In most clinical settings, the tacrolimus dosing regimen is determined by the clinical judgment of the physicians, often based on a telephone consultation after trough levels are reported by the laboratory. Based on our own experience and evaluations, determination of the appropriate subsequent tacrolimus dose, given the present trough concentration and the target therapeutic range, is subject to considerable variability. Our study aimed to propose and implement a prag-matic decision aid for tacrolimus dose adjustments. We defined specific rules for tacrolimus dose adjustments and developed a table of standardized adjustment increments to facilitate individualized dosing regimens, considering multiple variables, including prior trough levels, renal function and concomitant use of other medications, particularly itraconazole. We evaluated our institutional experience during a period of more than 1 year. The proposed rules and dose adjustment table have helped standardize tacrolimus dose adjustments reproducibly by a simple intervention. The rule-based tacrolimus dose adjustment table and accompanying clinical rules still require validation studies.

Key words : Calcineurin inhibitor treatment, Immunosup-pression, Personalized medicine, Systematic dosing, Therapeutic drug monitoring

Dear Editor:

At our center in Zurich, tacrolimus was introduced relatively late as the first-line calcineurin inhibitor within the standard triple immunosuppression regimen, beginning in January 2022.¹ Prior to this change, cyclosporin had been our preferred cal-cineurin inhibitor, and we accumulated extensive experience with its use during the course of 3 decades. This experience included individualized target level determination and also incorporated area-under-the-curve-based monitoring.
In our view, cyclosporin is an effective immuno-suppressant when used with appropriate expertise. The ScanCLAD study shifted clinical practice toward tacrolimus as the preferred calcineurin inhibitor and demonstrated superior long-term outcomes, a finding that may in part reflect its relative ease of use in many clinical settings.² Nevertheless, tacrolimus presents distinct challenges in routine practice, and overdose is not uncommon, which may result in renal dysfunction or other adverse clinical outcomes.³
A systematic literature search did not identify standardized tacrolimus dosing instructions suitable for routine clinical practice; therefore, we developed structured dosing rules and a dose-adjustment table to support physicians to determine the appropriate subsequent tacrolimus dose. These tools are based on predefined criteria, including the target trough concentration range, the present and preceding trough levels, renal function, and concomitant use of itraconazole.
When applied in isolation, the dosing table is insufficient to reliably determine the subsequent tacrolimus dose in certain cases and requires the application of additional rules. This is particularly relevant during maintenance immunosuppression in the setting of ongoing concomitant use of itraconazole, where very low tacrolimus doses are often sufficient to achieve target trough concentrations and for which unadjusted dose changes may be disproportionate. An important exception comprises patients who express functional cytochrome P450 3A5 variants, in whom adequate tacrolimus exposure may not be achieved even in combination with itraconazole.
The tacrolimus dose finder applies to immediate-release tacrolimus, administered every 12 hours, as well as to extended-release formulations. This tool was developed using the original tacrolimus immediate-release and extended-release formulations, both available as 0.5 mg, 1 mg, and 5 mg strengths; additionally, the extended-release formulation is available as a 3-mg capsule. Part of the evaluation was a 6-month observational phase, in which experienced transplant physicians were routinely asked to determine the need and magnitude of dose adjustment based on the trough levels and the predefined trough target range. These physicians performed this assessment first in the conventional manner (expert opinion) and subsequently deter-mined the dose adjustment systematically by using the table and rules. Both dose adjustments were docu-mented (n > 300). Most resulting dose adjustments were identical (concordant) for both approaches (>92%). In the cases of discordant dose adjustments, this systematic approach (use of the table and rules) led more often to lower tacrolimus doses. It was at the discretion of the physician to choose which dose adjustment was appropriate for the patient. Two other experts conducted post-hoc verification of the dose adjustments. In some cases, the rules/table had been applied incorrectly (Hosari S, Schuurmans M, December 2025, unpublished observations). The following instructions are reproduced from the internal tacrolimus dosing guidelines of the University Hospital Zurich lung transplant program, after a data-driven evaluation phase of more than 1 year:

Tacrolimus Dose Adjustment Table and Rules for Determination of Appropriate Subsequent Dose, Based on a Systematic Approach to Therapeutic Drug Monitoring and Tacrolimus Dosing Regimen

