Pharmacokinetics and Therapeutic Drug Monitoring

William Clarke, PhD, MBA, DABCC Johns Hopkins Medical Institutions

Learning Objectives
At the conclusion of this session, you should be able to:
Describe the basic components of pharmacokinetics Discuss the impact of altered pharmacokinetics on therapeutic drug management List important considerations for TDM methods Recognize clinical areas where implementation of TDM may have a positive impact on patient care

Clinical Pharmacokinetics
The study of the rate of movement of drugs within biological systems, as affected by multiple factors including absorption, distribution, metabolism, and elimination of medications

Clinical Pharmacokinetics
Liberation release from dosage form Absorption movement from administration
site into circulation Distribution reversible movement through circulation and body tissues Metabolism chemical conversion to active and inactive compounds Excretion elimination from the body

Distribution
After absorption, drugs distribute throughout the body via the circulatory system, lymphatic system and tissue fluids The amount of free drug available to act at organ receptors is affected by both protein and tissue binding Distribution can be affected by multiple factors

Drug Distribution
Drugs can be characterized by partition coefficients
Ratio of solubility in an aqueous, polar solvent vs. a lipophilic, non-polar solvent

Although we treat the body as one-compartment for PK calculations, it really consists of multiple compartments with variable polarity Body composition is an important variable in this process pH (both urine and blood) can also be important, depending on the drug

Volume of Distribution (Vd)

Vd = dose/[plasma] Requires drug distribution to be complete; most useful at Css Plasma volume of an average adult is ~3 L
Vd > 3 L indicates the drug is distributed outside of the plasma

Published Vd are available

General descriptor; dependent on multiple variables

Does not estimate actual sites of distribution, or account for individual differences in protein binding or tissue binding

Applications of Vd
Loading dose for desired target concentration:
(Vd) * ( [drug]ss )

Determining dose adjustments =

(Vd) * ([drug]desired - [drug]initial)

Metabolism
Drugs can undergo metabolism in the blood, liver, or lungs Metabolism alters the chemical structure of the parent drug, generally making lipophilic molecules more polar to enhance elimination Metabolites can be:
Active (procainamide N-acetyl procainamide) Inactive (theophylline 3-methylxanthine) Partially active (lidocaine monoethylglycinexylidide)

Drug Metabolism
Phase I reactions include the CYP 450 system and alcohol dehydrogenase Susceptible to:
Enzyme induction/inhibition Drug interactions

Phase II reactions result in increased polarity of drug and include:

Glucuronide conjugation Sulfate conjugation Glycine conjugation

Elimination
Elimination is the sum of clearances by all body pathways: Cltotal = Clrenal+Clhepatic+Clpulmonary+
Hepatic clearance depends on delivery of drug to the liver (blood flow, Q) and metabolic activity (E) Clhepatic = Q x E

Renal Clearance (Cl)

Renal clearance is also dependent on blood flow
Like Vd, published expected Cl rates are available but depend on many factors
Body weight, BSA, genetics Cardiac output, hepatic fx, renal fx, protein status Drug-drug interactions

Linear Pharmacokinetics
120 100
concentration

80 60 40 20 0 dose

First-order kinetics are linear Rate of elimination is proportional to drug concentration Increase in dose gives a proportional increase in plasma drug levels

Nonlinear Pharmacokinetics
Also called zero-order kinetics The rate of elimination is constant regardless of drug concentration Dosage increases saturate binding sites; resulting in non- proportional changes of drug concentration
50 45 40 35 30 25 20 15 10 5 0 dose

concentration

Mixed-Effect Kinetics
This happens in a saturable system Linear kinetics occur until enzymes become saturated Enzymes responsible for metabolism or elimination become saturated, resulting in non-proportional change in drug concentration relative to dose
30 25 20 15 10 5 0 dose

concentration

Pharmacokinetics: Steady State

Steady State = when the amount of drug administered is equal to the amount of drug eliminated within one dosing interval This results in a constant mean serum drug concentration, or a concentration plateau Drugs with short half-life reach steady state rapidly; drugs with long half-life can take days to weeks to reach steady state

Getting to Steady State

Half-life = time required for drug concentrations in blood to decrease by onehalf (50%) It takes 4-5 half-lives to reach steady state It also takes 4-5 half-lives for drug to be cleared from the system after dosing is stopped
100 90 80 70 % 60 steady 50 state 40 30 20 10 0 1 2 3 4 5 Half-life

Altered Pharmacokinetics
Standard dosage regimens for normal adults must be adjusted for particular patient populations due to differences in clearance, metabolism and protein binding Drugs can also affect pharmacokinetic parameters and combination therapy must account for these interactions This is why we need therapeutic drug monitoring

Renal Disease
Altered renal function can impair GFR, particularly affecting drugs with low protein binding These drugs are primarily eliminated by renal filtration Examples include: digoxin, lithium, procainamide and aminoglycosides

