Is there literature supporting dose rounding of Thymoglobulin to the nearest vial size?

Comment by InpharmD Researcher

While the literature appears scattered, several retrospective studies and a 2021 review indicate that rounding thymoglobulin doses to the nearest 25 mg vial is a common practice employed to reduce waste. The literature shows mixed outcomes: two studies found that modest dose variations from rounding and capping did not increase rejection risk when combined with triple maintenance immunosuppression, while a third study reported that rounding down was associated with significantly higher biopsy-proven acute rejection, suggesting that doses should be rounded up or supplemented when necessary. The review acknowledges that dose rounding is widely used despite limited supporting evidence and lack of FDA endorsement, and it concludes that rounding can likely be implemented safely, though caution is warranted in patients with higher body weights.

thymoglobulin dose rounding vial

Background

A 2021 review on transplant stewardship discusses rATG dose rounding and capping as cost-reduction strategies that, despite being relatively common in practice, carry limited supporting evidence and are not endorsed by FDA labeling. Two retrospective studies were highlighted. The first examined 242 adult kidney transplant recipients undergoing early steroid withdrawal who received four doses of rATG 1.5 mg/kg (total body weight), rounded to the nearest 25 mg vial and capped at a single dose of 150 mg; patients with cumulative doses ≥6 mg/kg had significantly lower biopsy-proven acute rejection (BPAR) compared to those receiving <6 mg/kg (11% vs. 21.2%, p <0.042), but no differences in patient/graft survival, renal function, leukopenia, or thrombocytopenia were observed. The second study involved 261 recipients with continued steroids, targeting a total cumulative dose of 5 mg/kg but capped at 500 mg, and found no difference in BPAR (8.9% vs. 8.7%) or other clinical endpoints between those receiving <5 mg/kg and ≥5 mg/kg, concluding that modest cumulative dose variations due to capping did not compromise efficacy in the context of triple immunosuppression, though cost savings were not directly measured. Additional published studies note that rounding to the nearest 25 mg is common practice to minimize waste, and the review suggests that rounding and capping can likely be implemented safely, with caution warranted for individuals with higher body weights. Importantly, there is no evidence supporting a maximum lifetime cumulative dose, and because dose capping has not been specifically studied for rejection treatment, the review recommends excluding those patients from capping protocols. [1]

References: [1] Jorgenson MR, Descourouez JL, Brady BL, et al. A call for transplant stewardship: The need for expanded evidence-based evaluation of induction and biologic-based cost-saving strategies in kidney transplantation and beyond. Clin Transplant. 2021;35(9):e14372. doi:10.1111/ctr.14372
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there literature supporting dose rounding of Thymoglobulin to the nearest vial size?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

Evaluation of a Weight-based Rabbit Anti-thymocyte Globulin Induction Dosing Regimen for Kidney Transplant Recipients
Design

Single-center retrospective cohort study

N= 261
Objective To evaluate the potential consequences of rounding and capping rATG doses in patients receiving steroid-containing maintenance immunosuppression when calculating the dose based on actual body weight
Study Groups

rATG dose ≥5 mg/kg (n=138)

rATG dose <5 mg/kg (n=123)
Inclusion Criteria Adult kidney transplant recipients between July 1, 2010, and December 31, 2012, who received rATG induction and were maintained on tacrolimus, mycophenolate, and prednisone
Exclusion Criteria Patients who received a prior or simultaneous nonrenal transplant, underwent desensitization, experienced primary graft nonfunction, expired within 7 days of transplantation, and those who received a positive crossmatch graft, investigational medications, or rATG for nonprotocol indications
Methods

Incidences of biopsy-confirmed acute rejection, opportunistic infections, and hematologic effects within 12 months posttransplant were assessed for patients receiving a cumulative rATG dose of 5 mg/kg or higher compared with those who received a cumulative rATG dose lower than 5 mg/kg. Doses were rounded to the nearest vial size and capped at a total of 500 mg. Data were collected retrospectively.
Duration July 1, 2010, to December 31, 2012
Outcome Measures

Primary: Incidence of biopsy-confirmed acute rejection (BCAR) grade 1A or greater within 12 months posttransplant

