Mechlorethamine (nitrogen mustard)

Mechlorethamine is the prototype anticancer chemotherapeutic drug. Successful clinical use of mechlorethamine gave birth to the field of anticancer chemotherapy. It is used mostly in Hodgkins lymphoma and as palliative treatment for malignant effusions of metastatic carcinomas. The dosage is based on ideal dry weight and the drug is rapidly metabolized with minimal urinary excretion, hence no adjustment is needed in kidney failure. There are no data available regarding its use in hemodialysis (HD) or in peritoneal dialysis (PD).

Cyclophosphamide

The oxazaphosphorine alkylating agent, cyclophosphamide, is used across a wide range of tumor types and was introduced to clinical practice in 1958. The drug may be administered either parenterally or orally. Systemic availability after oral administration is greater than 75%. Cyclophosphamide is inactive until it undergoes hepatic transformation to form 4-hydroxycyclophosphamide, which then breaks down to form the ultimate alkylating agent, phosphoramide mustard and other inactive products. The drug is minimally protein bound but some of its metabolites are more than 60% protein bound. The metabolites and up to 25% of the unchanged parent compound are ultimately eliminated by the kidneys. ^, Pharmacokinetics studies of cyclophosphamide in kidney failure have yielded conflicting results. Some authors have not found any alterations in the presence of hepatic or renal insufficiency, ^, leading them to not recommend any adjustment of the dose in the presence of kidney failure, whereas others have reported a significantly decreased clearance of the drug in the presence of severe renal insufficiency. ^, Myelosuppression is usually the dose-limiting toxicity; however, in the setting of bone marrow transplantation, escalation beyond that dosage range is limited by cardiac toxicity. Synergistic hematopoietic toxicity may occur with concomitant use of allopurinol. Both unchanged cyclophosphamide and its metabolites are extensively cleared by HD. For optimal dosing, the use and timing of HD should be considered. There are no data in PD.

Ifosfamide

Ifosfamide, an isomer of cyclophosphamide, is extensively used in the treatment of solid tumors in children and in soft tissue sarcoma. Other indications include refractory germ cell cancer, as a third-line agent, ^, osteosarcoma, bladder cancer, small cell lung cancer, cervical cancer, ovarian cancer, and non-Hodgkin lymphoma. Like cyclophosphamide, it should be coadministered with 2-mercaptoethane sulfonate sodium (MESNA) to prevent hemorrhagic cystitis. It is extensively metabolized, principally in the liver, to active and inactive metabolites and principally excreted in the urine. The terminal half-life is 4 to 8 hours on average in adults. The drug itself is not directly toxic to the kidney, but its metabolite chloracetaldehyde, has been shown to be toxic to renal tubular cells in vitro and in vivo. Both acute and reversible kidney damage along with chronic toxicity may develop. Proximal tubular dysfunction is the commonest presentation, and may lead to a Fanconi syndrome, including hypophosphataemic rickets and proximal renal tubular acidosis (RTA). Other manifestations include distal RTA and nephrogenic diabetes insipidus. Younger age at exposure and cumulative ifosfamide dose are considered the major determinants of nephrotoxicity. ^, Nephrotoxicity is also associated with previous or concurrent cisplatin therapy along with preexisting kidney impairment. ^, Neurotoxicity is another major side effect that is increased in patients with compromised kidney function and is characterized by confusion, auditory and/or visual hallucinations, mutism, and encephalopathy, which may progress to stupor and coma. Despite the lack of pharmacokinetic data, in a small case series, ifosfamide use in HD has been shown to be feasible. Dose could be adjusted based on degree of myelosuppression and neurotoxicity. In vitro studies suggest that HD can decrease ifosfamide concentrations by 87% and chloracetaldehyde by 77% and HD has been used to treat ifosfamide toxicity. There are no data about its use in PD.

