- Email: [email protected]
Dosing of Cancer Patients with Low or Absent Renal Function
S EMINAR
Thérapie 2007 Mars-Avril; 62 (2): 117–120 DOI: 10.2515/therapie:2007022 c 2007 Société Française de Pharmacologie et de Thérapeutique
Dosing of Cancer Patients with Low or Absent Renal Function Dosage médicamenteux chez les patients cancéreux avec une fonction rénale faible ou nulle Alan Boddy, Melanie Griffin, Sarah Knowles, Mojca Persic, Ian Scott, Julie Errington and Gareth Veal Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne And Derby Hospitals NHS trust, Derby Keywords: renal function; carboplatin; etoposide Mots clés : fonction rénale ; carboplatine ; étoposide
Patients with low or absent renal function present a number of problems in cancer chemotherapy.[1] For drugs where renal clearance is only a small proportion of total clearance from the body, there may not be a need to decrease doses of chemotherapeutic agents. However, renal clearance is significant for many agents. The importance of renal impairment is often identified initially as an increase in toxicity for those patients with less than normal renal function. Thus toxicity to melphalan[2] has previously been associated with decreased renal function, and recommendations for a reduction in dose in those patients have been made.[3] However, subsequent pharmacological studies have not always found an association between plasma clearance of the drug and renal function.[4, 5] Similarly, although approximately half of the clearance of etoposide is attributable to renal elimination,[6, 7] dose adjustment recommendations in renal impairment for this drug have varied.[8, 9] Dose adjustments for methotrexate dosing in renal impairment have also varied[10, 11] and have to take into account the potential nephrotoxicity of this drug. Cisplatin, a drug that is only 20% eliminated via the kidney, may require dose adjustment in renally-impaired patients due to the toxicity of metabolites or by products of the drug reacting with proteins.[12, 13] The problem of renal elimination of toxic metabolites is an issue for a number of other drugs, including ifosfamide.[14] The best example of a drug that is eliminated by renal excretion, and for which dosing should always be based on renal function, is carboplatin.[15] In the original observations by Calvert et al.[16] and by Egorin et al.[17] a clear linear relationship between the clearance of carboplatin and glomerular filtration rate was identified. The pharmacological effects, both toxic and therapeutic, of carboplatin are dependent on the area under the plasma
concentration-time curve (AUC).[18] It is important to remember that for carboplatin, the relevant measurement is the concentration of free carboplatin (as elemental platinum) in plasma ultrafiltrate. Given the dependence of effect on AUC, it is possible to calculate the dose required to achieve a target AUC, simply by multiplying that value (in mg/ml.min) by the sum of glomerular filtration rate [GFR] and a small correction for non-renal clearance.[16] Thus, for a patient with a GFR of 120 ml/min, a dose of 580 mg is required to achieve a target AUC of 4 mg/ml.min. It should be remembered that these equations were based mostly on patients with normal renal function and, in the case of the Calvert equation, that the measure of GFR is based on EDTA clearance. Other measures of GFR, particularly those such as the Cockcroft and Gault equation for estimating creatinine clearance as a measure of GFR, are less reliable.[19] Extrapolating the Calvert equation to a patient with low (less than 40 ml/min) or absent renal function is simple mathematically. At the extreme of the patient with bilateral nephrectomy, the clearance of carboplatin is dependent on the non-renal component of the Calvert equation i.e. 25 ml/min. Thus, to achieve the same target AUC or 4 mg/ml.min, a dose of only 100 mg would be necessary. To provide some reassurance to clinicians, we have monitored the carboplatin ultrafiltrate concentrations in a number of patients. In every case, the achieved AUC has been within 20% of the target, and we have repeated this analysis in some cases over several courses of treatment. An example of the pharmacokinetics of carboplatin in an anephric patient is given in Figure 1. In paediatric patients, the dosing of carboplatin is slightly more complex. We have shown that the estimation of renal function is more difficult in children.[20] Nevertheless, a useful formula
Article published by EDP Sciences and available at http://www.journal-therapie.org or http://dx.doi.org/10.2515/therapie:2007022
118
Boddy et al.
