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Online First                                                                                                                     Indian J Pharm Drug Studies | 1  

Review Article 

Therapeutic Drug Monitoring (TDM): A Necessity in Critical Care and 

Transplant Settings 

Rashmi Agrawal 

From, Consultant, Devmata Hospital, Bhopal, Madhya Pradesh, India 

ABSTRACT  

Therapeutic drug monitoring (TDM) personalizes dosage by quantifying plasma concentrations to enhance treatment effectiveness 

and reduce toxicity. In critically sick patients and transplant recipients, pathophysiological alterations, restricted therapeutic indices, 

and organ support measures frequently result in unexpected pharmacokinetics (PK). This study emphasizes TDM's significance in 

critical care and transplantation, concentrating on antimicrobials such as vancomycin, β-lactams, antifungals, and 

immunosuppressants like tacrolimus, cyclosporine, and mycophenolic acid, substantiated by PubMed-cited literature. 

Key words: TDM, critical illness, transplantation, vancomycin, β-lactams, antifungals, immunosuppressants 

herapeutic drug monitoring (TDM) is the practice of 

adjusting a patient's medication dosage to maintain 

drug concentrations within a specified therapeutic 

range in the bloodstream [1]. TDM employs a comprehensive 

analysis of pharmaceutics, pharmacokinetics, and 

pharmacodynamics to assess the safety and efficacy of a 

medication across many clinical contexts.  

For therapeutic drug monitoring (TDM) to be effective, the 

concentration of a medication must be assessed in several 

physiological fluids. A depiction of these concentrations in 

relation to significant clinical considerations is provided [2].  

In the last ten years, the theory, practice, and clinical 

relevance of therapeutic drug monitoring (TDM) have 

significantly evolved due to the advent of widely accessible 

and technically proficient modelling, simulation, and dosing 

software tools [3].  

Consequently, TDM, once a peripheral area of clinical 

chemistry, has evolved into a multidisciplinary domain of 

clinical medicine, enabling laboratory and pharmacometrics 

experts to provide extremely pertinent clinical information to 

support pharmacotherapy management. The emerging field is 

termed “model-informed precision dosing” and is poised to 

revolutionize medicine through enhancements in performance 

and usefulness facilitated by machine learning and artificial 

intelligence technologies. The ultimate objective of the 

revolution in model-informed precision dosage is to establish 

individualized, patient-centric therapies [4].  

Access this article online 

 

Received –  20th April 2025 

Initial Review –  27th April 2025 

Accepted – 15th May 2025 

Quick Response Code 

TDM-guided therapy is particularly beneficial for 

individuals exhibiting significant susceptibility and unique 

pharmacokinetic characteristics regarding the supplied 

medicines. Examples encompass cancer patients, seriously ill 

individuals, organ transplant recipients, and people who have 

undergone significant surgical procedures. Moreover, specific 

groups, like children and those with obesity, should be 

regarded as subjects for specialized dosage procedures. 

Individuals that possess abnormal biological characteristics, 

such as pharmacogenomic mutations or liver diseases, need 

personalized therapy strategies [5].  

Critical illness alters absorption, distribution, metabolism, 

and excretion of drugs, making fixed dosing strategies 

inadequate [6]. Post-transplant, maintaining 

immunosuppressant levels is crucial to prevent rejection while 

avoiding toxicity. TDM enables dose individualization based 

on plasma concentrations, integrating PK/pharmacodynamic 

(PD) principles to optimize therapy [7].  

Consequently, in both critical care and transplant 

medicine, the clinical significance of therapeutic drug 

monitoring (TDM) is highlighted by the administration of 

medications with a narrow therapeutic index, including 

aminoglycosides, vancomycin, tacrolimus, and cyclosporine 

[8]. Insufficient exposure in these patients may lead to 

therapeutic failure, the development of antimicrobial 

resistance, and graft rejection, while concentrations exceeding 

the sub-therapeutic threshold are linked to severe toxicities, 

including nephrotoxicity, hepatotoxicity, and neurotoxicity, 

__________________________________________________ 

Correspondence to: Dr. Rashmi Agrawal. Devmata Hospital, 

Bhopal, Madhya Pradesh, India. 

Email: atharvapub@gmail.com 

T 

mailto:atharvapub@gmail.com


Agrawal                                                                        Therapeutic Drug Monitoring in Critical Care and Transplants 

Online First                                                                                                                     Indian J Pharm Drug Studies | 2  

culminating in end-stage organ failure [9].  