Melphalan

Melphalan was synthesized in 1953, and it has been an important therapy for multiple myeloma (MM) for 50 years despite the introduction of many novel agents. It acts both as cytotoxic agent through damage to deoxyribonucleic acid, and as immunostimulatory drug by inhibiting interleukin-6, as well as interacting with dendritic cells, and immunogenic effects in tumor microenvironment. The absorption of melphalan is incomplete and prone to large interindividual variations, leading to a poorly predictable response. It is eliminated renally and the kidney function has an effect on its pharmacokinetics with an increased median half-life (t1/2) and area under the concentration curve (AUC) when creatinine clearance (CrCl) is less than 40 mL/min. Hence a dose reduction of 25% has been recommended for patients with CrCl between 10 and 40 mL/min and a further reduction to 50% if the clearance is less than 10 mL/min. However, high unadjusted melphalan doses followed by stem cell transplantation has been safely used in patients on HD. ^, There are no data regarding its use in PD ( Table 19.1 ).

Chlorambucil

Chlorambucil is mostly used to treat chronic lymphocytic leukemia (CLL) but also Hodgkin and non-Hodgkin lymphoma, breast, ovarian and testicular cancers, Waldenstrom macroglobulinemia, and choriocarcinoma. It is well absorbed orally and is metabolized by a microsomal β-oxidation process to phenylacetic acid mustard, which by itself has antineoplastic activity. Less than 1% of both the unchanged drug and its phenylacetic acid metabolite are excreted unchanged in the urine. Hence dosage reduction is not recommended in renal failure, even if some authors have advocated reducing the dose by 50% if the CrCl is less than 50 mL/min and by 75% if it is less than 10 mL/min. The dose should also be reduced by 50% in PD.

Altretamine (hexamethylmelamine)

Altretamine undergoes rapid hepatic metabolism and less than 1% of the drug is retrieved in the urine 24 hours after administration. ^, Hence no dose reduction is necessary in renal failure. There are no data about its use in HD or PD.

Thiotepa

Thiotepa is rapidly metabolized by cytochrome P450 to triethylene phosphoramide (TEPA), which is the main and active metabolite with similar alkylating properties. Less than 2% of the administered dose of thiotepa is eliminated unchanged in the urine. Elimination of TEPA by the kidneys accounts for approximately 11% of the administered dose. ^, Many experts recommend no dosage adjustment in kidney failure; however, a pharmacokinetics study done in a patient with moderate renal insufficiency showed increased exposure to thiotepa and especially TEPA with subsequent toxicity, leading the authors to recommend reduced dosing in similar cases. There are no data available about its use in HD or PD.

Busulfan

Busulfan is an alkylating agent used primarily in hematologic malignances as a preparative regimen before hematopoietic stem cell transplantation (HSCT). Busulfan is primarily eliminated by conjugation with glutathione, and less than 2% of an oral dose is eliminated unchanged in the urine and dose reduction is usually not necessary in renal failure. Busulfan is effectively removed by HD but according to a report, a standard HD period (i.e., 4 hours) does not significantly affect busulfan apparent clearance. There are no data regarding the use of busulfan in PD.

Carmustine, lomustine, and semustine

Carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU) cross the blood-brain barrier and are mostly used for the treatment of gliomas. Urinary excretion of BCNU, CCNU, and methyl-CCNU is significant with 43%, 50%, and 47% of the drugs, respectively, retrieved in the urine 24 hours following drug administration. ^, Dose adjustment is recommended in kidney failure. For BCNU, it has been recommended to administer 80% of the dose if the CrCl is less than 60 mL/min, 75% if the CrCl is less than 45 mL/min, and to avoid its use for a CrCl of less than 30 mL/min. For CCNU, the dose should be reduced by 25% if the CrCl is less than 60 mL/min and by 50% if the CrCl is less than 45 mL/min. The drug should also be avoided if the CrCl is less than 30 mL/min. No formal recommendations exist for methyl-CCNU, but likely the same dose reductions apply. BCNU is not dialyzable; however, there have been documented cases when BCNU was used with a dose reduction in patients on HD with the doses escalated and reduced depending on white cell count. There is no documentation of its use in PD. Moreover, there is no documentation about the use of either CCNU or methyl-CCNU in HD or PD.

