http://www.jhltonline.

org

RESEARCH CORRESPONDENCE
Dose conversion factor between
cyclosporine and tacrolimus in pediatric
heart transplant recipients
Eliza Notaro, BS,a Lisa Brown, BS,b
Erin Albers, MD,c Sabrina Law, MD,c and
Mariska Kemna, MDc
From the aSchool of Medicine; bDepartment of
Biostatistics; and the cDivision of Pediatric
Cardiology, Seattle Childrens Hospital,
University of Washington, Seattle, Washington

Calcineurin inhibitors (CNIs) are the cornerstone of

immunosuppression after pediatric heart transplantation
(HTx).1 However, many patients require conversion from
one drug to another because of undesired adverse effects or
breakthrough rejection.2 After conversion, it is important to
achieve stable target blood levels of the newly introduced
CNI as soon as possible to limit the risk of rejection, graft
loss, and drug toxicity.3
Current guidelines direct clinicians converting patients
between cyclosporine A (CyA) and tacrolimus (TAC) to
dose pediatric patients according to weight (mg/kg), then
adjust the dose relative to blood levels. However, dose
requirements between patients vary widely because of
individual differences in metabolism. Because both drugs
are metabolized through the cytochrome P-450 pathway,
dose requirements are strongly associated with each other as
shown in adults after kidney transplant.4
Our primary aim was to examine the relationship between
CyA and TAC dosing in pediatric HTx patients, seeking a
conversion factor between CNIs that would account for
individual differences in drug metabolism. This conversion
factor could be used to dose the new drug relative to each
patients unique, stable dosing of the previous drug and
might provide more accurate dosing than the traditional
mg/kg guidelines.
A conversion factor for CNIs is dened as a patients
stable 24-hour CyA dose/stable 24-hour TAC dose. For
adult kidney transplant patients, conversion factors have
been determined to be 254 and 305. These conversion factors
may not apply to children because their drug metabolism is
different from adults. CNI dosing at 1 year post-HTx was
also compared with current mg/kg dosing recommendations.
The mean CNI dose at 1 year post-HTx was recorded for
all HTx patients aged r18 years receiving post-HTx care at
Seattle Childrens Hospital. All patients who were switched
from a stable CyA dose to TAC, or vice versa, were

identied retrospectively. Conversions within 1 month of

HTx were excluded.
Medical records were reviewed for indication for HTx,
gender, age, and weight at time of conversion, indication for
conversion, pre-conversion drug and dose, and postconversion drug and dose at date of stability. Stability
was dened as the CNI dose that resulted in a level within
the target range for at least 3 subsequent blood checks
without requiring dose adjustments of 410%.
Supplementary Table 1 (available on the jhltonline.org
Web site) demonstrates our standard target ranges for CyA
and TAC. Institutional Review Board approval was obtained.
At 1 year post-HTx, 87 patients were receiving mean
doses of 0.24 mg/kg/day for TAC (n 42) and 10.39
mg/kg/day for CyA (n 45). The mean dosing for TAC
was within the Seattle Childrens Hospital guideline range
of 0.1 to 0.3 mg/kg/day; however, the mean dosing for CyA
was above the guideline range of 5 to 10 mg/kg/day.
Fifty-six HTx recipients who converted between CyA and
TAC from 1996 to 2013 met inclusion criteria. Three
patients underwent multiple conversions which were treated
as separate events, totalling 59 conversions, comprising 50
from CyA to TAC and 9 from TAC to CyA. Dosing
intervals were every 12 hours, except for 9 patients who
were adjusted from every 8 hours to every 12 hours during
conversion from CyA to TAC. Indications for converting
from CyA to TAC included gum hypertrophy (48%),
rejection (22%), gastrointestinal symptoms (6%), hirsutism
(4%), renal dysfunction (4%), frequent infections (4%),
bone marrow dysfunction (2%), and a combination of
indications (10%). Patients were converted from TAC to
CyA due to hyperglycemia (33%), gastrointestinal symptoms (22%), renal dysfunction (11%), frequent infections
(11%), encephalopathy (11%), and skin problems (11%).
Patient demographics are summarized in Table 1.
A stable CyA dose strongly correlated with a stable TAC
dose (r 0.81, Figure 1). The mean conversion factor for
all patients was 51, and conversion factors were very similar
across groups converting in both directions. Given this
concordance between the groups, we chose to model the
relationship between CyA and TAC using both conversion
direction groups together instead of separate. Of note,
6 patients converting from CyA to TAC for rejection were
designated increased target ranges after conversion. A
separate analysis, excluding these 6 events, did not reveal
a change in the mean conversion factor of 51.
A priori, we suspected CNI metabolism might be different
in younger children (aged o2 years) than in older children

1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved.
http://dx.doi.org/10.1016/j.healun.2014.04.004

Research Correspondence

767

Figure 1
Individual patients stable tacrolimus (TAC) and
cyclosporine A (CyA) dose requirements per day are shown by age
group (r 0.81).