Hepatic Disease
Hepatic clearance is affected by metabolism Loss of hepatic cells can lead to limited sites for enzyme conversion, affecting clearance of drugs that are dependent on hepatic metabolism Examples include: lidocaine, theophylline and quinidine Loss of protein synthesis in hepatic disease affects protein binding and the ratio of free drug for highly protein bound drugs

Hepatic Disease
These include drugs such as phenytoin and albumin Ascites from liver disease leads to an increase in body water and Vd for drugs which primarily distribute in body water Examples include: aminoglycosides and digoxin

Cardiac Disease
Delivery of drugs to tissue receptor sites and liver metabolic sites is affected by the efficiency of the circulatory system Hepatic clearance is decreased for lidocaine and b-blockers (primarily flow related, Q) in cardiac failure

Malignancies
Chemotherapy causes a loss of rapidly dividing cells and can affect the GI availability of drugs with variable absorption (digoxin) Disorders such as multiple myeloma can cause an increase in plasma proteins that can affect drug-protein binding

Pediatric Populations
Pediatric patients can have different pharmacokinetics compared to the general population Larger Vd for polar drugs (digoxin, aminoglycosides) Altered metabolism (theophyllinecaffeine) Altered protein binding (phenytoin)

Geriatric Populations
Older patients also exhibit different pharmacokinetics Decreased renal clearance (lidocaine, digoxin) Decreased hepatic metabolism (phenobarbital)

Drug Interactions
When drugs are co-administered the pharmacokinetics can be altered significantly GI Absorption
Drugs and food when ingested in combination can result in chelation within the gut (antacids and tetracycline) Alterations in gut motility can lead to increased (propranolol) or decreased (penicillin) rates of absorption

Drug Interactions
Hepatic metabolism
Certain drugs (cimetidine, disulfiram and chloramphenicol) can inhibit hepatic metabolism by either blocking enzyme activity or downregulating the protein synthesis of enzymes Other drugs (char-broiled foods, smoking and phenytoin) can induce the activity and synthetic ability of the liver

Drug Interactions
Renal clearance
Drugs can compete for renal secretion in the renal tubules (quinidine and digoxin) Some other drugs (thiazide effect on lithium) increasing reabsorption in the proximal tubule

Therapeutic Drug Monitoring (TDM)

General Criteria for TDM

Narrow therapeutic index Poor relationship between drug dose and blood concentration Good relationship between blood concentration and clinical/toxic effect Serious consequences for under- or over-dosing Significant inter-individual variation

RATIONAL TDM Always have a question !!!

Establish baseline effective concentrations whenever possible Evaluate potential causes for lack of efficacy
Differential metabolizers (fast, slow, altered) Noncompliance Drug-drug interactions

Evaluate potential causes for toxicity

Altered drug utilization due to physiological conditions (puberty, geriatrics) Altered drug utilization due to pathological conditions (renal failure, liver failure) Differential metabolizers (fast, slow, altered) Drug-drug interactions

Courtesy of CE Pippenger

To Be Effective TDM Must Be

Accurate (Specific, Reliable, Objective) Precise (Predictable, Consistent) Valued (Understandable, Communicated) Timely (Local) Economical (Cost Recovery, Cost Avoidance, Affordable)

Specimens and Timing

Preferred specimen is serum or plasma, at steady state
Whole blood is needed for immunosuppressant monitoring For some tests, plasma is not acceptable due to interferences from anticoagulant

Trough levels are collected immediately prior to next dose

Must have defined window in which trough specimens can be collected

Accurate capture of dosing and specimen collection data is challenging Some new applications require multiple points for AUC calculation Specific guidelines depend on the drug, the approach to drug delivery, the clinical scenario, and the needs of the patient

Commonly Monitored Drugs

Cardioactive drugs: digoxin, procainamide Antiepileptic drugs: valproic acid, phenytoin (dilantin) Antbiotics: amikacin, gentamicin, vancomycin Immunosuppressants: cyclosporine, tacrolimus, sirolimus Antidepressants: nortriptyline, desipramine, lithium Bronchodilators: theophylline

Antiepileptic Drugs (AEDs)

Antiepileptic drugs have been monitored since the early 70s Routinely monitored AEDs include: valproic acid, phenytoin, carbamazepine, phenobarbital, primidone Newer AEDs such as lamotrigine, gabapentin, topiramate, levetiracetam, and oxcarbazepine are not as widely monitored
Commercial assays have recently been introduced into the market for these

Now, were on to the next generation

Lacosamide, rufinamide

AED Monitoring
These drugs are monitored because:
Defined relationship between blood concentration and seizure control Large individual difference between dose and blood level

These drugs are CYP450 metabolized, many patients are on multiple drugs, underlying complications may affect assessment of drug effectiveness Both under-dosing and over-dosing can result in seizures