Streptozocin

Streptozocin is active against pancreatic neuroendocrine tumors and pancreatic adenocarcinomas. Only 15% to 20% of streptozocin is excreted in the urine. ^, It has been recommended to reduce the dose by 25% for a CrCl of less than 50 mL/min and by 50% for a CrCl of less than 10 mL/min. However, the drug is known to have a dose-related nephrotoxic effect and to induce Fanconi syndrome. ^, It might be advisable to avoid it in the setting of advanced renal failure or deteriorating renal function. There are no reports of its use in HD or PD.

Dacarbazine

Dacarbazine (DTIC) is a cell cycle nonspecific antineoplastic alkylating agent used in the treatment of metastatic malignant melanoma and Hodgkin lymphoma. Up to 40% of the drug is excreted unchanged in the urine through tubular secretion. It has been recommended to decrease the dose by 25% for a CrCl of less than 60 mL/min, to administer 50% of the dose for a CrCl between 10 and 30 mL/min, and to avoid with CrCl less than 10 mL/min. DTIC is dialyzable and has been safely used in HD.

There is no report of use in PD.

Temozolomide

Temozolomide (TMZ) is used for the treatment of brain tumors and melanoma. The most important factor influencing the clearance of TMZ is body surface area (BSA) with increased BSA associated with increased clearance and clearance by the kidneys playing an insignificant role. TMZ has been safely administered in HD at full dose. There is no reported use in PD.

Methotrexate

Methotrexate (MTX) is a drug widely used in the treatment of malignancies and rheumatologic disorders. Because of almost exclusive renal elimination (> 90%) and a known possible nephrotoxic effect at high doses (> 1 g/m ² ), its use is usually relatively contraindicated in severe kidney failure. Clearance by the kidneys is under the influence of both tubular secretion and reabsorption. ^, Drug–drug interactions may play an important role in MTX excretion. Previous cisplatin use alters its elimination and may increase MTX toxicity, as well as concomitant use of piperacillin-tazobactam.

MTX has a high molecular weight and is highly protein bound, with 50% plasma protein binding at therapeutic plasma concentrations; hence conventional HD with a low flux filter does not result in a substantial removal of the drug. PD alone results in a minimal decrease in plasma MTX concentrations. The use of high-flux HD can decrease plasma MTX concentration significantly (median, 75.7%; range, 42%–94%). ^, However, the major limitation of dialysis-based methods is the marked rebound in plasma MTX concentrations that can occur when the dialysis is stopped. Sequential use of charcoal hemoperfusion and single-pass albumin dialysis with albumin dialysate at 44 g/L, using a continuous renal replacement therapy machine, was recently reported as successful in treating MTX-induced oligoanuric acute kidney injury (AKI) with reversal of the toxicity and recovery of the kidney function.

Pemetrexed

Pemetrexed belongs to a new generation of multitargeted antifolate cytotoxic agents. It was first approved in 2004 by the U.S. Food and Drug Administration in combination with cisplatin for nonresectable pleural mesotheliomas. It is also currently approved for the treatment of locally advanced or metastatic non-small cell lung cancer. Pemetrexed is eliminated almost entirely in the urine by both tubular secretion and glomerular filtration in the original drug form. Accumulation may occur in case of pleural or peritoneal effusion, and cumulative side effects may appear. HD does not seem to be efficient for eliminating pemetrexed and hence cannot be used in case of acute toxicity. Clinical trials with pemetrexed excluded patients with CrCl less than 45 mL/min but subsequent studies showed that standard dose of 500 mg/m ² can be given to patients with CrCl greater than 40 mL/min. Pemetrexed should be avoided in patients with more significant renal dysfunction because of the potential for drug retention leading to severe myelosuppression. There are no reports on pemetrexed use in PD.

5-Fluorouracil

5-Fluorouracil (5-FU) is one of the major components of different folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimens used for the treatment of metastatic colorectal cancer. 5-FU undergoes extensive metabolic degradation to several catabolites, which are excreted mainly by the kidneys. More than 80% of an intravenous (IV) dose is inactivated by dihydropyrimidine dehydrogenase (DPD), mainly in the liver but also in other tissues. Fluorouracil plasma clearance varies greatly among patients, partly because of dose- and time-dependent kinetics and partly as a result of genetic polymorphism of DPD. In general, 5-FU and its initial catabolite dihydrofluorouracil do not accumulate in renal failure, but the final 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) does and it might increase its toxicity. Usually no dose reduction is necessary in patients with kidney failure; however, it has been recommended to reduce the dose by 50% in patients on HD.