AUC : area under the curve 14 Course 1 Course 2 Course 3
12
10
8
6
4
2
0 0
60
120
180
240
Time (min) Fig. 1. Pharmacokinetics of carboplatin administered to an anephric patient at a dose of 150 mg to a target AUC of 6 mg/ml.min. AUCs achieved were 6.1, 4.3 and 3.9 mg/ml.min.
for the dosing of carboplatin in paediatrics has been developed and validated in a randomised cross-over study.[21] This model, sometimes referred to as the Newell formula, uses the half-life of EDTA and an estimate of total body water based on body weight to estimate GFR.[22] Also, the non-renal component of carboplatin clearance varies proportional to body weight. Thus, in a paediatric patient with no renal function, the dose of carboplatin required to achieve a target AUC is a function of body weight. Again, in a number of patients, we have verified the predictive value of this model to achieve a target carboplatin AUC.[23] As well as being useful in patients receiving carboplatin doses to a normal AUC value, we have also shown that this approach, backed by appropriate monitoring of carboplatin in plasma ultrafiltrate, can be applied in high-dose protocols.[24] In such studies, the margin for error is very narrow as high doses of carboplatin are known to cause multiple organ toxicities.[25] In anephric patients, another important consideration is the potential influence of dialysis on plasma concentrations of drug. The potential for haemodialysis or peritoneal dialysis to decrease plasma concentrations of drug depends on the physicc 2007 Société Française de Pharmacologie et de Thérapeutique
ochemical and protein binding characteristics of the individual agent. Thus, haemodialysis is able to eliminate carboplatin from plasma, providing a clearance not dissimilar to that provided by renal elimination, but limited to the duration of the period of haemodialysis.[1, 26–29] Thus, when attempting to achieve a target AUC of carboplatin in an anephric patient on haemodialysis, it is important to delay haemodialysis to later than 12 hours after the dose of carboplatin. Otherwise, the AUC obtained will be less than the target. Peritoneal dialysis on the other hand has no effect on plasma concentrations of carboplatin.[26] This is somewhat surprising as studies of intraperitoneal chemotherapy with carboplatin indicate a rapid absorption and almost complete bioavailability in plasma.[30] As mentioned above, etoposide is eliminated at least partially by renal elimination.[7, 31] Therefore, dose reductions of up to 50% have been recommended in patients with low or absent renal function.[9, 32] In contrast to the situation with carboplatin, the application of haemodialysis in anephric patients treated with etoposide has little or no effect on plasma clearance.[26, 29] This is presumably due to the high level of protein binding of etoposide Thérapie 2007 Mars-Avril; 62 (2)
Dosing of cancer patients
in plasma (greater than 98%)[9, 32] and the ability of haemodialysis to remove only unbound drug. Not surprisingly, peritoneal dialysis has little or no effect on plasma concentrations of etoposide.[26] A number of other drugs have been studied in terms of pharmacokinetics in renally-impaired patients undergoing haemodialysis. Renal elimination of cyclophosphamide is less than 20% of total clearance in patients with normal renal function, but urinary excretion of metabolites may be important in relation to toxicity.[33] Haemodialysis can be used to increase the clearance of parent drug and metabolites,[34, 35] but the therapeutic significance of this is unclear. Likewise, haemodialysis of the toxic metabolites of ifosfamide has been shown to be beneficial.[36] Of the antimetabolites, where renal elimination often plays a large role in elimination, haemodialysis is effective at eliminating methotrexate[37] and the toxic metabolites of gemcitabine,[38] but has no effect on the clearance of pemetrexed.[39] Conversely, paclitaxel is not eliminated by haemodialysis, but normal doses of this drug can be used in anephric patients as renal elimination is relatively minor.[40] Renal impairment or nephrectomy is relatively common in patients with cancer. These patients still require effective and safe treatment. Use of normal doses of chemotherapy, or carefully modulated doses combined with haemodialysis allows the safe and effective treatment of such patients. Decisions of which drug to use, at what dose and how to combine with dialysis need to be based on available data or a knowledge of the physicochemical properties and pharmacology of the relevant drugs.[1]
