- Email: [email protected]
Basiliximab in paediatric liver-transplant recipients
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Basiliximab in paediatric liver-transplant recipients Sir—Juergen Strehlau and colleagues (Oct 14, p 1327)1 report significantly increased blood concentrations of ciclosporin within the first 10 days of paediatric renal-transplant recipients receiving basiliximab. As the CD25 saturation fades at days 28–50, ciclosporin trough concentrations decline, which suggests alteration by the mediated interleukin-2 receptor of the cytochrome P450 system. We treated 54 paediatric livertransplant recipients with basiliximab in addition to ciclosporin and steroids. The frequency of acute graft rejections was significantly lower than that in 57 controls treated with ciclosporin and steroid dual therapy (16·6 vs 54·0%). Six of nine patients treated with basiliximab had acute graft rejection between days 21 and 28 after surgery, after CD25 epitope saturation was decreased. These patients, similar to those of Strehlau and colleagues, had low ciclosporin trough concentrations with an increased need of oral ciclosporin at the time of acute graft rejection. In contrast to the paediatric kidney graft recipients, however, we saw no significant alteration of ciclosporin dose requirements in our 54 basiliximab-treated patients overall. Calculation of an individual ratio of ciclosporin dose per ciclosporin trough concentration (eg, 9 mg ciclosporin/kg bodyweight daily gave a ciclosporin trough concentration of 200 g per L⫻1000, which equals a ratio of 45 on a monoclonal TDx assay), we found no significant differences between basiliximabtreated patients and controls. The effect of basiliximab on the hepatic cytochrome P450 system (CYP3A4) suspected by Strehlau and colleagues might play a minor part in our series because of significantly lower aimed ciclosporin trough concentrations (130–170 g/L for basiliximab-treated patients and 170–200 g/L for controls in the first 4 weeks after transplantation). Median ciclosporin trough concentrations were only 145 g/L in the basiliximab group and 180 g/L in our control group, compared with 258 g/L and 228 g/L in the kidney-transplant recipients. Ciclosporin dose requirements do not change in paediatric liver-
388
transplant recipients induced by basiliximab, but we agree with Strehlau and colleagues that ciclosporin concentrations in blood should be closely monitored over a 3–8 week period when the CD25 saturation starts to fade. On the basis of Strehlau’s and our findings, the value of a third dose of basiliximab, given in the high-risk period 3–4 weeks after transplantation, in addition to the application on days 0 and 4, has to be discussed. *Rainer Ganschow, Enke Grabhorn, Martin Burdelski Department of Pediatrics, University of Hamburg, 20246 Hamburg, Germany (e-mail: [email protected]) 1
Strehlau J, Pape L, Offner G, Nashan B, Ehrich JHH. Interleukin-2 receptor antibody-induced alteration of ciclosporin dose requirements in paediatric transplant recipients. Lancet 2000; 356: 1327–28.
