
Limitation of BSA
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
What is the Clr equation and why is it important?
Assessment of renal function important for appropriate dosage regimen design
Impaired renal function
↓ClR
Alteration in MD
Why is Crcl used?
Estimates glomerular filtration rate (GFR) and, hence, ClGFR
GFR is best overall index of renal function
Varies with age, sex, body size
Describe creatinine clearance physiologically?
Describe the intact nephron hypothesis
Reductions in GFR result in…..
Increases in SCr
What is eGFR?
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)
Caveats of eGFR
–> Possible inaccurate estimates with early stage kidney disease
–> Can miss early acute GFR changes
Why is a correction factor applied in females when using the Cockcroft-Gault equation?
Females have smaller muscle mass, so SCR is lower and correction factor applied
Assumptions for Cockcroft-Gault
When do the assumptions for Cockcroft Gault Breakdown
Salazar-Corcoran Equation Use
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
MDRD Variables
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
CKD-EPI
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
Standardized Creatinine CL
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