The tacrolimus dose adjustment rules used in combination with Table 1 are described as follows.
If itraconazole has been administered for more than 5 days, then the dose correction value (correction values are shown in bold font in Table 1) must be reduced by 50% (ie, a “half-dose correction”). If other azole antifungals or potent inhibitors of the cytochrome P450 3A4 enzyme system and/or P-glycoprotein (eg, clarithromycin) are coadminis-tered, then the lung transplant physician should be consulted to determine the appropriate tacrolimus dose. Itraconazole should not be discontinued or modified without explicit consultation with the lung transplant physician, as it is intentionally prescribed to achieve a stable pharmacokinetic interaction. Any change in the itraconazole dosing regimen necessitates repeated tacrolimus trough level measurements during subsequent weeks; therefore, this potentially excessive workload for monitoring tacrolimus trough levels can be avoided by maintaining itraconazole therapy without modification.

Deviation direction and magnitude of delta from target margin
The presently measured trough concentration is classified in Table 1 as either “too low” or “too high” relative to the predefined target range. The magnitude of deviation from the nearest boundary/margin of the target range is defined as the delta. If the trough level deviates by ≤0.4 units from either the lower or upper target limit, then no dose adjustment is performed and the dose remains unchanged. Consequently, the first dose correction category applies to delta values of 0.5 to 1.0 units, at both the lower and upper margins of the target range.

Tacrolimus trough level trend
The dose correction value (shown in bold font in Table 1) is determined by the trend of the present trough concentration relative to the previously measured (penultimate) trough level. Based on this comparison, the trend is classified as either “falling” or “increasing.”

Renal function
Renal function (Table 1) is a key determinant of dose adjustment. The dose correction value is selected from the left column (of either the “falling” or “increasing” option) when renal function is within standard reference range or not severely impaired (urea <10 or cystatin C-based estimated glomerular filtration rate [eGFR] ≥50 mL/min/1.73 m²). However, if renal function is impaired (urea ≥10 mmol/L or cystatin C-based eGFR <50 mL/min/1.73 m²), then the value from the right column (of either the “falling” or “increasing” option) applies.

Rounding of calculated dose adjustment values
If itraconazole has been administered for more than 5 days, then the dose correction value is reduced by 50%. If division of the dose correction value by 2 (“half-dose correction”) results in nonfeasible doses (eg, 0.25 or 0.75 mg), then rounding is performed in the following manner. By default, rounding should favor a lower final tacrolimus dose, thereby priori-tizing nephroprotection. Only if renal function has clearly improved over time (as indicated by decreasing urea levels or improved cystatin C-based eGFR) should rounding be performed toward a higher tacrolimus dose, with acknowledgment of the reduced nephroprotective effect.

Proportionality
When tacrolimus trough concentrations deviate markedly from the target range, proportional dose adjustments should be applied. If the measured trough level is approximately twice the target value, then the tacrolimus dose should be reduced by 50%. Conversely, if the trough level is approximately half of the target value, then the tacrolimus dose may be doubled. This rule is particularly important in situations where the dose adjustment suggested by Table 1 appears excessive or disproportionate.

Pause tacrolimus and half-dose continuation
A decision to “pause tacrolimus and half-dose continuation” is needed when trough concentrations substantially exceed the target range. If the measured trough level exceeds the upper limit of the target range by more than 3 ng/mL, then tacrolimus should be withheld for 1 dose (1 dosing interval) and subsequently resumed at half of the previous dose. If the trough level exceeds the upper target limit by more than 6 ng/mL, then tacrolimus should be withheld for 2 doses (2 dosing intervals) and then resumed at half of the prior dose. Tacrolimus trough levels may be remeasured the following day; however, no further immediate dose adjustments should be made unless the trough concentration increases by more than an additional 2 ng/mL, or unless renal function deteriorates markedly. In such cases, tacrolimus should be withheld for multiple dosing intervals until trough levels return to the target range. Under these circumstances, tacrolimus levels are typically monitored every second day.

