Risk Factors for Subtherapeutic Tacrolimus Levels After Conversion from Intravenous to Oral Dosing Posttransplant in Adults

Design

Single-center, retrospective chart review 

N= 236

Objective

To identify patients with target tacrolimus serum concentration levels within 72 hours of conversion from intravenous (IV) to oral dosing, as well as the factors that affect tacrolimus levels after conversion

Study Groups

Hematopoietic stem-cell transplant patients (HSCT; N= 236)

Inclusion Criteria

Patients aged > 18 years who received IV tacrolimus, received an allogeneic HSCT for a hematologic malignancy and were admitted by day 0 of HSCT

Exclusion Criteria

Patients aged < 18 years, received IV tacrolimus outside the peritransplant period, had tacrolimus therapy interrupted for > 24 hours, received an allogeneic HSCT for an underlying disease other than hematologic malignancy, or received only oral tacrolimus as part of an outpatient transplant

Methods

Eligible patients were selected after reviewing electronic medical records at the University of Kansas. The institutional standard conversion factors from IV to oral tacrolimus based on antifungal drug coverage included the following: 2 for fluconazole, 4 for micafungin, and 1.5 each for posaconazole and for voriconazole. In addition, for patients with serum creatinine > 2 mg/dL or > 2 times the patient’s baseline, tacrolimus was held for at least 12 hours and then resumed at a 50% dose reduction. For patients receiving IV tacrolimus, serum concentrations could be drawn at any time; for those taking PO tacrolimus, the first trough concentration was drawn 10 hours to 12 hours after the last dose and before administering the next oral dose between 48 hours and 72 hours after conversion from IV to oral tacrolimus. 

For patients who received myeloablative or reduced-intensity conditioning regimens, the target tacrolimus concentrations were 10 ng/mL to 15 ng/mL on day 0 through day 30, and 5 ng/mL to 15 ng/mL on day 31 through day 100. For patients who received nonmyeloablative conditioning regimens (nonhaploidentical), target tacrolimus concentrations were 10 ng/mL to 20 ng/mL day 0 through day 30, then 5 ng/mL to 20 ng/mL on day 31 or later. For patients who received haploidentical transplants, the target tacrolimus concentrations were 5 ng/mL to 15 ng/mL on day 7 through day 180. Doses were adjusted by 25% to 50% based on serum concentrations and clinical judgment, rounded to tablet size. 

Univariate and multivariate analyses were conducted to identify the risk factors associated with prolonged time to reach tacrolimus target serum concentrations. A logistic regression model was used to evaluate the time to reach target tacrolimus serum concentrations by the incidence of acute graft-versus-host disease (GVHD). 

Duration

Outcome Measures

Primary outcome: proportion of patients who attained a therapeutic tacrolimus level within 72 hours after conversion from IV to oral formulation

Secondary outcome: time to target tacrolimus levels after conversion, and the effect of age, race, change in renal function, total bilirubin, albumin, antifungal agent, total parenteral nutrition use, diarrhea and mucositis at conversion, time to reaching target tacrolimus serum concentrations, the incidence of grade II to grade IV acute GVHD in patients with subtherapeutic versus therapeutic tacrolimus levels, and the mean IV to oral conversion factor producing therapeutic concentrations

Baseline Characteristics

HSCT patients (N= 236)

Median age, years (range)

Female

Race

White

African American 

Asian 

Hispanic

200 (84.7%)

Laboratory results (mean) 

Hematologic malignancy 

Conditional regimen 

Myeloablative

Reduced intensity 

Nonmyeloablative

Degree of human-leukocyte antigen-match 

4/8

8/8 or 6/6

Matched-unrelated donor transplant

Antifungal agent coverage 

Tacrolimus target concentration 

Results

Endpoint

HSCT patients (N= 236)

Initial tacrolimus level 

Subtherapeutic 

Therapeutic 

Supratherapeutic 

Median time to target tacrolimus level, days

Median tacrolimus dose

IV, mg/kg daily (range) 

Oral, mg/kg daily (range)

Antifungal drug coverage - conversion factor to reach target (range)

Fluconazole (n= 184)

Micafungin (n= 16)

Posaconazole (n= 24)

Voriconazole (n= 12)

Incidence of acute GVHD 

Grade II to IV

Grade III or IV

120 (50.8%)

27 (11.4%)

Adverse Events

Study Author Conclusions

The majority of the patients were not within the target range after the initial conversion from IV to oral tacrolimus. The patients required a median of 7 days to reach the target concentrations, which was increased by having diarrhea or by haploidentical donor cells. However, increased time to target levels did not increase the incidence of acute GVHD after conversion.