Immunosuppressants
2 major mechanisms: IL-2 inhibiting (cyclosporine A, tacrolimus, sirolimus) and purine synthesis inhibiting (mycophenolic acid, 6mercaptopurine) These drugs are monitored because:
Defined relationship between blood concentration and degree of immunosuppression High degree of inter-individual variability

Immunosuppressant Monitoring
Getting patients into the therapeutic interval quickly is very important
Avoids acute rejection episodes; a risk factor for chronic rejection and allograft loss

Adverse effects from overdosing include myelosuppression, nephrotoxicity, hepatotoxicity, neurotoxicity, and GI effects (nausea, anorexia) Assay performance is critical as therapeutic targets shift lower and lower

Antibiotics
Most antibiotics (b-lactams, macrolides, quinolones) have a wide therapeutic index and do not require monitoring Aminoglycosides (gentamicin, amikacin, streptomycin and tobramycin) and vancomycin have a narrow index and toxicity may be severe/irreversible
Ototoxic and nephrotoxic in overdose

Aminoglycoside Monitoring
Aminoglycoside kinetics display great variation dependent on disease state Infections are associated with altered hydration and membrane permeability Severe infection (or burns) can cause increased Vd, requiring higher doses to reach desired peak levels PK are also altered when GFR is impaired (common in elderly patients and neonates) Elderly patients may be more susceptible to nephrotoxicity and ototoxicity

Antifungal Agents
No specific guidelines developed for routine monitoring of antifungal therapy Occasionally, monitoring may be warranted to ensure adequate concentrations are achieved Strongest case can be made for flucytosine and itraconazole
Flucytosine can cause both bone marrow toxicity (thrombocytopenia) and hepatotoxicity (>100 mg/L) Itraconazole is highly protein bound, has non-linear PK and is subject to enzyme inhibition Itraconazole absorption is highly variable, particularly in unfed state , as well as patients with AIDS or bone marrow transplants (Good indications for TDM)

Antifungal Monitoring
In addition to itraconazole, there has been increased interest in monitoring voriconazole and posaconazole
Used primarily in Oncology and Transplant patients CYP450 metabolized; high degree of variability

Therapeutic target intervals are still being established Significant risk of hepatotoxicity in overdose

HIV Drug Monitoring

HIV drugs are not routinely monitored; typically they have a wide therapeutic index Blood concentrations below the therapeutic target can result in diminished clinical effect and risk of future resistance Ritonovir boosting has diminished the risk of sub-therapeutic blood concentrations Primary utility is to distinguish resistance from non-compliance when viral load increases

Antidepressants
Most commonly measured antidepressants are the tricyclic antidepressants:
Amitriptyline, nortriptyline, imipramine, desipramine CYP450 metabolized

Primary toxic effect in overdose (> 500 ng/mL) is cardiac arrhythmia Very low demand for monitoring SSRIs and SNRIs
Low risk of toxicity Therapeutic targets not well established

Antipsychotic Drugs
Increased interest in monitoring drugs such as clozapine, olanzapine, and risperidone
High degree of inter- and intra-individual variability Patient population is high-risk for non-compliance

One obstacle is lack of a clear evidence-based therapeutic target interval Another is lack of commercial assay for measurement of the drugs

Cytotoxic Drugs and Chemotherapy

For the most part, chemotherapeutic drugs are not routinely monitored
Typically managed by normalizing dose to body surface area Focus is on clinical outcome with respect to dose, rather than blood level

There are 2 notable exceptions:

Methotrexate: anti-folate agent used in various malignancies and some autoimmune disorders Busulfan: pre-treatment for bone marrow transplant

Chemotherapy Monitoring
However, many of these drugs fit the typical TDM profile: high degree of variability with respect to dose, blood concentration-related effect, significant toxic effects Adverse effects include significant myelodepression, immunosuppression and diverse organ damage in overdose Time is essential to cancer patients; its important to achieve the maximum tolerated dose, while avoiding toxicity Current interest is focused on drugs such as 5-fluorouracil, docetaxel, and imatinib, among others

Methods for TDM

Some automated assays (primarily immunoassays) are available, but limited; many laboratory-developed methods exist Technology of choice becoming LC-MS/MS Reference labs important resource
Assays and TAT vary widely

QUESTIONS???
wclarke@jhmi.edu

Self-Assessment Question #1
A drug is a good candidate for TDM if:
A) it has a wide therapeutic index B) there is a good correlation between dose and blood concentration C) the drug is administered orally as needed D) there is a good correlation between blood concentration and clinical effect

Self-Assessment Question #2
Which of the following is NOT a phase I reaction?
A) oxidation B) methylation C) reduction D) glucuronidation

Self-Assessment Question #3
Which of the following drugs is routinely monitored in patient care?
A) mycophenolic acid B) citalopram C) valproic acid D) olanzapine

Self-Assessment Question #4
Which of the following drugs is commonly measured in its free form?
A) phenytoin B) tacrolimus C) theophylline D) clozapine