Clinical Pharmacokinetics & Therapeutic Drug Monitoring

Clinical Pharmacokinetics

What is Clinical Pharmacokinetics and Why is it Important?

• Definition: Clinical pharmacokinetics is concerned with the process of using pharmacokinetic principles and pharmacodynamic criteria to assist in the selection of appropriate drug dose regimens for individual patients.
• Pharmacokinetics: The study and knowledge of the factors that determine the time-course of a drug within the body, including its absorption, distribution, metabolism, and excretion.
• Pharmacodynamics: The study of the relationship between drug concentration and pharmacological and toxicological response.
• Importance: Critical for individualising and improving drug therapy. Variability in pharmacokinetics can arise from genetic influences, disease states, environmental factors (e.g., smoking), ageing, and drug interactions.

Pharmacokinetic Parameters of Clinical Importance

1. Clearance (CL)

• Definition: The pharmacokinetic parameter that describes the efficiency of elimination (or clearance) of a drug from the body.
• Total Body Clearance: Describes the irreversible elimination of a drug from the body as unchanged drug (e.g., excretion in urine) and by biotransformation to metabolites.
• Units: Volume per unit time or flow (e.g., L/min).
• Linear Clearance: For most drugs, total clearance remains relatively constant across clinically relevant plasma concentrations; doubling the dose doubles the plasma concentration and AUC.
• Non-linear Pharmacokinetics: Occurs when there is a non-linear relationship between plasma concentration and administered dose. This is uncommon but clinically important for drugs like phenytoin, where dose doubling can lead to a disproportionately larger increase in plasma concentration due to enzyme saturation.
• Clinical Importance: Critically important for designing maintenance dose regimens to achieve a desired steady-state concentration.

2. Volume of Distribution (V)

• Definition: Provides a measure of a drug’s extent of distribution within the body. It is an apparent volume and usually bears no relationship to the actual physical volume of the body.
• Relationship to Total Drug in Body: V is the proportionality constant relating the total amount of drug in the body (A) to its concentration in plasma (C) (A = V × C).
• Unbound Drug: Only unbound drug moves across cell membranes; the total concentration (bound + unbound) in plasma is commonly measured.
• Clinical Importance: Important for calculating a loading dose to achieve a desired initial concentration. The rate of distribution can determine the onset and offset of pharmacological effect depending on the tissue site of action.

3. Half-life (t1/2)

• Definition: A secondary pharmacokinetic parameter whose magnitude is determined by the relative magnitudes of clearance (CL) and volume of distribution (V).
• Clinical Importance:
  • May determine the duration of action of a drug.
  • Determines the time required to achieve a steady-state plasma drug concentration on chronic administration (typically 4-5 half-lives).
  • May be a determinant of the dosage interval in intermittent dosing regimens to minimise peak-to-trough fluctuations.

4. Bioavailability (f)

• Definition: The fraction of an administered dose that reaches the systemic circulation intact; it is a dimensionless parameter. For intravenous administration, f=1.
• Determination: Most commonly determined from the area under the plasma concentration-time curve (AUC) after extravascular administration, relative to intravenous dosing, normalised for differences in dose.
• Factors Affecting Oral Bioavailability: Can include acid-labile drugs (e.g., requiring enteric-coated formulations), interactions with food/other drugs (e.g., antacids), or altered GI metabolism.
• Clinical Importance: One of the pharmacokinetic determinants of plasma concentrations achieved after extravascular dosing. Factors affecting it are sometimes amenable to alteration in the clinic.

Pharmacokinetic Symbols

• C(t): Plasma drug concentration at a given time t
• CSS: Plasma drug concentration at steady state (constant-rate infusion)
• C̄ss: Average plasma drug concentration at steady state (fixed dose, fixed dosage interval)
• CL: Total body clearance of drug
• CLR: Renal clearance of drug
• CLNR: Non-renal clearance of drug
• D: Size of drug dose
• f: Fraction of administered drug dose that reaches systemic circulation intact (bioavailability)
• fe: Fraction of dose that reached systemic circulation, excreted unchanged in urine
• fu: Fraction of drug in plasma that is in unbound form
• k: First-order rate constant for elimination
• R0: Rate of intravenous infusion
• t: Time elapsed after drug administration or commencing administration
• τ (tau): Dosage interval
• t1/2: Half-life of drug
• V: Volume of distribution of drug

Therapeutic Drug Monitoring (TDM)

