for prevention of graft-versus-host disease, the consensus initial intravenous dose of tacrolimus for adults is 0.03 mg/kg/day. whether target whole blood concentrations of tacrolimus in children undergoing hematopoietic stem cell transplantation can be achieved reproducibly with this dose is not known. we reviewed the tacrolimus blood levels and calculated clearances for 55 children (aged 6 months to 18 years, median 9 years) using tacrolimus after allogeneic marrow, blood stem cell or cord blood transplantation. the tacrolimus dose regimen was 0.03 mg/kg/day by continuous infusion starting on day −1 or day −2. at the first sampling in the peritransplant period, 71% of the tacrolimus blood levels were within the target range of 5–15 ng/ml, 87% were in the safe range of 5–20 ng/ml, 9% were toxic, and 4% were subtherapeutic. twenty-five children were converted to oral drug using the recommended oral/intravenous dose ratio of 4.0. at the first sampling after oral conversion, 80% were in the target range, and 20% were subtherapeutic. clearance of tacrolimus was calculated from the blood levels for patients during intravenous dosing and normalized by ideal body weight. there was a decreased clearance over the first 2 weeks only for the children >12 years old (P = 0.014). The initial calculated clearances of tacrolimus did not differ between age groups, but at steady state the mean tacrolimus clearance (± s.d.) was higher for those <6 years old (0.159 ± 0.082 l/h/kg) than for those 6–12 years old (0.109 ± 0.053 l/h/kg) or >12 years old (0.104 ± 0.068 l/h/kg). Children <6 years old undergoing hematopoietic stem cell transplantation have a higher weight-normalized tacrolimus clearance than older children and adults, and careful therapeutic monitoring is needed in the first 2 weeks after transplantation to avoid prolonged subtherapeutic dosing for this age group. Bone Marrow Transplantation (2000) 26, 601–605.
The superiority of tacrolimus over cyclosporine for prevention of acute graft-versus-host disease (GVHD) was demonstrated in three randomized trials.123 The appropriate dose schedule of tacrolimus for use in adults was developed by consensus after review of safety and efficacy data,4 and use of tacrolimus for GVHD prophylaxis has been increasing. There is much less experience with tacrolimus for GVHD treatment5 and prophylaxis67 in pediatric patients, and whether the consensus dose regimen is appropriate for children is not established. Pediatric solid organ transplant recipients reportedly require higher tacrolimus doses8910 and have higher tacrolimus clearances1112 in comparison to adults. We have therefore reviewed the tacrolimus blood levels and clearances in our pediatric hematopoietic stem cell transplant recipients receiving tacrolimus to determine if the consensus dose schedule is appropriate for prevention of GVHD in children.
Patients and methods
From October 1994 until June 1999, 53 children underwent transplantation at the MD Anderson Cancer Center or Texas Children's Hospital using tacrolimus-based GVHD prophylaxis. Two children were in relapse after first transplantation and were transplanted a second time at 8 and 20 months after the first procedure, respectively, for a total of 55 transplant courses with evaluable data. Treatment was approved by the Institutional Review Boards, and written informed consent was obtained from the guardian of each patient. Patient characteristics at the time of transplantation are listed in Table 1. There were 16 patients <6 years old, 22 patients 6–12 years old, and 17 patients >12 years old. Patients with nonmalignant diseases included two with aplastic anemia, two Wiskott–Aldrich syndrome, one Hunter's syndrome, one sickle cell anemia, one congenital thrombocytopenia, and one osteopetrosis. All patients received a myeloablative preparative regimen. Transplant procedures and supportive care measures were as reported.67
Tacrolimus was administered at 0.03 mg/kg/day i.v. by continuous infusion from day −1 or −2 (Table 1). Doses were adjusted to maintain whole blood steady-state or trough levels at 5–15 ng/ml. The range of 5–20 ng/ml was considered to be safe. Tacrolimus was discontinued or reduced in dose when blood levels were elevated or the serum creatinine was increased as described previously.4 Following engraftment when the patient was able to take medications orally, the 24-h dose of tacrolimus was to be converted at an oral/intravenous dose ratio of 4:1 and given orally (1 mg dose form or as the liquid preparation at 0.5 mg/ml in Simple Syrup USP) in a twice daily divided dose. Oral doses were rounded to conform to the oral dose units available. The oral/intravenous dose conversion ratio was >4 when the last tacrolimus level was subtherapeutic and <4 when in the toxic range. Fourteen patients expired prior to conversion to oral drug. Blood samples for tacrolimus assay13 were taken by phlebotomy or drawn through indwelling catheters not used for infusion of tacrolimus. Methotrexate was administered according to protocol or standard care policy at the time of transplantation. Two patients received no methotrexate, one received standard methotrexate (15 mg/m2 day 1 and 10 mg/m2 days 3, 6 and 11), 32 received minimethotrexate (5 mg/m2 days 1, 3, 6 and 11), and 20 received micromethotrexate (5 mg/m2 days 1, 3 and 6).