References 1. Tomita M, Aoki Y and K. Tanaka K. Effect of haemodialysis on the pharmacokinetics of antineoplastic drugs. Clinical Pharmacokinetics 2004; 43(8): 515-27 2. Cornwell GG, Pajak TF, McIntyre OR, et al. Influence of renal failure on myelosuppressive effects of melphalan: Cancer and Leukemia Group B experience. Cancer Treatment Reports 1982; 66(3): 475-81 3. Tosi P, Zamagni E, Ronconi S, et al. Safety of autologous hematopoietic stem cell transplantation in patients with multiple myeloma and chronic renal failure. Leukemia 2000; 14(7): 1310-3 4. Nath CE, Shaw PJ, Montgomery K, and Earl JW. Melphalan pharmacokinetics in children with malignant disease: influence of body weight, renal function, carboplatin therapy and total body irradiation. British Journal of Clinical Pharmacology 2005; 59(3): 314-24 5. Tricot G, Alberts DS, Johnson C, et al. Safety of autotransplants with highdose melphalan in renal failure: A pharmacokinetic and toxicity study. Clinical Cancer Research 1996; 2(6): 947-52 6. Pfluger KH, Hahn M, Holz JB, et al. Pharmacokinetics of Etoposide - Correlation of Pharmacokinetic Parameters with Clinical Conditions. Cancer Chemotherapy and Pharmacology 1993; 31(5): 350-6 7. Dincalci M, Rossi C, Zucchetti M, et al. Pharmacokinetics of Etoposide in Patients with Abnormal Renal and Hepatic-Function. Cancer Research, 1986. 46(5): 2566-71 8. Lowis SP, Price L, Pearson ADJ, et al. A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children. British Journal of Cancer 1998; 77(12): 2318-23
c 2007 Société Française de Pharmacologie et de Thérapeutique
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9. Joel SP, Shah R, Clark PI and Slevin ML. Predicting etoposide toxicity: Relationship to organ function and protein binding. Journal of Clinical Oncology 1996; 14(1): 257-67 10. Murry DJ, Synold TW, Pui CH and Rodman JH. Renal-Function and Methotrexate Clearance in Children with Newly-Diagnosed Leukemia. Pharmacotherapy 1995; 15(2): 144-9 11. Donelli MG, Zucchetti M, Robatto A, et al. Pharmacokinetics of Hd-Mtx in Infants, Children, and Adolescents with Non-B Acute LymphoblasticLeukemia. Medical and Pediatric Oncology 1995; 24(3): 154-9 12. Erdlenbruch B, Nier M, Kern W, et al. Pharmacokinetics of cisplatin and relation to nephrotoxicity in paediatric patients. European Journal of Clinical Pharmacology 2001; 57(5): 393-402 13. Fox JG, Kerr DJ, Soukop M, et al. Successful Use of Cisplatin to Treat Metastatic Seminoma During Cisplatin-Induced Acute-Renal-Failure. Cancer 1991; 68(8): 1720-3 14. Boddy AV, Yule SM, Wyllie R, et al. Pharmacokinetics and Metabolism of Ifosfamide Administered as a Continuous-Infusion in Children. Cancer Research 1993; 53(16): 3758-64 15. Boddy AV and Calvert AH. Individualized dosing of anticancer drugs., in Principles of Antineoplastic Drug Development and Pharmacology, R.L. Schilsky, G.A. Milano, and M.J. Ratain, Editors. 1996, Marcel Dekker: New York. 435-56 16. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. Journal of Clinical Oncology 1989; 7(11): 1748-56 17. Egorin M, Van Echo D, Olman E, et al. Prospective validation of a pharmacokinetically based dosing scheme for the cis-diamminedichloroplatinum(II) analogue diamminecyclobutanedicarboxylatoplatinum. Cancer Research 1985; 45: 6502-6 18. Jodrell DI, Egorin MJ, Canetta RM, et al. Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. Journal of Clinical Oncology, 1992; 10(4): 520-8 19. Wright JG, Boddy AV, Highley M, et al. Estimation of glomerular filtration rate in cancer patients. British Journal of Cancer 2001; 84(4): 452-9 20. Cole M, Price L, Parry A et al. Estimation of glomerular filtration rate in paediatric cancer patients using (CR)-C-51-EDTA population pharmacokinetics. British Journal of Cancer 2004; 90(1): 60-4 21. Thomas HD, Boddy AV, English MW, et al. Prospective validation of renal function-based carboplatin dosing in children with cancer: a United Kingdom Children’s Cancer Study Group trial. Journal of Clinical Oncology 2000; 18: 3614-21 22. Newell DR, Pearson ADJ, Balmanno K, et al. Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. Journal of Clinical Oncology 1993; 11(12): 2314-23 23. Veal GJ, English MW, Grundy RG, et al. Pharmacokinetically guided dosing of carboplatin in paediatric cancer patients with bilateral nephrectomy. Cancer Chemotherapy and Pharmacology 2004; 54(4): 295-300 24. Veal GJ, BoddyAV, Thomas HD, et al. Real-time monitoring of carboplatin pharmacokinetics in paediatric patients receiving high dose chemotherapy. British Journal of Cancer 1999; 80: 93 [letter] 25. Grigg A, Szer J, Skov K, and Barnett M. Multi-organ dysfunction associated with high-dose carboplatin therapy prior to autologous transplantation. Bone Marrow Transplantation 1996; 17(1): 67-74 26. English MW, Lowis SP, Peng B, et al. Pharmacokinetically guided dosing of carboplatin and etoposide during peritoneal dialysis and haemodialysis. British Journal of Cancer 1996; 73(6): 776-80 27. Chatelut E, Rostaing L, Gualano V, et al. Pharmacokinetics of Carboplatin in a Patient Suffering from Advanced Ovarian-Carcinoma with HemodialysisDependent Renal Insufficiency. Nephron 1994; 66(2): 157-61 28. Hall KS, Nordal KP, Brekke IB and Fossa SD. Pharmacokinetics of Carboplatin in a Patient with Both Testicular Cancer and HemodialysisRequiring Kidney Failure. International Journal of Oncology 1994; 4(2): 359-62
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29. Suzuki S, Koide M, Sakamoto S and Matsuo T. Pharmacokinetics of carboplatin and etoposide in a haemodialysis patient with Merkel-cell carcinoma. Nephrology Dialysis Transplantation 1997; 12(1): 137-40 30. Miyagi Y, Fujiwara K, Kigawa J, et al. Intraperitoneal carboplatin infusion may be a pharmacologically more reasonable route than intravenous administration as a systemic chemotherapy. A comparative pharmacokinetic analysis of platinum using a new mathematical model after intraperitoneal vs. intravenous infusion of carboplatin - A Sankai Gynecology Study Group (SGSG) study. Gynecologic Oncology 2005; 99(3): 591-6 31. Lowis SP, Pearson ADJ, Newell DR and Cole M. Etoposide Pharmacokinetics in Children - the Development and Prospective Validation of a Dosing Equation. Cancer Research 1993; 53(20): 4881-9 32. Stewart CF. Use of Etoposide in Patients with Organ Dysfunction Pharmacokinetic and Pharmacodynamic Considerations. Cancer Chemotherapy and Pharmacology 1994; 34: S76-S83 33. McCune JS, Adams D, Homans AC, et al. Cyclophosphamide disposition in an anephric child. Pediatric Blood & Cancer 2006; 46(1): 99-104 34. Haubitz M, Bohnenstengel F, Brunkhorst R et al. Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney International 2002; 61(4): 1495-1501 35. Perry JJ, Fleming RA, Rocco MV, et al. Administration and pharmacokinetics of high-dose cyclophosphamide with hemodialysis support for allogeneic bone marrow transplantation in acute leukemia and end-stage renal disease. Bone Marrow Transplantation 1999; 23(8): 839-42
c 2007 Société Française de Pharmacologie et de Thérapeutique
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36. Carlson L, Goren MP, Bush DA, et al. Toxicity, pharmacokinetics, and in vitro hemodialysis clearance of ifosfamide and metabolites in an anephric pediatric patient with Wilms’ tumor. Cancer Chemotherapy and Pharmacology 1998; 41(2): 140-6 37. Wall SM, Johansen MJ, Molony DA, et al. Effective clearance of methotrexate using high-flux hemodialysis membranes. American Journal of Kidney Diseases 1996; 28(6): 846-54 38. Kiani A, Kohne CH, Franz T, et al. Pharmacokinetics of gemcitabine in a patient with end-stage renal disease: effective clearance of its main metabolite by standard hemodialysis treatment. Cancer Chemotherapy and Pharmacology 2003; 51(3): 266-70 39. Brandes JC, Grossman SA and Ahmad H. Alteration of pemetrexed excretion in the presence of acute renal failure and effusions: Presentation of a case and review of the literature. Cancer Investigation 2006; 24(3): 283-7 40. Woo MH, Gregornik D, Shearer PD, et al. Pharmacokinetics of paclitaxel in an anephric patient. Cancer Chemotherapy and Pharmacology 1999; 43(1): 92-6
Correspondence and offprints: Alan Boddy, University of Newcastle upon Tyne, Northern Institute for Cancer Research, Paul O’Gorman Building Medical School, Framington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom. E-mail: [email protected]
Thérapie 2007 Mars-Avril; 62 (2)
Thérapie 2007 Mars-Avril; 62 (2): 117–120 DOI: 10.2515/therapie:2007022 c 2007 Société Française de Pharmacologie et de Thérapeutique
