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Oral Oncolytics Oral Chemotherapeutic Agents... Continued from cover agents in patients with renal tic effects by binding to the side is cell-cycle-phase–specific, activity dysfunction are limited. N7 position of guanine to cre- is best achieved when administered in ate intra- and interstrand divided doses over multiple days rather Renal dysfunction repreDNA cross-linkages.8 Cyclo - than in large single doses.13 Oral bioavailsents one of the most imporphosphamide has been used ability of etoposide capsules appears to be tant contributors to drug to treat a wide variety of linear and ranges from 25% to 75%, with accumulation, which may oncologic diseases, such as mean bioavailability of 50%.14 Etoposide manifest as mild to severe Hodgkin and non-Hodgkin and its metabolites are primarily elimiadverse effects. Dose reduclymphomas, acute and chronic nated via renal clearance, which actions are often necessary to Melinda Tran, PharmD leukemias, as well as breast, counts for 44% to 60% of plasma clearprevent the accumulation of renally metabolized and/or eliminated ovarian, and testicular cancers.3 In addi- ance (67% as unchanged drug).15 Multiple studies have correlated dedrugs to prevent toxicities, such as pro- tion, cyclophosphamide possesses potent longed myelosuppression, mucositis, immunosuppressive activity and may be creased renal function with decreased peripheral neuropathies, or central used to treat various nonneoplastic etoposide systemic clearance, which sugneurotoxicities.1,2 Treatment goals autoimmune disorders where disease- gests that doses should be reduced in eldshould be considered carefully, because modifying antiinflammatory drugs have erly patients and/or patients with imthey may influence the clinical deci- been ineffective, such as refractory paired renal function.16-19 Pflüger and colleagues evaluated the sion of proceeding with a more aggres- nephritic syndrome in children. pharmacokinetic parameters sive dose or pursuing a reduced dose for Oral cyclophosphamide is well of etoposide in 35 patients, palliative purposes. absorbed, usually nearing comwhich demonstrated that The following review presents the plete absorption.8,9 As a prodrug, cyclophosrenal impairment resulted in available data to help guide the manincreased terminal eliminaagement of oral chemotherapeutic phamide requires hepatic actition half-life and area under agents in patients with renal dysfunc- vation via CYP2B6, CYP2C9, the curve (AUC) as well as tion. Based on the information provid- and CYP3A4 to generate a 4decreased volume of distribued, dose adjustment recommendations hydroxycyclophosphamide intion at steady state and sysin renally compromised patients have termediate that exists in equiEmily Mackler, librium with aldophosphamide. temic clearance of etopobeen summarized in the Table. PharmD, BCOP The spontaneous cleavage of side.16 Kintzel and Dorr Capecitabine aldophosphamide generates the cytotox- recommend a 15% dose reduction for 5-Fluorouracil (5-FU) is a pyrimidine ic component phosphoramide mustard CrCl 46 mL/min to 60 mL/min, 20% for analog with antitumor activity against a and the urotoxic metabolite, acrolein.8 CrCl 31 mL/min to 45 mL/min, and 25% wide variety of solid tumors, such as col- Although cyclophosphamide and its for CrCl ≤30 mL/min.20 Interestingly, orectal, esophageal, gastric, bladder, and metabolites are eliminated in the urine etoposide also is cleared via nonrenal breast.3 Capecitabine, an oral prodrug of (5%-25% as unchanged drug), no processes, such as metabolism and bil5-FU, exhibits nearly 100% bioavailabil- consistent evidence indicate dose mod- iary excretion; thus, there is a potential ity and is activated preferentially in ifications in renally compromised for compensatory elimination in tumor cells. After absorption through patients.8,10,11 Aronoff and colleagues rec- patients with impaired hepatic and/or the gastrointestinal tract, capecitabine ommend a 25% dose reduction in renal function.14,18 undergoes hepatic metabolism to gen- patients with a glomerular filtration rate Hydroxyurea erate 5′-deoxy-5-fluorocytidine and <10 mL/min.12 Hydroxyurea produces antineoplastic 5′-deoxy-5-fluorouridine (5′-DFUR). effects by interfering with ribonuUltimately, 5′-DFUR is converted to cleotide reductase to cause “immediate 5-FU by the enzyme thymidine phospho- Renal clearance of inhibition of DNA synthesis.”21 In rylase, which is found in both normal and hydroxyurea is doing so, significant tumor response to tumor tissues. Thymidine phosphorylase approximately 75% of the hydroxyurea has been demonstrated in concentrations, however, are 3 