Definition and Criteria for Use

• Definition: TDM refers to the measurement and interpretation of principally blood or plasma drug concentration measurements with the purpose of optimising a patient’s drug therapy and clinical outcome while minimising the risk of drug-induced toxicity.
• Primary Goal: To maximise the benefit of a drug to a patient in the shortest possible time with minimal risk of toxicity, potentially reducing hospitalisations and costs.
• Criteria for Routine Clinical Use:
  • Narrow therapeutic index: Small changes in dose result in loss of efficacy or toxicity (e.g., digoxin, theophylline, lithium, phenytoin).
  • Beneficial concentration-response relationship: A clear correlation between blood drug concentration and pharmacological effects (efficacy and toxicity).
  • No other easily measurable physiological parameter: TDM is less useful if clinical effects (e.g., blood pressure, blood glucose) can be easily monitored.
  • Unpredictable dose-response curve or non-linear pharmacokinetics (e.g., phenytoin).
  • Clinically important drug interactions or large pharmacokinetic variations between individuals.

Drugs for Which TDM is Commonly Performed

• Aminoglycosides (e.g., gentamicin, amikacin, tobramycin)
• Antiepileptics (e.g., carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid)
• Antifungals (e.g., flucytosine, voriconazole)
• Antipsychotics
• Antiretrovirals (e.g., protease inhibitors, NNRTIs)
• Bronchodilators (e.g., theophylline)
• Cardiac drugs (e.g., digoxin, amiodarone, procainamide, quinidine, lidocaine)
• Cytotoxic drugs (e.g., busulfan, methotrexate, cisplatin, etoposide, 5-fluorouracil, irinotecan, paclitaxel)
• Immunosuppressants (e.g., cyclosporine, tacrolimus, mycophenolic acid)
• Psychotropics (e.g., amitriptyline, desipramine, imipramine, lithium, nortriptyline, tricyclic antidepressants)
• Analgesics (e.g., paracetamol [overdose], methadone)
• Others: Perhexiline, chloramphenicol, clozapine, dapsone, quinine.

Reference Range, Therapeutic Range, and Target Range

• Reference Range (Normal Range): Determined by testing a large number of healthy individuals; used for routine electrolytes.
• Therapeutic Range: The range of drug concentrations that is effective for a particular indication in most patients, with a minimal risk of toxicity. It is an initial guide and not a guarantee of response.
• Target Range: A specific range of concentrations within the therapeutic range, chosen for an individual patient based on their clinical status, indication, and risk factors.

Clinical Situations Where TDM May Be Useful (Indications)

• Inadequate Clinical Response: To assess if dosing regimen achieves minimum effective concentration (e.g., cyclosporine in transplant patients).
• Suspected Drug Toxicity: If patient shows signs/symptoms (e.g., nausea with theophylline).
• Minimising Toxicity Risk: To keep concentrations within a target range (e.g., aminoglycosides for nephrotoxicity/ototoxicity).
• Individualising Dosing: For drugs with unpredictable dose-response curves (e.g., phenytoin due to non-linear kinetics).
• Predicting Dose Requirements: Combining TDM with pharmacokinetics for rapid dose titration.
• Assessing Medication Compliance (Adherence): E.g., anticonvulsants in patients with poor seizure control.
• Poisoning Emergency: To identify poisons, assess severity, and monitor antidote effectiveness or poison excretion (e.g., paracetamol poisoning).
• Suspected Drug-Drug or Drug-Food Interactions.
• Physiological and Anatomical Changes: That impair absorption or metabolism (e.g., GI issues).

Factors Affecting Serum Drug Concentrations and Interpretation

When interpreting TDM results, consider:

• Patient Data: Age, sex, lean body weight (important for renally cleared drugs, e.g., for creatinine clearance calculation).
• Dosage Regimen: Dose, dosing frequency, route, duration of therapy. Allow sufficient time to reach steady state before TDM for new drugs.
• Sampling Time: Critical. The serum concentration depends on when the blood sample was drawn relative to the last dose.
  • Trough samples: Collected immediately before the next dose, especially for drugs with short half-lives (e.g., theophylline, vancomycin).
  • For drugs with long half-lives (e.g., digoxin, phenytoin), samples can be collected any time after the distribution phase is complete, though trough is still preferred.
  • Peak levels are usually not routinely monitored.
• Indication for Therapy: Different target ranges may apply for different indications (e.g., digoxin for atrial fibrillation vs. heart failure; amiodarone for ventricular tachyarrhythmias vs. atrial fibrillation; vancomycin for serious MRSA infections).
• Patient Adherence: Low concentrations may indicate non-adherence; investigate this before increasing doses.
• Reduced Protein Binding: Most assays measure total drug, but only unbound drug is active. Conditions like malnutrition or nephropathy can reduce plasma proteins (e.g., albumin), increasing unbound drug fraction. For strongly protein-bound drugs (e.g., phenytoin), measuring free drug concentrations can be useful.
• Drug Interactions: Other concomitant drugs can affect TDM results (e.g., amiodarone/verapamil increasing digoxin levels; inducers/inhibitors of CYP450 isoenzymes affecting hepatically cleared drugs).
• Pathological Factors: Co-morbidities affecting drug absorption (vomiting, diarrhoea, IBD, surgery, infections), distribution, metabolism, or excretion (e.g., hepatic cirrhosis, tuberculosis) can alter serum concentrations.
• Tobacco Use: Cigarette smoking increases hepatic clearance of some drugs (e.g., clozapine, theophylline).
• Active Metabolites: The presence of active metabolites (e.g., primidone to phenobarbital, procainamide to NAPA) can contribute to therapeutic effect or toxicity and shift the therapeutic range. Monitoring both parent drug and active metabolites is often necessary.

