What do you know about targeted concentration intervention
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Here is a thorough overview of Target Concentration Intervention (TCI):
What Is Target Concentration Intervention (TCI)?
TCI is a science-based pharmacological strategy for individualizing drug dosing by using pharmacokinetic (PK) and pharmacodynamic (PD) principles to select a specific target drug concentration and then calculate and administer the dose needed to achieve it. It was formally articulated by Holford (1999) as an evolution beyond therapeutic drug monitoring (TDM).
TCI vs. Therapeutic Drug Monitoring (TDM)
TDM and TCI are often confused, but they represent fundamentally different philosophies:
| Feature | TDM | TCI |
|---|---|---|
| Core concept | Monitor concentration within a "therapeutic range" | Aim for a specific target concentration linked to a desired effect |
| Pharmacodynamics | Largely ignored | Explicitly incorporated (Emax, C50 models) |
| Goal | Passive surveillance | Active dose intervention |
| Dose guidance | Vague - "keep within range" | Specific - calculates the exact dose required |
| PK model use | Often absent | Central to the approach |
The PMC classic paper (PMID: 10383553, Holford 1999) sums this up well: "TDM has become tedium because of its focus on the passive concept of 'monitoring' and its failure to explicitly take drug effects into account."
The Core Algorithm (6 Steps)
As described in Katzung's Basic and Clinical Pharmacology (16th ed.):
- Choose the target concentration (TC) - based on PD modeling of the concentration-effect relationship for the intended therapeutic goal
- Predict V and CL from population values, adjusted for patient-specific covariates (weight, renal function, age, sex)
- Calculate and give the loading dose and/or maintenance dose using: Maintenance Dose Rate = CL × TC
- Measure the patient's response (drug concentration and/or pharmacodynamic effect)
- Revise PK parameters (V and/or CL) based on observed response in this individual
- Repeat steps 3-5, iteratively refining the dose until TC is achieved
Pharmacokinetic Principles Behind Dose Calculation
- Loading dose = TC × Volume of Distribution (V)
- Maintenance dose rate = TC × Clearance (CL)
- For oral dosing: Dosing rate (oral) = (CL × TC) / F (bioavailability)
- For intermittent dosing: Maintenance dose = Dosing rate × Dosing interval
For example, to achieve a theophylline target of 10 mg/L in a 70 kg patient with CL = 2.8 L/h: Infusion rate = 2.8 × 10 = 28 mg/h.
Why TCI Is Superior to a Fixed Therapeutic Range
The concept of a "therapeutic range" (e.g., "phenytoin 10-20 mg/L") is an oversimplification because:
- Individual patients may achieve the desired effect at the lower or upper end of the range
- A single target concentration linked to the specific clinical objective is more precise
- For example, digoxin for atrial fibrillation may need TC ~2 ng/mL, while heart failure is managed with TC ~1 ng/mL - the same drug, but different targets for different indications
Drugs Where TCI Is Commonly Applied
| Drug | Typical Target Concentration |
|---|---|
| Aminoglycosides | Peak ~20 mg/L; Css ~3 mg/L |
| Phenytoin | ~10 mg/L |
| Digoxin | ~1 ng/mL |
| Theophylline | ~10 mg/L |
| Tacrolimus | ~7 mcg/L |
| Warfarin | INR 2-3 (indirect PD target) |
| Propofol (anesthesia) | Effect-site concentration in mcg/mL |
| Remifentanil (anesthesia) | Effect-site concentration in ng/mL |
TCI in Anesthesia (a Special Application)
In total intravenous anesthesia (TIVA), TCI has a very specific technical meaning: a computerized infusion pump uses validated PK/PD models (e.g., Marsh or Schnider for propofol; Minto for remifentanil) to automatically adjust infusion rates to achieve and maintain a clinician-specified plasma or effect-site concentration. The anesthetist selects a target (e.g., propofol 3 mcg/mL effect-site), and the pump continuously adjusts delivery. This is different from the broader pharmacological TCI framework, though the principles are the same.
Recent Developments
A 2021 pilot study (PMID: 34548626) applied a TCI strategy to alemtuzumab in bone marrow transplant conditioning, showing the feasibility of individualized dosing in that context. A 2022 review titled "TDM is dead. Long live TCI!" (Holford, Br J Clin Pharmacol, 2022) continued advocacy for replacing passive TDM with active TCI as the standard of care for drug monitoring.
Summary
TCI reframes drug management from "keep this patient's level in a range" to "give this patient the dose that will achieve the specific concentration needed to produce the desired therapeutic effect." It integrates PK (predicting concentrations) with PD (linking concentrations to effects) and iteratively individualizes therapy using real patient measurements. It is applicable across a wide range of drugs - from antibiotics to immunosuppressants to anesthetic agents.
- Katzung's Basic and Clinical Pharmacology, 16th ed., pp. 85-88
- Holford N. "Target concentration intervention: beyond Y2K." Br J Clin Pharmacol. 1999 (PMC2014870)
- Holford N et al. "TDM is dead. Long live TCI!" Br J Clin Pharmacol. 2022
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