(aged Z2 years). The mean conversion factor was 69 39

for 14 patients aged o2 years and 45 18 for 45 patients
aged Z2 years. A t-test allowing for unequal variances in the
age groups indicated that the difference in mean conversion
factors was statistically signicant (p 0.0396). Owing to
Table 1

two outlying conversion factors (127 and 160) and an interest

in multiplicative increases in dose, we used the geometric
mean of conversion factors, which was 60 for children aged
o2 years and 42 for children aged Z2 years.
Prediction accuracy of the overall conversion factor and age
groupspecic conversion factors were assessed by using
leave-one-out cross-validation. TAC dose predictions were
performed independently of CyA dose predictions. Predictions
of stable CNI dose using conversion factors had lower mean
absolute error (mg/day) than weight-based predictions for both
TAC and CyA. For predicting TAC, the mean absolute error
of the weight-based model was 2.13, compared with 1.48 (all
ages), 1.03 (o2 years), and 1.55 (Z2 years) when conversion
factors were used. For predicting CyA, the mean absolute
error of the weight-based model was 71.0, compared with
68.0 (all ages), 63.0 (o2 years), and 65.7 (Z2 years).
Therefore, stable CNI dosages were more strongly predictive
of one another than weight.
This is a small, single-center retrospective study. Our
analysis did not control for other factors, such as other
medications, that might inuence CNI metabolism.
This study conrms a strong correlation between CyA
and TAC doses. We show that a previous stable TAC dose
is a stronger predictor of a new stable CyA dose than weight
and that a previous stable CyA dose is a stronger predictor
of a new stable TAC dose than weight. Dosing based on
prior CNI dose rather than mg/kg may improve accuracy
and safety because it reects individual differences in

Descriptive Statistics of the Study Population

Variablesa
Sex
Male
Female
Indication for transplant
Cardiomyopathy
Congenital
Transplant to conversion, months
Age at conversion, years
Weight at conversion, kg
Post-conversion adjustments, No.
Time to stabilization, days
Stable TAC dose, mg/kg/day
Stable CyA dose, mg/kg/day
Conversion factor
Geometric mean conversion factor

Transplant to conversion, months

Age at conversion, years
Weight at conversion, kg
Post-conversion adjustments, No.
Time to stabilization, days
Conversion factor
Geometric mean conversion factor

CyA to TAC
(n 50)

TAC to CyA
(n 9)

Combined
(N 59)

25 (50)
25 (50)

5 (56)
4 (44)

30 (51)
29 (49)

21 (42)
28 (56)
35 40
8.4 6.3
27 18
3.6 3.4
55 54
0.22 0.16
8.9 3.9
51 26
46

2 (22)
7 (78)
50 49
7.4 4.8
26 16
2.3 1.4
20 15
0.20 0.12
7.7 2.6
50 29
44

23 (39)
35 (59)
37 41
8.2 6.1
27 18
3.4 3.2
50 51
0.21 0.15
8.7 3.7
51 26
46

o2 years old
(n 14)
10 4.5
1.5 0.26
9.6 1.4
5.6 4.4
75 74
69 39
60

Z2 years old
(n 45)
46 44
10 5.5
32 17
2.7 2.4
42 40
45 18
42

Combined
(N 59)
37 41
8.2 6.1
27 18
3.4 3.2
50 51
51 26
46

CyA, cyclosporine A; TAC, tacrolimus.

a
Mean standard deviation are given for continuous variables and count (percentage) are given for continuous variables.

768

The Journal of Heart and Lung Transplantation, Vol 33, No 7, July 2014

patients drug metabolisms. When converting from CyA to

TAC or vice versa, a conversion factor of 60 should be used
for patients aged o 2 years, and a factor of 42 should be
used for pediatric patients aged Z 2 years.

Disclosure statement
E.N. was supported by the University of Washington Medical
Student Research Training Program.
None of the authors have a nancial relationship with a
commercial entity that has an interest in the subject of the
presented manuscript or other conicts of interest to disclose.

Supplementary material
Supplementary Table 1 is available in the online version
of this article at jhltonline.org.

References
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rescue therapy in children using a double immunosuppressive regimen
after heart transplantation. Transplant Proc 2012;44:2483-5.
3. Pollock-BarZiv SM, Finkelstein Y, Manlhiot C, et al. Variability in
tacrolimus blood levels increases the risk of late rejection and graft loss
after solid organ transplantation in older children. Pediatr Transplant
2010;14:968-75.
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