Role of the Pharmacist in the TDM Team

A reliable TDM service relies on teamwork. Pharmacists:

• Provide Advice: On appropriate use, timing, and interpretation of TDM results to medical staff.
• Initial Drug Regimen Selection: Advise on drug choice, dose, dosing interval, route, dosage form, considering patient factors.
• Dosage Regimen Adjustment: Based on TDM results and clinical response.
• Assess Unexpected Results: Investigate non-compliance, bioavailability problems, medication errors, drug interactions, or pharmacogenetic variability.
• Dose Adjustment: For patients on haemodialysis or peritoneal dialysis.
• Poisons Information: Provide information related to poisoning cases.
• Education: Educate physicians and others involved in the TDM process.

Limitations of TDM

• Available for a limited number of drugs.
• Analytical accuracy of drug assay methods and validity of recommended target ranges can be issues.
• Standard therapeutic ranges are often derived from studies in small groups of Caucasian patients, with inter-ethnic differences in pharmacokinetics (e.g., Chinese, Afro-Caribbean patients).
• Lack of clinical interpretation by laboratories (providing only ‘measuring’ service rather than ‘monitoring’) in some settings.
• The cost-benefit of assays should be carefully considered.

Communication of TDM Results

• Results should be communicated to clinical staff as quickly as possible, ideally before the next dose, to allow rapid intervention.
• Methods:
  • By telephone: For results significantly above the therapeutic range, explain factors influencing interpretation.
  • By hard copy reports: Include dosing and sampling details, assay results (preferably in mass units), and validated target range. Note that the same drug may have multiple therapeutic ranges depending on the indication.

Quality Control of Pathology Testing (Drug Analysis)

• Most drug assays use automated immunoassay methods, or HPLC and GLC for some drugs.
• Assay methods should have adequate specificity, sensitivity, accuracy, and precision.
• In India, TDM is available via biochemistry departments in large teaching hospitals or private labs, often using automated equipment and kits.

Interpretation for Specific Drug Classes (Examples)

1. Antiepileptics

• Phenytoin: Displays non-linear pharmacokinetics (saturable metabolism); small dose increases can cause disproportionately large serum concentration increases. Half-life is progressively prolonged at higher doses, requiring longer to reach steady state. Highly protein-bound; unbound concentrations correlate better with effect, especially in altered binding states (e.g., malnutrition, nephropathy).
• Phenobarbital/Primidone: Phenobarbital (active metabolite of primidone) exhibits first-order elimination. Both are moderately protein-bound. TDM useful for non-adherence, toxicity, lack of efficacy, and altered renal/hepatic function.
• Lamotrigine: Significant pharmacokinetic variability due to drug-drug interactions makes it a good TDM candidate. Therapeutic range 2.5–15 mg/L.
• Gabapentin: Renally eliminated, minimal protein binding. TDM for concomitant antiepileptics is recommended.