The significant inter- and intra-patient pharmacokinetic 

heterogeneity in these groups is affected by variables 

including organ failure, sepsis, polypharmacy, drug-drug and 

drug-disease interactions, and genetic variants that influence 

drug metabolism. As a result, personalized concentration-

guided treatment is becoming acknowledged as a fundamental 

aspect of precision medicine in many contexts [10].  

By sustaining medication concentrations within specified 

therapeutic ranges, therapeutic drug monitoring (TDM) boosts 

clinical efficacy, mitigates adverse drug reactions, shortens 

hospital stays, and improves overall cost-effectiveness [11]. 

Therefore, incorporating TDM into standard clinical practice 

is essential for enhancing patient outcomes in critically sick 

and transplant groups.  

I. TDM in Critical Care 

In the intensive care unit (ICU), where patients frequently 

undergo significant physiological alterations, therapeutic drug 

monitoring (TDM) plays a crucial role in directing 

pharmacotherapy. Critical illness is linked to hemodynamic 

instability, hypoalbuminemia, disrupted fluid balance, 

increased renal clearance, and organ failure, all of which 

affect pharmacokinetics (PK) and pharmacodynamics (PD) 

[12]. These alterations render traditional dosage techniques 

insufficient, necessitating individualized dosing informed by 

therapeutic drug monitoring as a crucial element of critical 

care treatment. 

The ICU population is particularly susceptible owing to 

the severity of illnesses, the frequent administration of life-

sustaining treatments, and the prevalence of polypharmacy 

[13]. Extracorporeal techniques, including continuous renal 

replacement therapy (CRRT) and extracorporeal membrane 

oxygenation (ECMO), significantly modify medication 

distribution and clearance, resulting in sub-therapeutic 

exposure or drug toxicity when traditional dosing protocols 

are utilized [14].  

TDM facilitates precise dosage by guaranteeing goal 

attainment, particularly for medications with narrow 

therapeutic indices or those necessitating specific 

pharmacokinetic/pharmacodynamic thresholds for 

effectiveness [15]. This is especially pertinent for 

antimicrobials, since under-dosing can lead to therapeutic 

failure and antimicrobial resistance, whilst overdoing 

heightens toxicity concerns [16].  

a. Antimicrobial TDM 

β-lactams are the most extensively researched antimicrobials 

in critical care environments.  These time-dependent 

medicines exhibit significant interpatient variability in 

critically sick patients; therapeutic drug monitoring (TDM) 

paired with longer or continuous infusions has demonstrated 

enhancement in pharmacokinetic/pharmacodynamic (PK/PD) 

goal achievement and perhaps improved clinical outcomes 

[17]. Similarly, vancomycin, aminoglycosides, and colistin 

necessitate vigilant monitoring owing to their limited 

therapeutic ranges and possible nephrotoxicity [18]. 

Antifungals like voriconazole and posaconazole benefit from 

therapeutic drug monitoring due to their variable 

bioavailability and considerable inter-individual variability 

[19].  

Evidence increasingly advocates for the widespread 

application of antimicrobial therapeutic drug monitoring 

(TDM) in intensive care unit (ICU) treatment, bolstered by 

recent consensus recommendations from the European Society 

of Intensive Care Medicine (ESICM) and the European 

Society of Clinical Microbiology and Infectious Diseases 

(ESCMID), which offer practical frameworks for 

implementation [20].  

b. Non-antimicrobial applications 

In addition to managing infectious diseases, therapeutic drug 

monitoring (TDM) plays a vital role in optimizing treatment 

with anticonvulsants, immunosuppressants, and 

cardiovascular medications in intensive care unit (ICU) 

patients.  Agents like phenytoin and valproic acid demonstrate 

modified protein binding in hypo-albuminemic conditions, 

requiring the assessment of free drug concentrations to inform 

dosage [21]. Similarly, immunosuppressants like tacrolimus 

and cyclosporine necessitate monitoring to equilibrate 

rejection risk with toxicity, especially in post-transplant 

patients in the ICU.  Digoxin, a cardiac glycoside 

characterized by a narrow therapeutic index, necessitates 

meticulous monitoring in critically sick patients with variable 

renal function.  These instances demonstrate the extensive 

applicability of TDM beyond antimicrobials, underscoring its 

significance as a fundamental component of personalized 

medication in critical care [22].  