Dosing of Cancer Patients with Low or Absent Renal Function Dosage médicamenteux chez les patients cancéreux avec une fonction rénale faible ou nulle Alan Boddy, Melanie Griffin, Sarah Knowles, Mojca Persic, Ian Scott, Julie Errington and Gareth Veal Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne And Derby Hospitals NHS trust, Derby Keywords: renal function; carboplatin; etoposide Mots clés : fonction rénale ; carboplatine ; étoposide
Patients with low or absent renal function present a number of problems in cancer chemotherapy.[1] For drugs where renal clearance is only a small proportion of total clearance from the body, there may not be a need to decrease doses of chemotherapeutic agents. However, renal clearance is significant for many agents. The importance of renal impairment is often identified initially as an increase in toxicity for those patients with less than normal renal function. Thus toxicity to melphalan[2] has previously been associated with decreased renal function, and recommendations for a reduction in dose in those patients have been made.[3] However, subsequent pharmacological studies have not always found an association between plasma clearance of the drug and renal function.[4, 5] Similarly, although approximately half of the clearance of etoposide is attributable to renal elimination,[6, 7] dose adjustment recommendations in renal impairment for this drug have varied.[8, 9] Dose adjustments for methotrexate dosing in renal impairment have also varied[10, 11] and have to take into account the potential nephrotoxicity of this drug. Cisplatin, a drug that is only 20% eliminated via the kidney, may require dose adjustment in renally-impaired patients due to the toxicity of metabolites or by products of the drug reacting with proteins.[12, 13] The problem of renal elimination of toxic metabolites is an issue for a number of other drugs, including ifosfamide.[14] The best example of a drug that is eliminated by renal excretion, and for which dosing should always be based on renal function, is carboplatin.[15] In the original observations by Calvert et al.[16] and by Egorin et al.[17] a clear linear relationship between the clearance of carboplatin and glomerular filtration rate was identified. The pharmacological effects, both toxic and therapeutic, of carboplatin are dependent on the area under the plasma
concentration-time curve (AUC).[18] It is important to remember that for carboplatin, the relevant measurement is the concentration of free carboplatin (as elemental platinum) in plasma ultrafiltrate. Given the dependence of effect on AUC, it is possible to calculate the dose required to achieve a target AUC, simply by multiplying that value (in mg/ml.min) by the sum of glomerular filtration rate [GFR] and a small correction for non-renal clearance.[16] Thus, for a patient with a GFR of 120 ml/min, a dose of 580 mg is required to achieve a target AUC of 4 mg/ml.min. It should be remembered that these equations were based mostly on patients with normal renal function and, in the case of the Calvert equation, that the measure of GFR is based on EDTA clearance. Other measures of GFR, particularly those such as the Cockcroft and Gault equation for estimating creatinine clearance as a measure of GFR, are less reliable.[19] Extrapolating the Calvert equation to a patient with low (less than 40 ml/min) or absent renal function is simple mathematically. At the extreme of the patient with bilateral nephrectomy, the clearance of carboplatin is dependent on the non-renal component of the Calvert equation i.e. 25 ml/min. Thus, to achieve the same target AUC or 4 mg/ml.min, a dose of only 100 mg would be necessary. To provide some reassurance to clinicians, we have monitored the carboplatin ultrafiltrate concentrations in a number of patients. In every case, the achieved AUC has been within 20% of the target, and we have repeated this analysis in some cases over several courses of treatment. An example of the pharmacokinetics of carboplatin in an anephric patient is given in Figure 1. In paediatric patients, the dosing of carboplatin is slightly more complex. We have shown that the estimation of renal function is more difficult in children.[20] Nevertheless, a useful formula
Article published by EDP Sciences and available at http://www.journal-therapie.org or http://dx.doi.org/10.2515/therapie:2007022
118
Boddy et al.