Secondary: Incidences of CMV, BK viremia, BK virus nephropathy
Baseline Characteristics   Group I (n=138) Group II (n=123)
Age, yrs, mean ± SD 50.3 ± 14.1 50.5 ± 11.9
Male, n (%) 82 (59.4) 76 (61.8)
ABW, kg, mean ± SD 80.3 ± 13.8 94.6 ± 24.4
IBW, kg, mean ± SD 64.4 ± 11.5 66.8 ± 10.9
BMI, kg/m2, mean ± SD 27.6 ± 4.8 31.3 ± 6.9
Results   Group I (n=138) Group II (n=123) p-value
BCAR grade ≥1A, n (%) 12 (8.7) 11 (8.9) 0.994
CMV, n (%) 11 (8.0) 12 (9.8) 0.385
BKV, n (%) 15 (10.9) 13 (10.6) 0.550
BKVN, n (%) 6 (4.3) 5 (4.1) 0.579
Adverse Events No significant differences in CMV, BKV, or BKVN incidences. Lymphopenia, thrombocytopenia, and leukopenia incidences did not differ significantly between groups
Study Author Conclusions

Modest differences in the cumulative rATG dose were not associated with increased risk of acute rejection when combined with triple maintenance immunosuppression. Optimizing rATG utilization can offer cost-saving opportunities without sacrificing efficacy.
Critique

The study's retrospective design and single-center setting may limit generalizability. Confounders such as adherence to maintenance immunosuppression regimen were not captured. The study did not include patients receiving cumulative rATG doses higher than 6 mg/kg, limiting insights into higher dosing effects.

 

References:
[1] [1] Pennington CA, Tischer SM, Lee E, Lee S, Sindelar J Jr, Park JM. Evaluation of a Weight-based Rabbit Anti-thymocyte Globulin Induction Dosing Regimen for Kidney Transplant Recipients. Pharmacotherapy. 2015;35(8):748-754. doi:10.1002/phar.1624
Induction with ATG in DCD kidney transplantation; efficacy and relation of dose and cell markers on delayed graft function and renal function
Design

Retrospective analysis of prospectively collected data

N= 140
Objective To analyse the efficacy of the Thymoglobulin dose used for induction in controlled DCD kidneys, and its initial impact on blood cell and CD3 count, as predictors of efficacy
Study Groups All patients (n= 140)
Inclusion Criteria All patients who received a renal transplant from a DCD donor (Maastricht III) and rATG, as an induction immunosuppression agent, between January 2005 and December 2013
Exclusion Criteria Recipients who participated in clinical trials during this period were excluded
Methods

140 DCD patients received ATG induction with an intended dose of 1.25 mg/kg/day over 5 days, rounded to nearest 25 mg, not exceeding 125 mg/dose. Outcomes included total dose in relation to rejection, DGF, graft survival, eGFR. Cell count response to ATG was assessed as predictors of outcome. Data were analysed using SPSS and GraphPad Prism.
Duration January 2005 to December 2013, with follow-up until 1st August 2019
Outcome Measures

Primary: 5-year graft survival

Secondary: Impact of rATG on recipient's blood cell lines (Leucocytes, Lymphocytes, CD3 counts)
Baseline Characteristics   Donors Recipients
Age, Median (range), yrs 50 (16–76) 55 (19–74)
Sex, M:F ratio 2.4:1 2.6:1
BMI, median (range) 27.4 (19–43) --
Cause of Death - ICH 66 --
Cause of Death - Hypoxic brain injury 34 --
Cause of Death - Trauma 12 --
Cause of renal failure - Polycystic kidney disease -- 25 (17.9%)
History of Diabetes Mellitus --  14 (10%)
Dialysis Status - Pre-dialysis --  3 (2%)
Dialysis Status - HD --  88 (63%)
Dialysis Status - PD --  49 (35%)
Cold Ischaemic Time Median (Range) hh:mm 12:30 (4:42–27:33) --
Total Mismatch, median (range) 4 (0–6) --
HLA DR Mismatch Median (range) 1 (0–2) --
Results   ATG dose >5 mg/kg ATG dose <5 mg/kg p-value
5-year graft survival 89% 80% 0.1
Day 5 leucocyte count correlation with ATG dose R = -0.305 -- <0.001
Day 5 lymphocyte count correlation with ATG dose R = -0.386 -- <0.001
CD3 count correlation with ATG dose R = -0.434 -- 0.05
Adverse Events No significant increase in CMV infection incidence among ATG dose groups. PTLD incidence was 1.5%, similar or lower than other studies
Study Author Conclusions Thymoglobulin provides excellent results in DCD kidneys that do not significantly differ with small dose variations. In higher doses it reduces DGF. Lymphocytes and CD3 count, may be useful surrogate markers of efficacy and outcome.
Critique

The study's retrospective design and limited availability of CD3 counts are notable limitations. However, it provides valuable insights into the efficacy of rATG in DCD kidney transplants, suggesting a protective role against DGF and potential use of CD3 counts as surrogate markers of efficacy.