In the case of PD, 5-FU penetrates the intraperitoneal cavity, but the contribution of PD to drug clearance is negligible and the overall clearance of the drug is decreased and in this setting 50% dose reduction is appropriate.

Capecitabine

Capecitabine is an orally administered precursor of 5’-deoxy-5-fluorouridine (5’-DFUR), which is preferentially activated to 5-FU in tumors. It is currently used in breast and colorectal cancers. Renal impairment has no effect on the pharmacokinetics of capecitabine or 5-FU, but leads to an increase in the systemic exposure to 5’-DFUR and FBAL with the AUC of 5’-DFUR correlating with safety. Hence because of concern for increased incidence of adverse events (AEs) with renal failure, it is recommended that patients with moderate renal impairment corresponding to a CrCl between 30 and 50 mL/min to be treated with a reduced dose corresponding to 75% of the usual recommended standard starting dose. This should maintain both the tolerability and antitumor activity of capecitabine. It should generally be avoided if the CrCl is less than 30 mL/min. However, with close monitoring of their clinical and laboratory data, and with dose modification based on reported AEs, capecitabine has been safely administered to patients with severe renal impairment, including patients on HD. Capecitabine use has not been reported in PD.

Cytarabine (cytosine arabinoside)

Cytosine arabinoside (ARA-C), a deoxycytidine analog, is an S-phase specific antimetabolite drug that, for more than 40 years, has served as the backbone of acute myeloid leukemia (AML) therapy. It is also used in the treatment of acute lymphoblastic leukemia (ALL) and lymphomas. Once administered, ARA-C has two fates: rapid deamination by deoxycytidine deaminase (DCD) into inactive metabolites or entry into a cell via specific membrane transport protein. As a result of its short half-life and the rapid inactivation by DCD outside of target cells, ARA-C is administered via continuous IV infusion (usually 0.1–0.2 g/m ² /day) or in high-dose infusions given over 1 to 3 hours (usually 2–3 g/m ² every 12 hours for 2–3 days). After IV administration, the drug is rapidly metabolized by deamination mainly in the liver to an inactive product, uracil arabinoside (ARA-U). Approximately 10% to 30% of cytarabine and 80% of its inactive metabolite are eliminated by urinary excretion. ARA-C use is associated with a wide range of adverse reactions, including severe neurologic and gastrointestinal toxicities that are dose dependent. Central nervous system toxicity, which may or may not be reversible, manifests as cerebral or cerebellar dysfunction following high-dose ARA-C therapy with an overall incidence of 5% to 20%. ^, No formal guidelines exist regarding dosage in renal insufficiency; however, in a series of 256 patients treated for AML, the following protocol was applied and was found to decrease the neurotoxicity of the drug: for patients with a serum creatinine (sCr) level of 1.5 to 1.9 mg/dL during treatment, or an increase in sCr during treatment of 0.5 to 1.2 mg/dL, ARA-C was decreased to 1 g/m ² per dose. For patients with sCr 2.0 mg/dL (or higher) or a change in sCr greater than 1.2 mg/dL, the dose was reduced to 0.1 g/m ² /day. Other authors recommend to administer 60% of the dose when the CrCL is less than 60 mL/min, 50% when the CrCl is less than 45 mL/min, and to avoid the use if the CrCl is less than 30 mL/min when doses of 1 to 3 g/m ² are administered. There is no pharmacokinetic rationale or clinical evidence to support dose reduction of standard dose cytarabine (100–200 mg/m ² /24 hours). HD is very effective in clearing ARA-C and its main metabolite ARA-U from the plasma in renal failure, and this maneuver could easily be used routinely to prevent ARA-U accumulation and minimize adverse effects in patients with kidney failure. ^, In patients receiving continuous ambulatory peritoneal dialysis (CAPD), plasma cytarabine concentrations may be considerably higher than those in patients with normal kidney function and in this case, dose reduction has been recommended.