Sir—A drop of ciclosporin concentration 4 weeks after renal transplantation is reported by Juergen Strehlau and colleagues1 in 24 paediatric patients receiving basiliximab and ciclosporin. They postulate a basiliximabcytochrome P450 interaction. Since we use the same induction protocol for paediatric renal-transplant recipients, we reviewed our experiences in 38 patients. We saw acute rejection episodes in eight patients. Three rejections were seen early (days 14, 20, and 21) when CD25 saturation was still documented using fluorescence-activated cell-sorter analysis of peripheral lymphocytes. Three rejections occurred 56, 63, and 145 days after transplantation; in only one the CD25 saturation faded less than 1 month before this event. Only two of the eight rejections occurred during the time between day 28 and day 50, when Strehlau and colleagues saw all seven rejections. Therefore, we cannot confirm the observation of an increased rejection rate between day 28 and 50. A basiliximab-cytochrome P450 interaction seems to be rather speculative. Basiliximab specifically binds to the ␣-chain (CD25) of the interleukin-2 receptor, but this subunit of the high-affinity interleukin-2
receptor is virtually absent on human hepatoma cells, as shown by U Treichel and colleagues.2 In addition, since CD25 cannot transduce the interleukin-2 signal,3 basiliximab is unlikely to exhibit biological activity. We believe that differences in ciclosporin monitoring are more likely to account for the difference between our and Strehlau and colleagues’ data. We aim at trough concentrations of 250–350 g/L (Abbott assay) and keep this value for up to 3 months, compared with Strehlau and colleagues, who reach trough concentrations lower than 250 g/L after 4 weeks. In addition, we monitor C2 concentrations (2 h after ingestion) to estimate the drug exposure at a time when interindividual differences are most prominent.4 Peak values of more than 1500 g/L were seen as appropriate. With this protocol, no histological evidence of toxic effects of ciclosporin was seen in 15 biopsy samples taken from 13 patients. As known from adult studies, the probability of being rejection-free does not correlate with trough concentrations but is more predictable with C2 measurement.5 We suspect that accelerated reduction of ciclosporin in the Strehlau and colleagues’ basiliximab group may have led to underimmunosuppression and increased risk of rejection. Therapeutic windows for adequate C2 concentrations in paediatric patients need to be elaborated to ensure effective immunosuppression when the effect of basiliximab fades. *U Vester, B Kranz, U Treichel, P F Hoyer Departments of *Paediatric Nephrology and Gastroenterology and Hepatology, University of Essen, 45122 Essen, Germany (e-mail: [email protected]) 1
2
3 4
Strehlau J, Pape L, Offner G, Nashan B, Ehrich JHH. Interleukin-2 receptor antibody-induced alteration of ciclosporin dose requirements in paediatric transplant recipients. Lancet 2000; 356: 1327–28. Treichel U, Paietta E, Poralla T, Meyer zum Bueschenfelde KH, Stockert RJ. Effects of cytokines on synthesis and function of the hepatic asialoglycoprotein receptor. J Cell Physiol 1994; 158: 527–34. Waldmann TA. The interleukin-2 receptor. J Biol Chem 1991; 266: 2681–84. Johnston A, David OJ, Cooney GF. Pharmacokinetic validation of neoral
THE LANCET • Vol 357 • February 3, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Basiliximab in paediatric liver-transplant recipients Sir—Juergen Strehlau and colleagues (Oct 14, p 1327)1 report significantly increased blood concentrations of ciclosporin within the first 10 days of paediatric renal-transplant recipients receiving basiliximab. As the CD25 saturation fades at days 28–50, ciclosporin trough concentrations decline, which suggests alteration by the mediated interleukin-2 receptor of the cytochrome P450 system. We treated 54 paediatric livertransplant recipients with basiliximab in addition to ciclosporin and steroids. The frequency of acute graft rejections was significantly lower than that in 57 controls treated with ciclosporin and steroid dual therapy (16·6 vs 54·0%). Six of nine patients treated with basiliximab had acute graft rejection between days 21 and 28 after surgery, after CD25 epitope saturation was decreased. These patients, similar to those of Strehlau and colleagues, had low ciclosporin trough concentrations with an increased need of oral ciclosporin at the time of acute graft rejection. In contrast to the paediatric kidney graft recipients, however, we saw no significant alteration of ciclosporin dose requirements in our 54 basiliximab-treated patients overall. Calculation of an individual ratio of ciclosporin dose per ciclosporin trough concentration (eg, 9 mg ciclosporin/kg bodyweight daily gave a ciclosporin trough concentration of 200 g per L⫻1000, which equals a ratio of 45 on a monoclonal TDx assay), we found no significant differences between basiliximabtreated patients and controls. The effect of basiliximab on the hepatic cytochrome P450 system (CYP3A4) suspected by Strehlau and colleagues might play a minor part in our series because of significantly lower aimed ciclosporin trough concentrations (130–170 g/L for basiliximab-treated patients and 170–200 g/L for controls in the first 4 weeks after transplantation). Median ciclosporin trough concentrations were only 145 g/L in the basiliximab group and 180 g/L in our control group, compared with 258 g/L and 228 g/L in the kidney-transplant recipients. Ciclosporin dose requirements do not change in paediatric liver-
388
transplant recipients induced by basiliximab, but we agree with Strehlau and colleagues that ciclosporin concentrations in blood should be closely monitored over a 3–8 week period when the CD25 saturation starts to fade. On the basis of Strehlau’s and our findings, the value of a third dose of basiliximab, given in the high-risk period 3–4 weeks after transplantation, in addition to the application on days 0 and 4, has to be discussed. *Rainer Ganschow, Enke Grabhorn, Martin Burdelski Department of Pediatrics, University of Hamburg, 20246 Hamburg, Germany (e-mail: [email protected]) 1
Strehlau J, Pape L, Offner G, Nashan B, Ehrich JHH. Interleukin-2 receptor antibody-induced alteration of ciclosporin dose requirements in paediatric transplant recipients. Lancet 2000; 356: 1327–28.