AUC : area under the curve 14 Course 1 Course 2 Course 3
12
10
8
6
4
2
0 0
60
120
180
240
Time (min) Fig. 1. Pharmacokinetics of carboplatin administered to an anephric patient at a dose of 150 mg to a target AUC of 6 mg/ml.min. AUCs achieved were 6.1, 4.3 and 3.9 mg/ml.min.
for the dosing of carboplatin in paediatrics has been developed and validated in a randomised cross-over study.[21] This model, sometimes referred to as the Newell formula, uses the half-life of EDTA and an estimate of total body water based on body weight to estimate GFR.[22] Also, the non-renal component of carboplatin clearance varies proportional to body weight. Thus, in a paediatric patient with no renal function, the dose of carboplatin required to achieve a target AUC is a function of body weight. Again, in a number of patients, we have verified the predictive value of this model to achieve a target carboplatin AUC.[23] As well as being useful in patients receiving carboplatin doses to a normal AUC value, we have also shown that this approach, backed by appropriate monitoring of carboplatin in plasma ultrafiltrate, can be applied in high-dose protocols.[24] In such studies, the margin for error is very narrow as high doses of carboplatin are known to cause multiple organ toxicities.[25] In anephric patients, another important consideration is the potential influence of dialysis on plasma concentrations of drug. The potential for haemodialysis or peritoneal dialysis to decrease plasma concentrations of drug depends on the physicc 2007 Société Française de Pharmacologie et de Thérapeutique
ochemical and protein binding characteristics of the individual agent. Thus, haemodialysis is able to eliminate carboplatin from plasma, providing a clearance not dissimilar to that provided by renal elimination, but limited to the duration of the period of haemodialysis.[1, 26–29] Thus, when attempting to achieve a target AUC of carboplatin in an anephric patient on haemodialysis, it is important to delay haemodialysis to later than 12 hours after the dose of carboplatin. Otherwise, the AUC obtained will be less than the target. Peritoneal dialysis on the other hand has no effect on plasma concentrations of carboplatin.[26] This is somewhat surprising as studies of intraperitoneal chemotherapy with carboplatin indicate a rapid absorption and almost complete bioavailability in plasma.[30] As mentioned above, etoposide is eliminated at least partially by renal elimination.[7, 31] Therefore, dose reductions of up to 50% have been recommended in patients with low or absent renal function.[9, 32] In contrast to the situation with carboplatin, the application of haemodialysis in anephric patients treated with etoposide has little or no effect on plasma clearance.[26, 29] This is presumably due to the high level of protein binding of etoposide Thérapie 2007 Mars-Avril; 62 (2)
Dosing of cancer patients
in plasma (greater than 98%)[9, 32] and the ability of haemodialysis to remove only unbound drug. Not surprisingly, peritoneal dialysis has little or no effect on plasma concentrations of etoposide.[26] A number of other drugs have been studied in terms of pharmacokinetics in renally-impaired patients undergoing haemodialysis. Renal elimination of cyclophosphamide is less than 20% of total clearance in patients with normal renal function, but urinary excretion of metabolites may be important in relation to toxicity.[33] Haemodialysis can be used to increase the clearance of parent drug and metabolites,[34, 35] but the therapeutic significance of this is unclear. Likewise, haemodialysis of the toxic metabolites of ifosfamide has been shown to be beneficial.[36] Of the antimetabolites, where renal elimination often plays a large role in elimination, haemodialysis is effective at eliminating methotrexate[37] and the toxic metabolites of gemcitabine,[38] but has no effect on the clearance of pemetrexed.[39] Conversely, paclitaxel is not eliminated by haemodialysis, but normal doses of this drug can be used in anephric patients as renal elimination is relatively minor.[40] Renal impairment or nephrectomy is relatively common in patients with cancer. These patients still require effective and safe treatment. Use of normal doses of chemotherapy, or carefully modulated doses combined with haemodialysis allows the safe and effective treatment of such patients. Decisions of which drug to use, at what dose and how to combine with dialysis need to be based on available data or a knowledge of the physicochemical properties and pharmacology of the relevant drugs.[1]