2. Antimicrobials

• Aminoglycosides (Gentamicin, Tobramycin, Amikacin): Narrow therapeutic index, dose-dependent nephrotoxicity and ototoxicity. TDM commonly involves trough samples. For traditional dosing, peaks 6-10 mg/L (gentamicin/tobramycin) and troughs 0.5-2 mg/L are recommended; for amikacin, peaks 20-30 mg/L and troughs 1-8 mg/L. Pulse dosing aims for high peaks and non-detectable troughs. <10% protein-bound, inactive metabolites.
• Vancomycin: Nephrotoxic and ototoxic, narrow therapeutic window. Target trough ranges (e.g., 10-20 mg/L, higher for serious MRSA infections). 30-55% protein-bound; inactive metabolites.
• Beta-lactams: Generally not routinely monitored due to wide therapeutic window, but TDM is gaining interest, especially in critically ill or obese patients due to altered pharmacokinetics and increasing multidrug resistance. Efficacy related to time free drug concentration stays above MIC (fT>MIC).
• Antitubercular Drugs (Isoniazid, Rifampin): TDM not routine but recommended due to variable concentrations, malabsorption (HIV patients), drug interactions, and potential for slow response, relapse, and resistance.
• Antiretrovirals (PIs, NNRTIs): Routine TDM generally not recommended due to lack of strong outcome data, but considered in specific scenarios (significant interactions, malabsorption, pregnant women with virologic failure, heavily treated patients). Some evidence supports monitoring PIs and NNRTIs due to pharmacokinetic variability and correlation with virologic response.
• Antifungal Agents (e.g., Flucytosine): TDM can be useful for individualisation and to guide dosing in specific patient populations.

3. Cardiac Drugs

• Digoxin: Narrow therapeutic index. TDM useful for assessing efficacy and toxicity. Target range 0.5–2 mcg/L, but 0.5–0.8 mcg/L for heart failure in sinus rhythm. 20-30% protein-bound, modest activity from metabolites.
• Amiodarone: Used for life-threatening arrhythmias. Poorly defined concentration-effect relationship. TDM limited benefit; activity associated with tissue concentrations. Serum concentrations useful for suspected non-adherence or toxicity. Active metabolite (DEA) has similar properties and accumulates.
• Procainamide: Used for arrhythmias. Active metabolite (N-acetylprocainamide, NAPA) has similar properties. Summing parent and metabolite concentrations for therapeutic range is discouraged; compare each to its own reference range.

4. Cytotoxic Drugs

• Often have narrow therapeutic indices and variable pharmacokinetics, but TDM can be difficult due to complex combination therapies and heterogeneous diseases.
• TDM often more helpful for avoiding toxicity than defining efficacy zones.
• Examples with established correlations between exposure (serum concentration, AUC) and response/toxicity: busulfan, carboplatin, methotrexate, etoposide, paclitaxel.

5. Immunosuppressants

• Cyclosporine: Potent, used for organ rejection prevention. Therapeutic range (whole blood troughs using specific assays) 100-500 mcg/L, highly dependent on specimen, assay, transplant type, and treatment stage. AUC is a more sensitive predictor of outcome.
• Tacrolimus: Used in combination. Trough blood concentrations targeted at 5-20 mcg/L initially, then 5-10 mcg/L. Nephrotoxic and neurotoxic. Unpredictable bioavailability contributes to TDM need. Pharmacogenomics (CYP3A4*22 allele) can affect pharmacokinetics.

6. Psychotropics

• Tricyclic Antidepressants (Amitriptyline, Imipramine, Desipramine, Nortriptyline): Well-defined therapeutic ranges. Active metabolites (e.g., desipramine from imipramine, nortriptyline from amitriptyline) contribute to activity. Combined concentrations are monitored, but caution needed as metabolites may have different activities.
• Lithium: Used for bipolar disorder. Therapeutic range 0.5–1.2 mEq/L, with distinct ranges for acute management (0.8–1.2 mEq/L, up to 1.5 mEq/L) and maintenance (0.6–1 mEq/L). Target concentrations can be as low as 0.2 mEq/L in elderly patients. Samples should be obtained just before the morning dose, at least 12 hours after the evening dose.

Future Directions of TDM

• Improved Assays: Increased specificity, sensitivity, speed, and convenience; methods for separating drug enantiomers, capillary electrophoresis-based assays.
• Novel Sample Types: Measurement of drugs in hair samples for long-term adherence; continuous monitoring using implanted biosensors or subcutaneous microdialysis probes (for unbound drug concentrations).
• Point-of-Care Testing (POCT): Potential for use in community pharmacies.
• Integration with Molecular Technologies: Determination of genotypes (pharmacogenomics), characterisation of proteins (proteomics), and analysis of drug metabolite profiles (metabonomics). These could identify non-responders/toxic responders, guide initial doses, and personalise therapy, potentially using non-invasive methods.

Target Concentration Intervention (TCI)

• A movement to change TDM terminology and practice to a “target concentration strategy” or “target concentration intervention.”
• Process:
  1. Choose a target concentration (within the therapeutic range) for a patient.
  2. Initiate therapy to attain that target using population pharmacokinetic parameters.
  3. Fully evaluate the response at the resulting steady-state concentration.
  4. Adjust the regimen as needed, refining pharmacokinetic parameters using drug concentration measurements.

Note: The information provided is for educational purposes and should not replace professional medical advice. Always refer to current guidelines and expert opinion for patient care.