InpharmD Researcher Critique

The mean conversion factors utilized in this study can be used as guidance in practice to achieve therapeutic tacrolimus concentrations from IV to PO conversion based on the different concomitant antifungal agents.

The retrospective nature at a single institution may limit the generalizability of the study results. Certain confounding factors, such as the timing when patients were converted to oral tacrolimus, the timing of patient discharge, and changes in antifungal coverage before achieving therapeutic tacrolimus serum concentration, were not clearly identified based on a chart review. 

Analysis of the variable factors influencing tacrolimus blood concentration during the switch from continuous intravenous infusion to oral administration after allogeneic hematopoietic stem cell transplantation

Design

Retrospective, observational dosing study

N= 73

Objective

To identify variable factors affecting tacrolimus blood concentration during the switch from continuous intravenous infusion to twice-daily oral administration in allogeneic hematopoietic stem cell transplant recipients (HSCT)

Study Groups

HSCT recipients (N= 73)

Inclusion Criteria

Inpatients ≥ 20 years, diagnosed with hematologic malignancies and received conditioning regimens followed by HSCT, with graft-versus-host disease (GVHD) prophylaxis of switching tacrolimus from continuous intravenous infusion to oral administration

Exclusion Criteria

Not explicitly stated

Methods

All data were retrospectively collected from the electronic medical record system. Patients received an initial dose of tacrolimus continuous intravenous infusion of 0.3 mg/kg/day, and the dose was adjusted to maintain blood concentrations between 10 and 15 ng/mL. When patients were able to tolerate oral administration, the route of administration was switched from continuous intravenous infusion to twice-daily oral capsules. The intravenous infusion was stopped just prior to the first oral administration of medication. After the switch to oral administration, the tacrolimus blood concentration was measured approximately three times per week, and dosing was modified at the discretion of each physician.

Blood concentration/dose ([ng/mL]/mg/day, [C/D]) ratio of tacrolimus just before the change from continuous intravenous infusion (C/Div) was compared with that from between 3 and 5 days after the change to oral administration (C/Dpo) when the increase in the tacrolimus blood level was stabilized.

Duration

December 2010 to December 2013

Outcome Measures

Primary outcome: variable factors associated with the variation of (C/Dpo) divided by (C/Div) [(C/Dpo)/(C/Div)]

Secondary outcomes: appropriateness of the conversion rate from intravenous to oral administration, associations between the (C/Dpo)/(C/Div) values, and the occurrence of acute GVHD and kidney injury during the two weeks after the switch of administration route

Baseline Characteristics

HSCT recipients (N= 73)

Median age, years (range)

Female

Median body weight, kg (range)

GVHD prophylaxis

Tacrolimus plus methotrexate

Tacrolimus plus mycophenolate mofetil

Tacrolimus plus methylprednisolone

Human-leukocyte antigen-mismatched

55 (75.3%)

13 (17.8%)

3 (4.1%)

39 (53.4%)

Median tacrolimus concentration prior to switch (range), ng/mL

12.4 (4.7 to 18.1)

Results

Endpoint

p-value

Median tacrolimus concentration after switch to oral administration, ng/mL (range)

Median (C/D), [ng/ml]/[mg/day] (range)

(C/Div)

(C/Dpo)

(C/Dpo)/(C/Div)

17.3 (6.7 to 44.7)

3.6 (0.6 to 17.9)

0.21 (0.04 to 0.58)

-

-

-

Univariate analysis to identify variable factors associated with variation of (C/Dpo)/(C/Div)

Female gender (n= 37)

Age

Body weight

Myeloablative conditioning regimen (n= 22)

GVHD prophylaxis

Without azole antifungals (n= 13)

Concomitant use of oral fluconazole (n= 30)

Concomitant use of oral itraconazole or voriconazole (n= 29)

Concomitant use of omeprazole (n= 4)

Concomitant use of lansoprazole (n= 25)

Concomitant use of steroid (n= 36)

Concomitant use of calcium channel blocker (n= 7)

History of gut GVHD (n= 20)

Serum albumin

Hematocrit

Serum creatinine

Total bilirubin

Aspartate aminotransferase

Alanine aminotransferase

N/A

0.069^a

0.55

0.117

0.602

0.712

0.021^a

0.022^b

< 0.001^b

0.074^a

0.907

0.913

0.071^a

0.564

0.752

0.302

0.825

0.23

0.76

0.567

^aA factor in the decrease of the (C/Dpo)/(C/Div) ratio of tacrolimus

^bA factor in the increase of the (C/Dpo)/(C/Div) ratio of tacrolimus

Tacrolimus was switched to an oral dose at a median of 3 times (range 1.7 to 4) higher than the intravenous dose, which was administered in two divided doses at a median of 45 days (range 21 to 162).