Ideal body weight was used to calculate the dose of tacrolimus and to normalize the calculated clearance. Clearance was calculated by the formula clearance = dose rate/blood concentration using whole blood concentrations of tacrolimus for patients receiving tacrolimus intravenously by continuous infusion. Tacrolimus whole blood concentrations and clearances were reported as the mean ± standard deviation (s.d.) for the population. Clearances were transformed logarithmically to maximize normality for statistical analyses. Fourteen patients were converted to oral tacrolimus or expired prior to sampling in the second week. One week after transplantation, there were no significant differences between those with or without data at the second week, suggesting no biases in data due to the drop-outs. Changes in clearance over time were assessed initially by one-way analysis of variance for repeated measures. This analysis showed evidence of a weak main effect for age group and a weak interaction between age and time period, suggesting that there were different time effects in different age groups and making main effects difficult to interpret. We therefore examined age-related differences in clearance at each timepoint with one-way analysis of variance, and we examined time-related changes in each age group with paired t-tests. The analyses were performed using SAS V6.12 (SAS Institute, Cary, NC, USA). A two-sided P value <0.05 was considered significant.
Initial tacrolimus levels achieved with standardized intravenous dosing
For the 55 cases in which tacrolimus was initiated at 0.03 mg/kg/day, the first whole blood concentration was measured at a median of 3 (range 2–7) days from start of prophylaxis. The mean ± s.d. tacrolimus whole blood concentration at first sampling on intravenous drug was 12.8 ± 6.0 ng/ml. The first sample was subtherapeutic in 4%, in the target range in 71%, in the safe range in 87%, and in the toxic range in 9% (Table 2). There was no difference between age groups in the distribution of tacrolimus blood levels at first sampling.
Initial tacrolimus levels achieved with standardized oral conversion
Forty-one patients were converted to oral tacrolimus after transplantation. The mean ± s.d. tacrolimus whole blood concentration at first sampling on oral drug was 7.2 ± 3.5 ng/ml. Sixteen patients were converted to oral tacrolimus using an oral/intravenous dose ratio <3.5 or >4.5 to compensate when the last tacrolimus whole blood concentration on intravenous administration was in the toxic range or subtherapeutic, respectively. The other 25 patients were converted to oral tacrolimus using a mean ± s.d. oral/intravenous dose ratio of 4.0 ± 0.2 at 22 (range 11–56) days after transplantation, and the first whole blood concentration was measured at a median of 2 (range 1–7) days after conversion to oral administration. For these 25 patients, the first tacrolimus whole blood concentration measured on oral drug was 6.7 ± 2.5 ng/ml; the level was subtherapeutic in 20% and in the target range in 80%. No patient with a tacrolimus level in the target range on intravenous drug had a toxic level when converted to oral drug using the standardized 4:1 conversion factor.
Effect of duration of intravenous therapy and patient age on calculated clearance of tacrolimus
The clearance of tacrolimus was calculated from the first whole blood concentration measured and from samples taken at approximately 1 and 2 weeks after transplantation for patients remaining on intravenous drug. The mean ± s.d. clearance of tacrolimus was 0.125 ± 0.055 l/h/kg (2.08 ± 0.91 ml/min/kg) initially, 0.123 ± 0.07 l/h/kg (2.04 ± 1.17 ml/min/kg) at the first week post transplant, and 0.114 ± 0.059 ml/min/kg (1.90 ± 0.98 l/h/kg) at the second week post transplant (P = 0.14). There was a decrease in clearance over the first 2 weeks for patients >12 years old (P = 0.014), but no significant change in clearance for those 6–12 years old (P = 0.26) or <6 years old (P = 0.28) (Figure 1).
At the first sampling timepoint, there were no significant differences in calculated clearance of tacrolimus when assessed by age group (P = 0.52). However, there was a trend for age-related differences in calculated clearance at 1 week (P = 0.11) and a significant effect of age at 2 weeks after transplantation (P = 0.03) (Figure 1). By multiple range test, clearances for the group <6 years old were higher in comparison to those for the older children (P = 0.05).
It was assumed that the steady-state had been achieved by the first week after transplantation, and the mean calculated tacrolimus clearance from this timepoint was used to calculate the expected whole blood concentration using the standardized dose of 0.03 mg/kg/day. The predicted tacrolimus level was within the target range for all three age groups, although the predicted level for children <6 years old was on the low side (Table 3). The dose calculated to achieve a whole blood tacrolimus concentration of 10 ng/ml using the calculated steady-state clearance was 0.038 mg/kg/day for the youngest age group (Table 3). When clearances were normalized by body surface area rather than weight, calculated clearance at steady state was 3.39 ± 1.91 l/h/m2, and there were no significant differences by age (3.63 ± 1.96, 3.04 ± 1.42, 3.59 ± 2.38 l/h/m2, respectively for the youngest to oldest groups). Using the mean calculated clearance for all patients, a dose of 0.8 mg/m2 would be expected to provide a tacrolimus blood level of 10 ng/ml.