 

References:
[1] [1] Sabah TK, Khalid U, Ilham MA, et al. Induction with ATG in DCD kidney transplantation; efficacy and relation of dose and cell markers on delayed graft function and renal function. Transpl Immunol. 2021;66:101388. doi:10.1016/j.trim.2021.101388
Impact of Small Variations in the Delivered Dose of Rabbit Antithymocyte Induction Therapy in Kidney Transplantation With Early Corticosteroid Withdrawal
Design

Retrospective study

N= 242
Objective To evaluate the effect of small changes in rabbit antithymocyte globulin (rATG) induction dosing on the incidence of biopsy-proven acute rejection, patient and graft survival, and allograft function in kidney transplant recipients
Study Groups 5 to 6 mg/kg rATG (n= 151) 6 mg/kg or more rATG (n= 91)
Inclusion Criteria Adult renal transplant recipients who received rATG induction between January 2009 and September 2010 at NewYork-Presbyterian Hospital/Columbia University Medical Center
Exclusion Criteria Patients who received other induction agents, multiorgan transplants, and those not eligible for early steroid withdrawal
Methods

Patients received rATG induction therapy with a protocol of four doses of 1.5 mg/kg, approximated to the nearest 25 mg and limited to a max of 150 mg. Patients were stratified by total rATG dose received (5 to 6 mg/kg and 6 mg/kg or more). Outcomes such as biopsy-proven acute rejection, patient and graft survival, and renal function were evaluated.
Duration January 2009 to September 2010
Outcome Measures

Primary: Incidence of biopsy-proven acute rejection(BPAR)

Secondary: Patient and graft survival, renal function (mean serum creatinine level)
Baseline Characteristics   5 to 6 mg/kg (n=151) 6 mg/kg or more (n=91)
Age, mean (SD), yr 50.4 (15) 50.3 (14)
Male, n (%) 92 (60.9) 47 (51.7)
Weight, mean (SD), kg 81 (17.3) 76.3 (15.6)
Weight ≥100 kg, n (%) 24 (15.9) 2 (2.2)
BMI, mean (SD), kg/m2 28.3 (8.2) 26.8 (4.9)
Living donors, n (%) 98 (64.9) 37 (40.7)
Cold ischemia time, mean (SD), hr 22.7 (16) 29.8 (10.8)
HLA mismatch, mean (SD) 4.1 (1.4) 4.4 (1.3)
Total rATG dose, mean (SD), mg 451.8 (96.2) 481.1 (93)
Results   5 to 6 mg/kg (n=151) 6 mg/kg or more (n=91) p-value
BPAR at any time after transplantation, n (%) 32 (21.2) 10 (11) 0.042
Serum creatinine level, mg/dL, mean (SD) - All patients last follow-up 1.64 (0.9) 1.76 (1.4) 0.404
White blood cells, x10^9/L, mean (SD) - 90 d 4.1 (2.3) 4.3 (7.8) 0.498
Platelet count, x10^9/L, mean (SD) - 90 d 217 (70.8) 213 (53.2) 0.720
Adverse Events Safety review of leukopenia or thrombocytopenia did not differ between groups. An equal percentage of patients in each group developed cytomegalovirus (CMV) viremia (9.93% vs. 6.59%; P=0.371)
Study Author Conclusions

Small changes in total rATG induction administered seem to significantly impact the incidence of rejection. Adequate rATG dosing is associated with improved rejection-free graft survival and should be achieved for all patients; doses should be rounded up when appropriate or additional doses should be administered if necessary.
Critique

The study highlights the importance of adequate dosing of rATG in kidney transplantation, showing a significant impact on rejection rates. However, the retrospective design and single-center nature may limit the generalizability of the findings. Additionally, confounding factors such as maintenance regimen compliance could not be assessed due to the retrospective nature of the study.

 

References:
[1] [1] Tsapepas DS, Mohan S, Tanriover B, et al. Impact of small variations in the delivered dose of rabbit antithymocyte induction therapy in kidney transplantation with early corticosteroid withdrawal. Transplantation. 2012;94(4):325-330. doi:10.1097/TP.0b013e318257ad1a