5-Azacitidine

Azacitidine is one of the hypomethylating agents available for the treatment of elderly patients with myelodysplastic syndromes (MDS) or AML. Even though urinary excretion is the main route of elimination of azacitidine and its metabolites, initial dosage modification for kidney dysfunction is not recommended. However, 5-azacytidine should be used with caution when the kidney function is unstable or impaired because of the nephrotoxicity of this agent. If an unexplained increase of blood urea nitrogen or sCr occurs after the drug is given, the start of the next cycle must be held until values return to baseline, and the dosage has to be reduced by 50% for the next treatment course. The adverse nephrotoxic effects include proximal and tubular dysfunction in addition to polyuria with salt wasting. Azacitidine has been used at a standard dose in HD without serious adverse events. There are no reports of its use in PD.

Gemcitabine

Gemcitabine, a nucleoside analog, is used to treat a variety of solid tumors. Gemcitabine pharmacokinetics appears to be linear over a dose range of 87 to 2500 mg/m ² administered as a 30-minute infusion. The majority of gemcitabine is rapidly inactivated in the liver and to a lesser extent in the blood by deamination into 2′,2′-difluoro-deoxyuridine (dFdU), through a reaction catalyzed by cytidine deaminase. In addition, 10% of unchanged gemcitabine can undergo renal filtration, and within 1 week, more than 90% of the injected dose is usually recovered in the urine, either as parent gemcitabine (1%) or dFdU (99%). Pharmacokinetics studies have reported conflicted findings regarding the impact of mild to moderate renal insufficiency on gemcitabine pharmacokinetics and toxicity in patients with advanced cancer. ^, It has been suggested to reduce the dose only if the CrCl is less than 30 mL/min. Studies of gemcitabine use in dialysis have reported normal pharmacokinetics of the drug administered without any dose reduction with, however, significant retention of dFdU, which was effectively removed by dialysis performed 6 to 12 hours after drug administration. There are no reports of its use in PD.

Pentostatin

Pentostatin (2′-deoxycoformycin) is a potent tight-binding inhibitor of adenosine deaminase, a key enzyme in the purine salvage pathway. The terminal elimination half-life is approximately 6 hours following doses ranging from 2 to 30 mg/m ² administered either as single doses or multiple daily doses over 3 to 5 days. The percentage of the intact drug recovered in the urine varies greatly according to studies and ranges between 32% to 48% at 48 hours and 95.9% at 24 hours. ^, Neurotoxicity and kidney toxicity are usually dose-limiting. In a study of 13 patients, pentostatin was used safely with the dose reduction of 25% in patients with a CrCl between 41 and 60 mL/min and 50% in patients with a CrCl between 21 and 40 mL/min. Pentostatin has been administered in HD at a dose ranging between 1 and 3 mg/m ² with no serious adverse events reported with HD, 1 to 2 hours after drug administration, to remove any drug remaining in the system. There is no experience of pentostatin use in PD.

Fludarabine

Fludarabine is a purine analog and is used in a variety of low-grade hematologic malignancies. After IV infusion, the parent drug is rapidly dephosphorylated to an active metabolite (F-ARA-A), which is to a large extent eliminated in the urine (60% within the first 24 h) at a rate dependent on the CrCl. Hence the dose of fludarabine should be adjusted according to the kidney function. In a study where 22 patients with varying levels of kidney function received a single IV dose of fludarabine (25 mg/m ³ ), followed 1 week later by five daily doses that were adjusted according to three predefined CrCl levels, fludarabine dose adjustments provided reasonably equivalent F-ARA-A exposure with acceptable safety. Patients received 80% of the dose if the CrCl was between 30 and 70 mL/min and 60% of the dose if the CrCl was lower than that. Fludarabine is dialyzable and it has been estimated that with HD, the drug clearance is 25% of the clearance in patients with normal kidney function. Fludarabine treatment can be considered in patients requiring dialysis, if dose reduction and adequate removal of the drug by HD is provided. There is one case described of fludarabine use in CAPD where the drug was used at reduced dose (20 mg/m ² twice) and was well tolerated.