References 1. Tomita M, Aoki Y and K. Tanaka K. Effect of haemodialysis on the pharmacokinetics of antineoplastic drugs. Clinical Pharmacokinetics 2004; 43(8): 515-27 2. Cornwell GG, Pajak TF, McIntyre OR, et al. Influence of renal failure on myelosuppressive effects of melphalan: Cancer and Leukemia Group B experience. Cancer Treatment Reports 1982; 66(3): 475-81 3. Tosi P, Zamagni E, Ronconi S, et al. Safety of autologous hematopoietic stem cell transplantation in patients with multiple myeloma and chronic renal failure. Leukemia 2000; 14(7): 1310-3 4. Nath CE, Shaw PJ, Montgomery K, and Earl JW. Melphalan pharmacokinetics in children with malignant disease: influence of body weight, renal function, carboplatin therapy and total body irradiation. British Journal of Clinical Pharmacology 2005; 59(3): 314-24 5. Tricot G, Alberts DS, Johnson C, et al. Safety of autotransplants with highdose melphalan in renal failure: A pharmacokinetic and toxicity study. Clinical Cancer Research 1996; 2(6): 947-52 6. Pfluger KH, Hahn M, Holz JB, et al. Pharmacokinetics of Etoposide - Correlation of Pharmacokinetic Parameters with Clinical Conditions. Cancer Chemotherapy and Pharmacology 1993; 31(5): 350-6 7. Dincalci M, Rossi C, Zucchetti M, et al. Pharmacokinetics of Etoposide in Patients with Abnormal Renal and Hepatic-Function. Cancer Research, 1986. 46(5): 2566-71 8. Lowis SP, Price L, Pearson ADJ, et al. A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children. British Journal of Cancer 1998; 77(12): 2318-23
c 2007 Société Française de Pharmacologie et de Thérapeutique
119
9. Joel SP, Shah R, Clark PI and Slevin ML. Predicting etoposide toxicity: Relationship to organ function and protein binding. Journal of Clinical Oncology 1996; 14(1): 257-67 10. Murry DJ, Synold TW, Pui CH and Rodman JH. Renal-Function and Methotrexate Clearance in Children with Newly-Diagnosed Leukemia. Pharmacotherapy 1995; 15(2): 144-9 11. Donelli MG, Zucchetti M, Robatto A, et al. Pharmacokinetics of Hd-Mtx in Infants, Children, and Adolescents with Non-B Acute LymphoblasticLeukemia. Medical and Pediatric Oncology 1995; 24(3): 154-9 12. Erdlenbruch B, Nier M, Kern W, et al. Pharmacokinetics of cisplatin and relation to nephrotoxicity in paediatric patients. European Journal of Clinical Pharmacology 2001; 57(5): 393-402 13. Fox JG, Kerr DJ, Soukop M, et al. Successful Use of Cisplatin to Treat Metastatic Seminoma During Cisplatin-Induced Acute-Renal-Failure. Cancer 1991; 68(8): 1720-3 14. Boddy AV, Yule SM, Wyllie R, et al. Pharmacokinetics and Metabolism of Ifosfamide Administered as a Continuous-Infusion in Children. Cancer Research 1993; 53(16): 3758-64 15. Boddy AV and Calvert AH. Individualized dosing of anticancer drugs., in Principles of Antineoplastic Drug Development and Pharmacology, R.L. Schilsky, G.A. Milano, and M.J. Ratain, Editors. 1996, Marcel Dekker: New York. 435-56 16. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. Journal of Clinical Oncology 1989; 7(11): 1748-56 17. Egorin M, Van Echo D, Olman E, et al. Prospective validation of a pharmacokinetically based dosing scheme for the cis-diamminedichloroplatinum(II) analogue diamminecyclobutanedicarboxylatoplatinum. Cancer Research 1985; 45: 6502-6 18. Jodrell DI, Egorin MJ, Canetta RM, et al. Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. Journal of Clinical Oncology, 1992; 10(4): 520-8 19. Wright JG, Boddy AV, Highley M, et al. Estimation of glomerular filtration rate in cancer patients. British Journal of Cancer 2001; 84(4): 452-9 20. Cole M, Price L, Parry A et al. Estimation of glomerular filtration rate in paediatric cancer patients using (CR)-C-51-EDTA population pharmacokinetics. British Journal of Cancer 2004; 90(1): 60-4 21. Thomas HD, Boddy AV, English MW, et al. Prospective validation of renal function-based carboplatin dosing in children with cancer: a United Kingdom Children’s Cancer Study Group trial. Journal of Clinical Oncology 2000; 18: 3614-21 22. Newell DR, Pearson ADJ, Balmanno K, et al. Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. Journal of Clinical Oncology 1993; 11(12): 2314-23 23. Veal GJ, English MW, Grundy RG, et al. Pharmacokinetically guided dosing of carboplatin in paediatric cancer patients with bilateral nephrectomy. Cancer Chemotherapy and Pharmacology 2004; 54(4): 295-300 24. Veal GJ, BoddyAV, Thomas HD, et al. Real-time monitoring of carboplatin pharmacokinetics in paediatric patients receiving high dose chemotherapy. British Journal of Cancer 1999; 80: 93 [letter] 25. Grigg A, Szer J, Skov K, and Barnett M. Multi-organ dysfunction associated with high-dose carboplatin therapy prior to autologous transplantation. Bone Marrow Transplantation 1996; 17(1): 67-74 26. English MW, Lowis SP, Peng B, et al. Pharmacokinetically guided dosing of carboplatin and etoposide during peritoneal dialysis and haemodialysis. British Journal of Cancer 1996; 73(6): 776-80 27. Chatelut E, Rostaing L, Gualano V, et al. Pharmacokinetics of Carboplatin in a Patient Suffering from Advanced Ovarian-Carcinoma with HemodialysisDependent Renal Insufficiency. Nephron 1994; 66(2): 157-61 28. Hall KS, Nordal KP, Brekke IB and Fossa SD. Pharmacokinetics of Carboplatin in a Patient with Both Testicular Cancer and HemodialysisRequiring Kidney Failure. International Journal of Oncology 1994; 4(2): 359-62
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29. Suzuki S, Koide M, Sakamoto S and Matsuo T. Pharmacokinetics of carboplatin and etoposide in a haemodialysis patient with Merkel-cell carcinoma. Nephrology Dialysis Transplantation 1997; 12(1): 137-40 30. Miyagi Y, Fujiwara K, Kigawa J, et al. Intraperitoneal carboplatin infusion may be a pharmacologically more reasonable route than intravenous administration as a systemic chemotherapy. A comparative pharmacokinetic analysis of platinum using a new mathematical model after intraperitoneal vs. intravenous infusion of carboplatin - A Sankai Gynecology Study Group (SGSG) study. Gynecologic Oncology 2005; 99(3): 591-6 31. Lowis SP, Pearson ADJ, Newell DR and Cole M. Etoposide Pharmacokinetics in Children - the Development and Prospective Validation of a Dosing Equation. Cancer Research 1993; 53(20): 4881-9 32. Stewart CF. Use of Etoposide in Patients with Organ Dysfunction Pharmacokinetic and Pharmacodynamic Considerations. Cancer Chemotherapy and Pharmacology 1994; 34: S76-S83 33. McCune JS, Adams D, Homans AC, et al. Cyclophosphamide disposition in an anephric child. Pediatric Blood & Cancer 2006; 46(1): 99-104 34. Haubitz M, Bohnenstengel F, Brunkhorst R et al. Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney International 2002; 61(4): 1495-1501 35. Perry JJ, Fleming RA, Rocco MV, et al. Administration and pharmacokinetics of high-dose cyclophosphamide with hemodialysis support for allogeneic bone marrow transplantation in acute leukemia and end-stage renal disease. Bone Marrow Transplantation 1999; 23(8): 839-42
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Boddy et al.
36. Carlson L, Goren MP, Bush DA, et al. Toxicity, pharmacokinetics, and in vitro hemodialysis clearance of ifosfamide and metabolites in an anephric pediatric patient with Wilms’ tumor. Cancer Chemotherapy and Pharmacology 1998; 41(2): 140-6 37. Wall SM, Johansen MJ, Molony DA, et al. Effective clearance of methotrexate using high-flux hemodialysis membranes. American Journal of Kidney Diseases 1996; 28(6): 846-54 38. Kiani A, Kohne CH, Franz T, et al. Pharmacokinetics of gemcitabine in a patient with end-stage renal disease: effective clearance of its main metabolite by standard hemodialysis treatment. Cancer Chemotherapy and Pharmacology 2003; 51(3): 266-70 39. Brandes JC, Grossman SA and Ahmad H. Alteration of pemetrexed excretion in the presence of acute renal failure and effusions: Presentation of a case and review of the literature. Cancer Investigation 2006; 24(3): 283-7 40. Woo MH, Gregornik D, Shearer PD, et al. Pharmacokinetics of paclitaxel in an anephric patient. Cancer Chemotherapy and Pharmacology 1999; 43(1): 92-6
Correspondence and offprints: Alan Boddy, University of Newcastle upon Tyne, Northern Institute for Cancer Research, Paul O’Gorman Building Medical School, Framington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom. E-mail: [email protected]
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