Sir—A drop of ciclosporin concentration 4 weeks after renal transplantation is reported by Juergen Strehlau and colleagues1 in 24 paediatric patients receiving basiliximab and ciclosporin. They postulate a basiliximabcytochrome P450 interaction. Since we use the same induction protocol for paediatric renal-transplant recipients, we reviewed our experiences in 38 patients. We saw acute rejection episodes in eight patients. Three rejections were seen early (days 14, 20, and 21) when CD25 saturation was still documented using fluorescence-activated cell-sorter analysis of peripheral lymphocytes. Three rejections occurred 56, 63, and 145 days after transplantation; in only one the CD25 saturation faded less than 1 month before this event. Only two of the eight rejections occurred during the time between day 28 and day 50, when Strehlau and colleagues saw all seven rejections. Therefore, we cannot confirm the observation of an increased rejection rate between day 28 and 50. A basiliximab-cytochrome P450 interaction seems to be rather speculative. Basiliximab specifically binds to the ␣-chain (CD25) of the interleukin-2 receptor, but this subunit of the high-affinity interleukin-2
receptor is virtually absent on human hepatoma cells, as shown by U Treichel and colleagues.2 In addition, since CD25 cannot transduce the interleukin-2 signal,3 basiliximab is unlikely to exhibit biological activity. We believe that differences in ciclosporin monitoring are more likely to account for the difference between our and Strehlau and colleagues’ data. We aim at trough concentrations of 250–350 g/L (Abbott assay) and keep this value for up to 3 months, compared with Strehlau and colleagues, who reach trough concentrations lower than 250 g/L after 4 weeks. In addition, we monitor C2 concentrations (2 h after ingestion) to estimate the drug exposure at a time when interindividual differences are most prominent.4 Peak values of more than 1500 g/L were seen as appropriate. With this protocol, no histological evidence of toxic effects of ciclosporin was seen in 15 biopsy samples taken from 13 patients. As known from adult studies, the probability of being rejection-free does not correlate with trough concentrations but is more predictable with C2 measurement.5 We suspect that accelerated reduction of ciclosporin in the Strehlau and colleagues’ basiliximab group may have led to underimmunosuppression and increased risk of rejection. Therapeutic windows for adequate C2 concentrations in paediatric patients need to be elaborated to ensure effective immunosuppression when the effect of basiliximab fades. *U Vester, B Kranz, U Treichel, P F Hoyer Departments of *Paediatric Nephrology and Gastroenterology and Hepatology, University of Essen, 45122 Essen, Germany (e-mail: [email protected]) 1
2
3 4
Strehlau J, Pape L, Offner G, Nashan B, Ehrich JHH. Interleukin-2 receptor antibody-induced alteration of ciclosporin dose requirements in paediatric transplant recipients. Lancet 2000; 356: 1327–28. Treichel U, Paietta E, Poralla T, Meyer zum Bueschenfelde KH, Stockert RJ. Effects of cytokines on synthesis and function of the hepatic asialoglycoprotein receptor. J Cell Physiol 1994; 158: 527–34. Waldmann TA. The interleukin-2 receptor. J Biol Chem 1991; 266: 2681–84. Johnston A, David OJ, Cooney GF. Pharmacokinetic validation of neoral
THE LANCET • Vol 357 • February 3, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.