TDM vs TCI: Therapeutic Ranges in Forensic Toxicology

Quick answer: therapeutic drug monitoring (TDM) and target concentration intervention (TCI) are clinical dosing frameworks, not forensic classification systems. Holford, Ma, and Metz argue that the traditional idea of a therapeutic range is too crude for individualized dosing and should give way to TCI, which uses pharmacokinetic and pharmacodynamic models to aim for a specific target. For forensic toxicology, the broader lesson is narrower but important: a measured concentration should not be labeled “therapeutic,” “toxic,” or “fatal” solely because it falls inside or outside a published range.

The distinction matters whenever a toxicology report, expert opinion, medical record, or cross-examination uses a reference range as though it were a biological boundary. Clinical TDM asks how a concentration can help manage a living patient. Forensic toxicology asks what a measured concentration can support about exposure, timing, effect, impairment, toxicity, or causation in a specific case. Those are not the same question.

What did “TDM is dead. Long live TCI!” actually argue?

In TDM is dead. Long live TCI!, Nick Holford, Guangda Ma, and David Metz distinguish traditional therapeutic drug monitoring from target concentration intervention. Their criticism is not that measuring drug concentrations is useless. Their criticism is that comparing a concentration with a broad “therapeutic window” often does not provide a rational, patient-specific dosing instruction.

TCI instead starts with a defined target effect or target exposure and uses pharmacokinetic/pharmacodynamic principles to estimate the dose needed to achieve that target in the individual patient. The authors discuss vancomycin, mycophenolate, tacrolimus, and other examples to argue that explicit target-based dosing can outperform empirical adjustment around a range.

The article appeared in the British Journal of Clinical Pharmacology, volume 88, issue 4, pages 1406-1413, DOI 10.1111/bcp.14434. It was first published online in 2020 and appears in the 2022 issue.

Is TDM literally dead?

No. The title is deliberately provocative, and the proposition is contested. In 2023, Florian Lemaitre and Dennis Hesselink published TDM Is Alive and Kicking! in Therapeutic Drug Monitoring. Their response underscores that TDM remains an established clinical discipline and that modern TDM can incorporate pharmacometrics, Bayesian methods, exposure targets, patient covariates, and individualized interpretation.

For forensic purposes, the scientific value of the exchange is not deciding which slogan wins. It is recognizing that even clinicians who rely on concentration monitoring do not treat a single population range as a complete substitute for dose history, sampling time, pharmacokinetics, patient characteristics, response, and clinical context.

Why therapeutic ranges are not bright-line forensic boundaries

Published concentration compilations are useful reference tools. The widely cited review by Schulz, Iwersen-Bergmann, Andresen, and Schmoldt compiled therapeutic, toxic, and comatose-fatal plasma concentrations for nearly 1,000 drugs and xenobiotics. But the value of those compilations depends on understanding what the numbers represent and how they were assembled.

Many therapeutic ranges describe concentrations expected under particular clinical circumstances, often plasma concentrations, steady-state measurements, or trough concentrations. A forensic specimen may instead be whole blood, serum, central postmortem blood, peripheral postmortem blood, urine, vitreous fluid, oral fluid, or another matrix. Sampling may occur at an unknown time after dosing, after emergency treatment, after redistribution, or after death. The numerical comparison therefore cannot be separated from specimen type and case context.

For a broader discussion of this problem, see Therapeutic Drug Monitoring and Postmortem Drug Concentrations: Why Reference Ranges Overlap.

Five reasons a concentration may overlap outcome categories

1. Tolerance and pharmacodynamic variability. Individuals exposed chronically to some drugs may experience different effects at the same measured concentration. Age, disease, receptor adaptation, and concurrent medications can also alter response.
2. Sampling time. A concentration measured near a peak is not equivalent to a trough measurement or a specimen collected many hours after the relevant event. Without a reliable dose and sampling timeline, comparison with a TDM target may be misleading.
3. Matrix differences. Plasma, serum, whole blood, and postmortem blood are not interchangeable. Distribution between plasma and cellular components can materially affect concentration.
4. Postmortem change. Redistribution, decomposition, diffusion, specimen site, and instability can alter a postmortem concentration. A clinical range established in living patients cannot simply be pasted onto a postmortem result.
5. Co-exposures and clinical context. Toxicity and impairment may reflect combined pharmacology rather than the concentration of one compound viewed in isolation.