II. TDM in Transplant settings 

TDM is crucial in managing transplant patients, since it is 

vital to maintain a delicate equilibrium between sufficient 

immunosuppression and the prevention of drug-related 

toxicity.  Post-transplant patients need prolonged use of 

immunosuppressive medications, including calcineurin 

inhibitors (cyclosporine, tacrolimus), mTOR inhibitors 

(sirolimus, everolimus), mycophenolate mofetil, and 

corticosteroids [23]. Drugs such as tacrolimus and 

cyclosporine exhibit a narrow therapeutic index, considerable 

inter-individual pharmacokinetic variability, and a substantial 

risk for drug–drug and drug–food interactions.  TDM is 

essential for personalizing treatment, reducing the likelihood 

of graft rejection, and preventing side effects such as 

nephrotoxicity, neurotoxicity, and infections [24].  

The pharmacokinetics of immunosuppressants in 

transplant recipients is affected by various patient-specific and 

procedural factors, including age, weight, genetic 

polymorphisms (particularly CYP3A5 variants impacting 



Agrawal                                                                        Therapeutic Drug Monitoring in Critical Care and Transplants 

Online First                                                                                                                     Indian J Pharm Drug Studies | 3  

tacrolimus metabolism), organ function, concomitant 

medications, and the type of transplanted organ. Additionally, 

the post-operative phase frequently exhibits erratic absorption 

and metabolism resulting from hemodynamic instability, 

polypharmacy, and fluctuating gastrointestinal motility. Thus, 

conventional dosage protocols may not consistently forecast 

drug exposure, rendering personalized TDM-guided 

modifications crucial for best results [25].  

In clinical practice, trough concentrations (C0) are the 

predominant monitoring metric for calcineurin inhibitors and 

mTOR inhibitors in clinical practice, owing to their simplicity 

and robust connection with clinical success.  Nevertheless, 

several studies indicate that monitoring the area under the 

concentration-time curve (AUC) may offer a more precise 

assessment of drug exposure, especially for mycophenolate 

mofetil, as trough levels may not reliably forecast therapeutic 

effectiveness.  Advancements in Bayesian forecasting and 

population pharmacokinetic models have facilitated limited 

sampling tactics for more reliable AUC estimation, therefore 

alleviating patient burden and enhancing accuracy [26]. 

The application of TDM in transplantation transcends 

effectiveness and safety, incorporating long-term graft 

survival. Evidence indicates that insufficient 

immunosuppressant exposure is a primary factor in acute 

rejection, but chronic overexposure correlates with growing 

nephrotoxicity and metabolic problems. Incorporating TDM 

into standard post-transplant treatment enables doctors to 

proactively manage inter-individual variability and customize 

regimens according to patients' changing clinical conditions. 

Moreover, the integration of pharmacogenomic testing with 

therapeutic drug monitoring (TDM) presents an opportunity to 

enhance dosing regimens, advancing the concept of precision 

medicine in transplantation [27].  

Overall, TDM in the transplant context is an emerging yet 

essential instrument. Current investigations into innovative 

biomarkers, non-invasive monitoring techniques, and model-

informed precision dosage aim to improve its efficacy, 

guaranteeing that transplant recipients have the most effective 

and safest immunosuppressive protocols for sustained graft 

function. 

Table 1- List of drugs requiring TDM in critical care and Transplant settings 

Drug / Class / Context TDM Target / Metric When to Sample 
Clinical Rationale & ICU/Transplant 

Notes 
Key References 

Vancomycin 
AUC/MIC 400–600 (or trough 15–
20 mg/L) 

Trough before 4th 
dose or steady-state 

AKI risk ↑ with high troughs; AUC-based 
dosing preferred over trough-only methods 

[4], [18], [29] 

Aminoglycosides 

(Amikacin, Gentamicin) 

Peak/MIC ≥8–10; Trough <1–2 
mg/L 

Peak: 30 min post-
infusion; Trough: 
before dose 

Nephrotoxicity, ototoxicity risk; altered PK 
in sepsis, ECMO, CRRT 

[6], [30] 

β-lactams (Pip-Tazo, 

Meropenem, etc.) 
Time > MIC: 100% for critically ill 

Random / steady-

state sampling 

ARC, CRRT, ECMO → altered PK; 

continuous/prolonged infusion often needed 

[16], [17], [31–

33] 