GVHD is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation, and optimal dosing of immunoprophylaxis is required to ensure efficacy without toxicity. Uncompensated age-related changes in the pharmacokinetics of tacrolimus in solid organ transplant recipients have been associated with adverse clinical outcomes,10 but whether tacrolimus pharmacokinetics varies with age has not been studied extensively in stem cell transplant recipients. In a case series of seven patients, Mehta et al14 reported that pediatric marrow transplant recipients had a higher tacrolimus clearance (0.097 l/h/kg) than reported for adult marrow transplant recipients (0.071 l/h/kg).15 In our analysis of 55 cases, we confirm that pediatric patients have a higher tacrolimus clearance (0.123 l/h/kg) than that reported for adults. More importantly, clearance varied with age within the pediatric population, with children <6 years old having the highest clearance (0.159 l/h/kg).
The reason for the age-dependent difference in tacrolimus clearance has not been established. Drug interactions can alter pharmacokinetics, but concomitant drugs used in our patients were essentially uniform across all age groups. Clearance of tacrolimus is largely by metabolism, and the hepatic P450 CYP3A4 isoenzyme is thought to be the major enzyme responsible for metabolism of tacrolimus.16 Function of CYP3A4 increases with age, but other P450 isoenzymes that metabolize tacrolimus may be more active in children.1617 Hepatic clearance is also altered by hepatic blood flow and relative hepatic mass, which are increased in children when normalized by weight.18 We and Yasuhara et al11 found that the clearance of tacrolimus rose most sharply in the youngest (<6 years) or smallest (<15 kg) children, those having the highest ratio of body surface area to weight. However, we also found no differences in clearance by age when normalized by body surface area rather than weight. As a result, it may be more accurate to dose tacrolimus according to body surface area rather than weight for pediatric patients as is done for many other drugs. This hypothesis requires prospective testing.
We evaluated tacrolimus blood levels in the children to determine if the current dose regimen provided therapeutic drug concentrations. The risk of drug-related toxicity increases substantially with tacrolimus levels >20 ng/ml after HLA-identical or unrelated donor marrow transplantation,1920 identifying this as the upper limit of the therapeutic range. In addition, we recently reported that tacrolimus levels <5 ng/ml were associated with an increased risk of acute GVHD after unrelated donor marrow transplantation,21 identifying this as the lower limit of the therapeutic range. Thus, 5–20 ng/ml defines a safe range of tacrolimus whole blood levels. We have lowered our upper limit to 15 ng/ml for an extra margin of safety and use 5–15 ng/ml as the target range. Using the standardized dose regimen for tacrolimus, only 4% of patients had a subtherapeutic tacrolimus whole blood level at the time of first sampling. Thus, it appears that the current regimen provides an adequate initial dose for the majority of pediatric patients.
For adults with therapeutic tacrolimus blood levels on intravenous administration, it has been recommended to convert to oral administration using a total daily oral dose four times the daily intravenous dose. Age-related changes in bioavailability of tacrolimus have not been found previously,16 so it was expected that the 4:1 ratio for oral conversion would be appropriate for children as well. For our patients converted at this ratio, 80% had therapeutic tacrolimus levels thereafter, but 20% were subtherapeutic. The interindividual variability in bioavailability of tacrolimus is well-established, and our experience underscores the need for close therapeutic monitoring when converting to oral drug, especially in children.
We previously reported that tacrolimus dose requirements in adults decrease 25–50% over the first few weeks after transplantation when doses were adjusted to maintain the target tacrolimus blood levels.2223 We here and Mehta et al14 also found a decrease in tacrolimus clearance over time in adolescents. By contrast, tacrolimus clearance appeared to be stable over time in the youngest age group. The basis for the age-related difference in stability of tacrolimus clearance over time is unknown.
Here we have found that adolescents had a higher clearance of tacrolimus than that reported for adults, but therapeutic tacrolimus blood levels were achieved using the consensus dose schedule. For children <6 years old, initial tacrolimus blood levels were also therapeutic, but the overall steady-state clearance for this youngest subgroup was substantially higher, and there was a risk for subtherapeutic levels on subsequent days. It has been suggested that young children should receive a higher initial dose of tacrolimus14 in order to avoid the subtherapeutic level. The inherent danger in this approach is that use of a higher initial dose may increase the proportion of patients who subsequently develop toxic drug levels. Whether use of higher initial doses of tacrolimus will be safer than close therapeutic monitoring for young children remains to be determined.
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Przepiorka, D., Blamble, D., Hilsenbeck, S. et al. Tacrolimus clearance is age-dependent within the pediatric population. Bone Marrow Transplant 26, 601–605 (2000). https://doi.org/10.1038/sj.bmt.1702588
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