The (C/Dpo)/(C/Div) of tacrolimus in patients using itraconazole or voriconazole (median 0.28, range 0.06 to 0.58) was significantly higher than patients receiving micafungin (median 0.11, range 0.04 to 0.52; p< 0.001) or patients receiving fluconazole (median 0.19, range 0.07 to 0.3; p< 0.01).

There was a statistically significant correlation between the (C/Dpo) and (C/Div) of tacrolimus in patients receiving fluconazole (p< 0.001) and patients receiving itraconazole or voriconazole (p< 0.001). The slopes of the lines that indicated a role of conversion ratio from intravenous to oral administration of tacrolimus were 0.12 for patients receiving micafungin, 0.21 for patients receiving fluconazole, and 0.39 for patients receiving itraconazole or voriconazole.

Five of 18 (27.8%) patients who had the lowest quartile (C/Dpo)/(C/Div) values had developed acute GVHD after the change in route of administration, which was significantly higher than that in other quartiles (5 of 55 [9.1%] patients, p= 0.045)

Adverse Events

The (C/Dpo)/(C/Div) values were divided into four quartiles with cutoff values of 0.15, 0.21, and 0.28. The lowest and highest quartiles included the 25% of patients with the lowest and the highest values, respectively.

Acute GVHD (all grades): lowest quartile 27.8% vs. other quartiles 9.1%; p= 0.045

The range of (C/Dpo)/(C/Div) ratio in the lowest quartile group was 0.04 to 0.15. The range of (C/Dpo)/(C/Div) ratio in the other quartiles was 0.15 to 0.58.

Average serum creatinine, mg/100 mL (range)

Day 0: highest quartile 0.72 (0.43 to 1.58) vs. other quartiles 0.73 (0.33 to 1.5); p= 0.949

Day 7: 0.78 (0.44 to 1.49) vs. 0.81 (0.39 to 1.88); p= 0.768

Day 14: 0.84 (0.46 to 1.43) vs. 0.84 (0.83 to 1.7); p= 0.451

The range of highest quartile of (C/Dpo)/(C/Div) ratio was 0.28 to 0.58. The range of other quartiles of (C/Dpo)/(C/Div) ratio was 0.04 to 0.28.

Study Author Conclusions

Although the conversion from continuous intravenous infusion to oral administration of tacrolimus at a ratio of 1:5 seemed appropriate, a lower conversion ratio such as 1:3 is suitable in patients taking oral itraconazole or voriconazole. In patients whose tacrolimus blood concentration decrease after switching the route of administration, the development of GVHD should be carefully monitored, and the dosage of tacrolimus should be frequently adjusted, considering its blood level.

InpharmD Researcher Critique

This retrospective study is subject to the inherent limitations and biases of retrospective chart reviews. Additionally, genetic polymorphisms, notably the CYP3A5 genotype that affect tacrolimus blood concentration, were not evaluated. Concomitant use of CYP3A4 inhibitors such as itraconazole and voriconazole appears to affect tacrolimus concentrations when switching from IV to oral and should be accounted for, which may necessitate a lower conversion ratio.

Summary of Initial Oral Prograf Capsules Dosage Recommendations and Whole Blood Trough Concentration Range in Adults

Patient Population

Kidney Transplant

With Azathioprine

Month 1-3: 7-20 ng/mL

Month 4-12: 5-15 ng/mL

With MMF/IL-2 receptor antagnoist^§

Liver Transplant

With corticosteroids only

Heart Transplant

With azathioprine or MMF

Month 1-3: 10-20 ng/mL

Month ≥ 4: 5-15 ng/mL

Lung Transplant

With azathioprine

Month 1-3: 10-15 ng/mL

Month 4-12: 8-12 ng/mL

MMF: mycophenolate mofetil

African-American patients may require higher doses compared to Caucasians.

^§In a second smaller trial, the initial dose of tacrolimus was 0.15-0.2 mg/kg/day and observed tacrolimus concentrations were 6-16 ng/mL. during month 1-3 and 5-12 ng/mL during month 4-12.

^¶Patients with cystic fibrosis may require higher doses due to lower bioavailability.