Frequency of trough drug level measurements and dose corrections
If a tacrolimus dose has been adjusted recently (ie, within the preceding 36 hours), then further dose modifications should generally not be implemented solely on the basis of a trough concentration measured 24 hours after the prior level that triggered the adjustment. In most cases, reassessment of trough concentrations is meaningful only after 48 hours, particularly following marked deviations from the target range. Nevertheless, clinicians may occasionally choose to obtain earlier measurements to document the trajectory of trough levels, especially when concentrations are markedly outside the target range. Additional dose adjustments should be avoided unless there is a substantial further increase in tacrolimus levels or a pronounced deterioration in renal function. In the case of a pronounced dete-rioration in renal function, prolongation of tacrolimus interruption or reduction of the dose to less than half of the previous dose may be considered.
With regard to the frequency of trough level monitoring, tacrolimus trough concentrations should ideally be measured daily during the first 3 weeks after transplant. Thereafter, measurements are typically performed every 2 to 3 days unless deviations from the target range are pronounced (>3 ng/mL). During rehabilitation and in the early outpatient setting, monitoring is usually performed once or twice weekly. Between 3 and 6 months after transplant, trough levels are measured every 2 weeks (±1 week); during the second half of the first year after transplant, trough levels are measured every 3 to 4 weeks (±1 week). After the first posttransplant year, monitoring intervals are generally extended to every 6 to 12 weeks, with intervals increasing over time. It is important to note that, due to the long elimination half-life of tacrolimus (up to 50 hours), any dose adjustment will only reach steady state, and thus stable trough concentrations, after approxi-mately 10 to 12 days.
If repeated dose adjustments result in alternating recommended doses on consecutive evaluations, then an intermediate or asymmetric dosing strategy should be applied. Examples include tacrolimus immediate-release dosing regimen of 1.5 mg/1.0 mg (morning/evening) or a 2.5 mg extended-release tacrolimus regimen. Alternatively, use of another for-mulation (eg, granules or sublingual administration) or generic extended-release formulation of tac-rolimus (with different dose strengths) may be considered.

General Comments on Tacrolimus Dose Adjustments, Trough Level Measurements, and Limitations of Creatinine for Long-Term Transplant Recipients

For a patient who has received a transplant many months (or years) previously, tacrolimus dose adjust-ments should generally be minimal (“never change a winning team”), and target trough concentrations should be reevaluated with a general aim of correction toward lower target ranges. Two important exceptions apply. First, marked deterioration of renal function may necessitate substantial dose reductions. Second, discontinuation of itraconazole typically requires major increases in the tacrolimus dose. Conversely, initiation of other azole antifungals will substantially increase trough concentrations and therefore would require substantial dose reductions, with voriconazole and systemic ketoconazole exerting stronger interac-tions versus the interactions of fluconazole and isavuconazole.
We suggest a word of caution regarding creatinine. That is, creatinine-based eGFR should not be used in this context because it is unreliable for the purposes outlined above based on our clinical experience. This is partly related to the fact that patients with end-stage lung disease and lung transplant recipients often have a reduced muscle mass. Although abnor-mal creatinine values may reflect a trend toward improving or worsening renal function, absolute creatinine values and creatinine-based eGFR estimates should not guide tacrolimus dose adjustments. Instead, urea (primarily) and cystatin C-based eGFR are preferred for the assessment of renal function in this setting.

Conclusions

The tool (Table 1) and rules mentioned here have been used by different teams at our institution to calculate individual doses or daily doses for lung transplant recipients, which has resulted in overall positive feedback. The evaluation of this concept is ongoing. Although this concept has been helpful in our setting, we acknowledge that its usefulness, appropriateness, and safety have not been proven in other settings (for example, in cohorts with other standard medication combinations), which are impor-tant limitations. Pending validation studies, this concept should be applied only in the context of research.

References:

1. Schuurmans MM, Raeber ME, Roeder M, Hage R. Adaptive immunosuppression in lung transplant recipients applying complementary biomarkers: the Zurich Protocol. Medicina (Kaunas). 2023;59(3):488. doi:10.3390/medicina59030488
   CrossRef - PubMed
2. Dellgren G, Lund TK, Raivio P, et al. Effect of once-per-day tacrolimus versus twice-per-day ciclosporin on 3-year incidence of chronic lung allograft dysfunction after lung transplantation in Scandinavia (ScanCLAD): a multicentre randomised controlled trial. Lancet Respir Med. 2024;12(1):34-44. doi:10.1016/S2213-2600(23)00293-X
   CrossRef - PubMed
3. Chatzidaki E, Schuurmans MM, Bonzon J, Hage R. Tacrolimus overdosing in lung transplant recipients: clinical manifestations and management. J Thorac Dis. 2025;17(10):8951-8959. doi:10.21037/jtd-2025-1253
   CrossRef - PubMed