Cladribine

Cladribine is a purine nucleoside analog used in hematologic malignancies and multiple sclerosis. Cladribine is a prodrug and needs intracellular phosphorylation to active nucleotides. The renal clearance of cladribine is 51% of total clearance and 21% to 35% of an intravenously administered dose is excreted unchanged in the urine. It has been suggested to administer 75% of the dose for a CrCl of less than 50 mL/min and 50% of the dose for a CrCl of less than 10 mL/min. Limited data exist regarding its use in HD with one pediatric case. Only limited clearance was observed and no specific recommendation could be made regarding dose adjustment. There are no data regarding its use in PD.

Etoposide

The urinary excretion of etoposide varies between 20% and 40% according to studies and CrCl is the strongest predictor of etoposide clearance, followed by albumin concentration, because the drug is strongly bound to protein. Patients with renal impairment are also at an increased risk of hematologic toxicity, therefore dose adjustments are recommended in kidney failure, with some authors advocating dose reduction of 20% to 25% if the CrCl is between 10 and 50 mL/min and by 50% if the CrCl is less than 10 mL/min. ^, However, etoposide has been used in HD at variable doses and has been found to be safe even when administered at full doses. Etoposide is not removed by either HD or PD and the pharmacokinetics are not affected by dialysis timing. ^,

Vinblastine, vincristine, vindesine, and vinorelbine

The vinca alkaloids vinblastine, vincristine, vindesine, and vinorelbine are not excreted significantly in the urine. Vinblastine and its active metabolite desacetylvinblastine, along with vincristine, have kidney clearances that account for less than 12% of their respective dose. Kidney clearance of vindesine is also low and accounts for less than 14% of the dose and 24 hours following administration of vinorelbine, less than 11% of the dose is found in the urine. No dose adjustment is necessary for vinca alkaloids in patients with renal impairment. However, despite a mostly hepatic metabolism, a reduction of 50% of the dose of vinorelbine has been advocated in HD because of increased risk of toxicity. No data are available for the other vinca alkaloids, but the same consideration likely applies. Their use in PD has not been reported.

Paclitaxel

Paclitaxel is used for treatment of a number of solid tumors. It inhibits mitosis and cell proliferation, resulting in the death of rapidly proliferating tumor cells. Paclitaxel is a high molecular weight drug with a very low solubility in water and is highly bound (90%) to plasma proteins. It is metabolized in the liver with minimal renal excretion (< 10%) and no dose adjustment is required in kidney failure. Paclitaxel has been used in HD and several pharmacokinetic studies have shown similar curves for paclitaxel plasma concentrations in patients undergoing HD and those with a normal renal function for a given dosage. Furthermore, because paclitaxel is not dialyzable, it may be used before or after HD sessions. Paclitaxel has also been used in CAPD in combination with carboplatin. In this case plasma pharmacokinetics of paclitaxel were unaltered, with negligible urinary and peritoneal clearance.

Docetaxel

Docetaxel is a semisynthetic analog of paclitaxel. Like paclitaxel, it is primarily cleared via hepatic metabolism with less than 10% excreted in the urine and does not require adjustment in renal failure. Docetaxel can be safely administered in HD at unadjusted doses, with no differences seen in the plasma concentration-time curves of the drug administered before or after dialysis. It has also been used in CAPD with unaltered pharmacokinetic parameters compared with normal kidney function.