Linezolid Trough 2–8 mg/L Pre-dose trough 
Toxicity risk if >10 mg/L; 

thrombocytopenia, lactic acidosis concerns 
[34] 

Azoles (Voriconazole, 

Posaconazole) 

Voriconazole: 2–5.5 mg/L; 
Posaconazole: >1 mg/L 

Trough after ≥5 days 
of therapy 

CYP2C19 polymorphism affects 
voriconazole levels; toxicity >5.5 mg/L 
(neurotoxicity) 

[19], [35], [36] 

Flucytosine 
Peak 30–80 µg/mL; Trough <25–
50 µg/mL 

Peak 2h post-dose; 
trough before next 
dose 

Myelotoxicity risk if >100 µg/mL; dose 
adjustment in renal failure 

[19], [37] 

Tacrolimus (Calcineurin 

inhibitor) 

Trough 5–15 ng/mL (organ/time-
specific) 

12-h trough (C0) 
Narrow TI; CYP3A5 polymorphism affects 
metabolism; toxicity: nephro/neurotoxicity, 
infections 

[22–27], [38] 

Cyclosporine 

(Calcineurin inhibitor) 

Trough 100–400 ng/mL; some 
centers use C2 sampling 

Trough (C0) or 2-h 
post-dose (C2) 

AUC-based dosing may improve outcomes; 
multiple interactions with drugs/food 

[39], [43] 

Sirolimus (mTOR 

inhibitor) 
Trough 5–15 ng/mL 24-h trough 

Long half-life; cytopenias, hyperlipidemia; 
erratic absorption post-transplant 

[40] 

Everolimus (mTOR 

inhibitor) 
Trough 3–8 ng/mL 24-h trough 

Renal-sparing protocols; post-op PK 
variability 

[41] 

Mycophenolate mofetil 

(MMF) 
AUC0–12 >30–60 mg·h/L 

Bayesian AUC or 
limited sampling 

Trough not reliable for efficacy; AUC-
based monitoring increasingly used 

[42] 

Corticosteroids No standard TDM 
Clinical + biomarker 

endpoints only 

PK variability post-op; risk of metabolic & 

infectious complications 
[7], [23–27] 

Precision Medicine & 

TDM Advances 

Bayesian modeling, 
pharmacogenomics (CYP3A5) 

Limited sampling + 
model-informed 
dosing 

Enables individualized regimens, reduced 
toxicity, improved graft survival 

[4], [10], [26–
27] 

 



Agrawal                                                                        Therapeutic Drug Monitoring in Critical Care and Transplants 

Online First                                                                                                                     Indian J Pharm Drug Studies | 4  

Challenges and Future Direction 

Notwithstanding its acknowledged advantages, therapeutic 

drug monitoring in the intensive care unit encounters several 

obstacles.  The restricted availability of tests for novel 

pharmaceuticals, inconsistencies in laboratory turnaround 

times, and the absence of standardized dosage algorithms 

impede its regular implementation. Furthermore, the 

interpretation of therapeutic drug monitoring necessitates the 

amalgamation of pharmacokinetic and pharmacodynamic 

principles with the evolving clinical situation, rather than 

dependence on fixed reference ranges.  Improvements in 

bedside tests, population pharmacokinetic modelling, and 

Bayesian dosing software are expected to increase the 

accessibility and clinical applicability of therapeutic drug 

monitoring in real time. Subsequent research must prioritize 

the validation of TDM-guided methods through extensive 

randomized controlled trials to enhance the evidence base and 

optimize dose recommendations for various ICU populations. 

CONCLUSION 

In conclusion, TDM in critical care serves as an essential 

instrument for precise dosage in patients exhibiting variable 

pharmacokinetics and a heightened risk of therapeutic failure 

or toxicity.  Its use in antimicrobials, anticonvulsants, 

immunosuppressants and cardiovascular medications 

underscores its extensive significance within the ICU domain.  

Despite ongoing logistical and interpretative obstacles, the 

incorporation of TDM into clinical workflows—bolstered by 

technology advancements and global consensus guidelines—

provides a pathway to safer, more effective, and personalized 

medication administration for critically sick patients. 

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How to cite this article: Agrawal R. Therapeutic Drug 

Monitoring (TDM): A Necessity in Critical Care and 

Transplant Settings. Indian J Pharm Drug Studies. 2025; 

Online First. 

Funding: None;                 Conflicts of Interest: None Stated 

 


	I. TDM in Critical Care

