Therapeutic Drug Monitoring (TDM) Arthur G. Roberts

Therapeutic Drug Monitoring (TDM) A.K.A. clinical pharmacokinetic (laboratory) services (CPKS) Purpose evaluate the response of the patient to the recommended dosage regimen. Benefits Reduce cost and adverse affects

Appropriate Use of TDM Maximizing & speeding up efficacy Minimizing toxicity Patient's drug history uncertain Poor response to initial drug or deterioration after good response Changing hepatic or renal function Drug-drug interactions (DDIs) Individualization of therapy Assist in future decisions about therapy Pharmacokinetic profiling

Considerations Number of drugs to monitor How to monitor? urine, [blood]P, response How many times to sample? daily, hourly and continuous Personal, reagents and equipment needed

Monitoring [drug]P pharmacodynamic or “surrogate parameters” therapeutic response adverse effects pharmacodynamic or “surrogate parameters” clotting warfarin anticoagulant therapy blood glucose monitoring in patients receiving insulin products chemotherapy  severity of side effects and patient’s ability to tolerate the drug

Situations where TDM is a limited value [drug]P doesn’t correlate to response. Active metabolites complicate interpretation Toxic effects can occur at any [drug]P No consequences with [drug]P wide therapeutic window (high therapeutic index)

Do not need TDM Clinical Endpoints Easily Monitored blood pressure, heart rate, cardiac rhythm, body temperature, urine volume and inflammation. [drug]p do correlate well to therapeutic or toxic effects

Do not need TDM (Example Drugs) wide therapeutic window nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen calcium channel blocking agents nifedipine over-the-counter (OTC) drugs cough and cold remedies

Other potential problems and roadblocks to TDM Hospital personnel do not know the existence of a TDM service Physicians do not understand the principles, benefits, and the limitations of TDM service Inappropriate sampling times Insufficient patient’s history and other necessary data

Therapeutic Range for Commonly Monitored Drugs

Drugs Commonly Measured in Serum, Plasma, or Other Tissues

Functions Drug Selection Dosage Regimen Design Evaluate Patient Response Need for measuring serum drug concentrations [Drug] in bodily fluids Pharmacokinetic evaluation Dosage regimen adjustments Drug abuse screening

Drug Selection

Designing Dosage Regimens

Designing Dosage Regimens: Factors Pregnancy, labor and delivery Nursing mothers Pediatric use Geriatric use Hepatic/Renal impairment Gender Pharmacogenomics (Ethnic groups)

Designing Dosage Regimens: Types Individualized Pharmacokinetic Partial pharmacokinetic (Assumptions) Population Averages Calculated from nomograms and tabulations Emperical http://en.wikipedia.org/wiki/Nomogram

Characteristics of Drug Assays Specificity Sensitivity Linearity and Dynamic Range Precision Accuracy Drug stability Ruggedness/Robustness

Pharmacokinetic Evaluation of [Drug]P [Drug]P lower than anticipated [Drug]P higher than anticipated [Drug]P correct, but little/no response

Theophylline caffeine PDE=Phosphodiesterase PKA=Protein Kinase A http://en.wikipedia.org/wiki/Theophylline http://www.nature.com/nrd/journal/v3/n10/fig_tab/nrd1524_F2.html caffeine PDE=Phosphodiesterase PKA=Protein Kinase A

TDM Patient variability DDIs Fatty meals Adverse drug reactions dose dumping Adverse drug reactions CNS excitation heart problems low therapeutic index Interpatient variability http://en.wikipedia.org/wiki/Theophylline#Adverse_effects http://en.wikipedia.org/wiki/Dose_dumping FEV= Forced expiratory volume in asthmatic patients.

Digoxin (Lanoxin) Foxglove Control Heart Cardiomyocyte Rate Inhibits cardiac isoform of Na/K ATPase and indirectly incrases intracellular Ca2+ concentration http://en.wikipedia.org/wiki/Inotrope http://en.wikipedia.org/wiki/Troponin Foxglove Control Heart Rate Cardiomyocyte known since the middle ages TN-C = Troponin C

TDM Reasons and Concerns Adverse Drug Reactions Low Therapeutic Index [Drug]toxic/[Drug]therapeutic Therapeutic (0.5-2.0 ng/L) Toxic (>2 ng/L) Electrolytes Low [K+] (Hypokalemia) High [Ca2+] or [Mg2+] Adverse Drug Reactions worsening heart problems xanthopsia (Vincent van Gogh’s “Yellow Period”) http://en.wikipedia.org/wiki/Hypokalemia http://en.wikipedia.org/wiki/Xanthopsia http://en.wikipedia.org/wiki/Vincent_van_Gogh%27s_health

Factors Considered Weight Renal Function (Creatine Clearance) Age infants advanced age (reduced renal function) http://www.nlm.nih.gov/medlineplus/ency/article/003611.htm http://en.wikipedia.org/wiki/Renal_function http://www.webmd.com/a-to-z-guides/creatinine-and-creatinine-clearance-blood-tests

Antidote Digoxin immune fab (ovine) http://en.wikipedia.org/wiki/Digoxin_Immune_Fab Made from sheep