TCI highlights a key forensic principle: concentration requires a model of context

TCI is fundamentally about connecting a measured response or concentration to an explicit pharmacological model and a target. That idea has a useful forensic analogue. A forensic concentration becomes meaningful only after the analyst or expert identifies the question being asked and the assumptions required to answer it.

If the question is exposure, detection may be enough. If the question is approximate timing, the expert may need a validated pharmacokinetic model, a known dose, reliable sampling time, and assumptions about absorption and elimination. If the question is impairment, concentration alone may not establish functional effect. If the question is cause of death, the concentration must be integrated with autopsy findings, circumstances, medical history, tolerance, co-intoxicants, specimen quality, and alternative causes.

This is consistent with the site’s broader pharmacokinetics and drug half-life guides: pharmacokinetic parameters can inform interpretation, but they do not create certainty that the underlying facts do not support.

What should be reviewed before using a therapeutic range in a forensic opinion?

• The exact analyte and metabolite reported.
• The specimen matrix and, for postmortem blood, the collection site.
• The analytical method, reporting units, calibration range, uncertainty, and quality-control status.
• The source of the cited reference range and whether it refers to plasma, serum, or whole blood.
• Whether the range represents a trough, peak, steady-state, average, or mixed collection timing.
• The person’s prescribed dose, adherence, last known dose, route, and dosing history when known.
• Relevant renal, hepatic, cardiovascular, and other physiological factors.
• Tolerance, pharmacogenetic factors, and interacting medications when supported by evidence.
• Co-intoxicants and potentially additive or synergistic pharmacology.
• For postmortem cases, redistribution, decomposition, stability, and the interval between death and collection.

Common forensic overstatements

“The concentration is in the therapeutic range, so it could not have contributed.” A population reference range is not a guarantee of safety for every individual or every combination of drugs.

“The concentration is above the therapeutic range, so the person was impaired.” Exceeding a clinical target does not by itself prove a particular behavioral or psychomotor effect at a specific time.

“The concentration is in a reported fatal range, so it caused the death.” Published fatal concentrations often overlap concentrations observed in survivors or in deaths with multiple contributing factors. Causation requires case-specific integration.

“Therapeutic range” and “reference range” mean the same thing in every source. They do not. Authors may use different matrices, populations, sampling schedules, endpoints, and terminology. The original source should be reviewed before the number is used as evidence.

FAQ

What is therapeutic drug monitoring?

TDM is the clinical use of measured drug concentrations, interpreted with patient and treatment information, to help guide dosing. It is most useful when concentration relates meaningfully to efficacy or toxicity and when dose-response variability is clinically important.

What is target concentration intervention?

TCI is an individualized dosing strategy that defines a target concentration or exposure and uses pharmacokinetic/pharmacodynamic principles, often with model-based or Bayesian methods, to estimate the dose needed to reach that target.

Does a therapeutic concentration prove lack of impairment?

No. A concentration that falls within a published therapeutic range does not, by itself, establish the absence of impairment, toxicity, or contribution to an event. The relevant pharmacology, timing, tolerance, co-exposures, and observed effects must still be evaluated.

Can a concentration above a therapeutic range prove toxicity?

Not by itself. It may support concern about excessive exposure, but toxicity is a clinical or forensic conclusion that depends on the individual, specimen, timing, drug, co-exposures, and other evidence.

Primary sources

• Holford N, Ma G, Metz D. TDM is dead. Long live TCI! Br J Clin Pharmacol. 2022;88(4):1406-1413. DOI: 10.1111/bcp.14434.
• Lemaitre F, Hesselink DA. TDM Is Alive and Kicking! Ther Drug Monit. 2023;45(1):3-5. DOI: 10.1097/FTD.0000000000001034.
• Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A. Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit Care. 2012;16:R136. DOI: 10.1186/cc11441.

Bottom line

The debate between TDM and TCI reinforces a point that forensic toxicology should already treat as fundamental: concentration ranges are reference information, not self-executing conclusions. A defensible opinion explains the source and purpose of the range, the specimen and timing to which it applies, the relevant pharmacokinetics and pharmacodynamics, and the case-specific evidence that supports—or limits—the inference being offered.

Scientific review framework: The Trillest, a working group of forensic toxicology and pharmacology experts from varied scientific backgrounds and viewpoints. Updated September 22, 2026.