Topotecan

Topotecan is a semisynthetic analog of camptothecin that inhibits the nuclear enzyme topoisomerase I. In adults with normal kidney function, approximately 49% of an intravenously administered dose is recovered in the urine as parent drug. Significant correlation exists between CrCl and the plasma clearance of both total topotecan and its main metabolite topotecan lactone. It is recommended to give 75% of the full dose if the CrCl is between 30 and 60 mL/min, 50% if the CrCl is between 10 and 30 mL/min, and to avoid the drug for lower clearances. Neutropenia is the dose limiting toxicity and life-threatening myelosuppression has been described in patients with renal impairment caused by increased systemic exposure. Some authors have recommended to decrease the dose in patients with renal failure not only on the basis of their renal function, but also on the extent of prior myelosuppressive therapy. In their opinion, no dose adjustments should be made for patients who have a CrCl higher than 40 mL/min if they have not received extensive prior chemotherapy. However, for patients with extensive prior chemotherapy or radiotherapy who are at increased risk of myelosuppression, the dose should be reduced by one-third if the CrCl is between 40 and 59 mL/min and by 50% if the CrCl is between 20 and 39 mL/min, with no recommendations made below that level of kidney function. Topotecan has been administered at a dose reduced by 50% in HD with tolerable hematologic toxicity. ^, The plasma clearance was increased fourfold by HD and 60% of the dose was removed, even as some rebound effect was reported. Topotecan was also safely used in PD with the dose reduction of 50% and was found to be removable to a certain extent by this modality as well.

Irinotecan

Irinotecan is a water-soluble camptothecin derivative that also inhibits topoisomerase I. After administration, irinotecan is converted by carboxylesterases to an active metabolite, SN-38. Urinary excretion of irinotecan and SN-38 after IV administration accounts for 15% to 30% of the elimination of the administered dose. It is usually not recommended to adjust the dose of irinotecan in kidney failure. ^, Irinotecan can be administered in HD patients; however, based on the occurrence of severe adverse events in three HD patients, ^, the dose should be reduced because even though irinotecan is partially dialyzable, SN-38 is not. It should be administered after HD sessions or on nondialysis days. There are no reports of use of irinotecan in PD.

Daunorubicin

Daunorubicin (DNR) is produced by strains of streptomyces and acts pharmacologically through interference with cellular nucleic acid metabolism. Urinary excretion of DNR and its main metabolite daunorubicinol accounts for 15% and 23% of the dose, respectively, and dose reduction is usually not needed in kidney failure. However, certain authors recommend administering 50% of the dose if the sCr level is less than 3 mg/dL or twice the upper limit of normal. DNR is not dialyzable and therefore has been used in HD at reduced doses. In one report, 66% of the dose was given as a consolidation treatment in a HD patient with acute promyelocytic leukemia and 50% of the dose in another. There are no available data related to the use of DNR in PD.

Doxorubicin

Less than 3% of an administered dose of doxorubicin appears in the urine as doxorubicinol. ^, Nonetheless, it has been recommended to administer 75% of the dose if the CrCl is less than 10 mL/min. There are two reports on reduced-dose (10% and 50%, respectively) doxorubicin use in lymphoma patients on chronic HD. ^, Indeed in HD patients, the AUC of doxorubicin and its metabolite doxorubicinol were found to be increased 1.5-fold to threefold compared with patients who were not on HD. There is also report of one case of doxorubicin administration in a pediatric patient with Wilms tumor on PD at reduced dose, with no adverse events reported.

Epirubicin and idarubicin

Epirubicin is a second-generation anthracycline from the same family as doxorubicin. Kidney elimination is poor and is around 9%. Dose reduction is usually not recommended except at a very low glomerular filtration rate (GFR). Epirubicin has been safely used in HD; however, there are no data available about its pharmacokinetics in that setting. It has intermediate dialyzability in vitro and should not be administered just before dialysis. There are no data available about its use in PD.

Idarubicin also has poor kidney elimination with a dose reduction advocated only if the sCr level is greater than 2.5 mg/dL. There is one report of its use in HD where two-thirds of the usual dose was administered. There are no data available about its use in PD.

Bleomycin

Bleomycin is a hydrophilic polypeptide antibiotic with a broad range of action. It is largely eliminated by the kidneys with a urinary excretion varying between 45% and 66% of the dose in patients with normal kidney function. In several reports, a correlation was reported between CrCl and the rate of bleomycin clearance from the plasma. Many studies have shown a relationship between renal function decline and increased bleomycin pulmonary toxicity especially in the setting of concomitant use of cisplatin. Some authors have recommended administering 70% if the CrCl is less than 50 mL/min and decrease it further to 50% for CrCL of 30 mL/min or below, whereas others advocate withholding it altogether at this later stage. Moreover, serial measurements of pulmonary function should be performed before each dose administration. To our knowledge, there is no report of its use in end-stage renal disease (ESRD).