to 10 melanoma; refractory chronic myelogetimes higher in solid tumors than in nor- glomerular filtration rate, nous leukemia; recurrent, metastatic, or mal tissues, which theoretically allows for which suggests that inoperable ovarian cancer; and squapreferential activation and fewer systemic hydroxyurea should be mous cell head and neck cancer.3 In toxicities, such as diarrhea, hand–foot reduced when used in 4 addition, hydroxyurea concentrates in syndrome, and neutropenia. Capecitabine and its metabolites are patients with renal erythrocytes and leukocytes and is used eliminated in the urine, with mean uri- impairment. widely for adjunctive management of nary recovery between 71% and 87%.5 sickle cell disease, rapid reduction of Renal impairment, therefore, may lead white blood cell count in patients with to an increase in the systemic exposure Etoposide elevated blast counts or leukostasis, and to certain metabolites; dosing at 75% of Since its introduction in 1971, etoposide supportive care induction therapy in the standard dose is recommended in has been used to treat a variety of cancers, acute myeloid leukemia patients aged 60 patients with moderate renal impair- such as lung, testicular, breast, bone years or older with poor performance ment (baseline creatinine clearance (Ewing sarcoma, osteosarcoma), ovarian, status or significant comorbidities.3,21 Hydroxyurea was found to be 79% [CrCl] 30-50 mL/min).6 In addition, esophageal, and gastric, as well as capecitabine is contraindicated in leukemias and lymphomas.3 Although bioavailable in cancer patients followpatients with severe renal impairment etoposide is a semisynthetic podophyllo- ing oral administration and eliminated toxin derivative, it exerts its antineoplas- via renal and nonrenal mechanisms (CrCl <30 mL/min).7 tic effects as a topoisomerase II inhibitor as unchanged drug, urea, and other Cyclophosphamide by forming a ternary complex with DNA metabolites.21-23 Renal clearance of Cyclophosphamide, a nitrogen mustard and topoisomerase II to prevent the reli- hydroxyurea is approximately 75% of alkylating agent, exerts its antineoplas- gation of DNA strands.13 Because etopo- the glomerular filtration rate, which
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suggests that hydroxyurea should be reduced when used in patients with renal impairment. In their summary, Kintzel and Dorr provided dose reduction recommendations for hydroxyurea: 15% for CrCl 46 mL/min to 60 mL/min, 20% for CrCl 31 mL/min to 45 mL/min, and 25% for CrCl ≤30 mL/min.20 Aronoff and colleagues recommended an 80% dose reduction for CrCl <10 mL/min.12 In general, the use of hydroxyurea requires close supervision and doses should be titrated based on the patient’s response and white blood cell count. Imatinib Imatinib and related tyrosine kinase inhibitors (TKIs) target the BCR-ABL oncogene, a constitutively activated protein kinase that resulted from the fusion of the Abelson proto-oncogene on chromosome 9 with the breakpoint cluster region on chromosome 22.24 In addition, imatinib inhibits tyrosine kinase receptors for c-KIT, which is often associated with gastrointestinal stromal tumors (GISTs), as well as platelet-derived growth factor, which is often associated with hypereosinophilic syndrome.3,24-26 All TKIs are predominantly metabolized by CYP3A4, with minor assistance from other pathways and eliminated in the feces.25 Although renal elimination plays a minor role in the elimination of imatinib, renal impairment can have a noticeable effect on imatinib pharmacokinetics, increasing the mean AUC by 1.5- to 2-fold compared with pa tients with normal renal function.27,28 The manufacturer recommends maximum doses of 600 mg and 400 mg in patients with CrCl 40 mL/min to 59 mL/min and CrCl 20 mL/min to 39 mL/min, respectively.28 In a phase 1 study conducted in 60 adult patients with varying renal function, imatinib exposure was significantly greater and serious adverse events were significantly more common in the mild-to-severe renal dysfunction groups than in the normal group. Despite having increased imatinib exposure, daily imatinib doses up to 800 mg were generally well tolerated in the mild-to-moderate group.27 Lenalidomide Lenalidomide is an immunomodulatory analog of thalidomide with antiangiogenic and antineoplastic properties.13 It is indicated for the treatment of patients with transfusion-dependent myelodysplastic syndrome (MDS) with or without deletion 5q cytogenetic abnormality and in combination with dexamethasone for multiple myeloma.29 Lenalidomide is absorbed rapidly from the gastrointestinal tract and approxi-
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