Mitomycin C

Mitomycin-C is metabolized by the liver and is rapidly cleared from plasma with less than 20% of the drug excreted in the urine. It has been recommended to give 75% of the full dose if the CrCl is between 30 and 60 mL/min, 50% if the CrCl is between 10 and 30 mL/min and to avoid it if the CrCl is less than 10 mL/min. Furthermore, this drug should be discontinued with the development of signs and symptoms of hemolytic uremic syndrome, as mitomycin has been associated with this syndrome when cumulative dose exceeds 40 mg/m ² . Mitomycin C has been used in HD at a dose of 4.7 mg/m ² and was administered after HD. There are no data regarding its use in PD.

Cisplatin

Cisplatin ( cis -diamminediachloroplatinum) is one of the most widely used drugs to treat various human malignancies and is highly effective for the treatment of testicular tumors and tumors of the head and neck, ovary, lung, cervix, endometrium, and bladder. ^, Cisplatin is rapidly bound to plasma and tissue proteins and only 10% of the drug remains free in the circulation at 2 h. Pharmacokinetic studies showed that cisplatin elimination is biphasic with initial t _1/2 of 48 min for kidney clearance of free platinum and second t _1/2 of 53 to 73 h for total protein bound platinum. Nephrotoxicity is its main dose-limiting adverse effect, with an incidence of around 31%. Hence the dose should be reduced by 50% for a CrCl of less than 60 mL/min, by 75% for a CrCl of less than 45 mL/min and its use is contraindicated if the CrCl is less than 30 mL/min. However, because of its significant potential for nephrotoxicity, most oncologists avoid cisplatin use in patients with CrCl less than 60 mL/min. Several studies have demonstrated good efficacy and tolerance of cisplatin in HD patients. However, it is recommended to reduce the dose to decrease potential dose-related adverse effects, such as anemia and neuropathy. The initial doses of cisplatin in HD patients must be reduced by 50%, at a recommended dose of 25 to 50 mg/m ² every 3 to 6 weeks. Only free cisplatin is dialyzable and because only free platinum exerts antitumor activity, cisplatin should be given following HD sessions or on nondialysis days. Administration of cisplatin in PD has been reported in three patients ^{, ,} with only nominal clearance in dialysate, suggesting that dose reduction is indicated in PD.

Carboplatin

Carboplatin is another platinum complex used to treat a wide range of solid tumors. Carboplatin is mainly cleared (70%) by kidney excretion, with most of the drug excreted unchanged in the urine over the first 24 hours, hence determination of GFR is important for accurate dosing. The carboplatin dose needed to achieve a target AUC has historically been calculated using the Calvert formula: Dose (mg) = target AUC ([mg/mL]·min) × (GFR+25) (mL/min), where the constant of 25 mL/min represents the non-GFR clearance of carboplatin. In the original Calvert et al. study, GFR was measured using the CrEDTA method. However, it is cumbersome and impractical for use in the clinical setting. Several formulas have been used to calculate the GFR in carboplatin administration with various degrees of accuracy. Recently, Janowitz et al. studied 2471 cancer patients who had chromium-51 labeled ethylenediamine tetraacetic acid ( CrEDTA) measured GFR and proposed a novel GFR calculation formula. Seven other GFR or CrCl calculators were compared and BSA adjusted Chronic Kidney Disease Epidemiology (CKD-EPI) formula appeared to correlate best with measured GFR in this patient population. It should be noted that the use of CKD-EPI in Calvert’s formula requires removal of BSA indexing as follows: estimated GFR (eGFR) (mL/min) = eGFR (mL/min/1.73 m ² ) × BSA (m ² )/1.73. Both measured and calculated GFR are prone to errors and may over- or underestimate carboplatin dose, leading to increased toxicity or decreased efficacy ( Fig. 19.1 ).

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