Originally published as JCO Early Release 10.1200/JCO.2005.03.8299 on January 3 2006

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Cytotoxic Anticancer Agents and Renal Impairment Study: The Challenge Remains

Food and Drug Administration, Silver Spring, MD

Although clinical trials for drug approval are conducted in patients with normal renal function, cancer patients in clinical practice may have compromised renal function because of the underlying disease or for other causes such as aging, diabetes, infectious and autoimmune diseases, or drug-related toxicities. In general, oncology drugs are approved and marketed with limited or no information on the pharmacokinetics and/or pharmacodynamics of the drugs in patients with organ dysfunction.^1-4 Based on the data submitted in the new drug application for drug approval, the US Food and Drug Administration may require pharmacokinetic and safety studies in organ dysfunction patients post-approval for safe use of the drug. This practice is suboptimal, and definitely does not benefit the organ dysfunction patients who may have no available therapy at the launch of the drug. The US Food and Drug Administration reviews the results of the studies, and any other necessary information subsequently submitted for inclusion in the drug label. Absence of information in the drug label poses a significant challenge to the treating physicians on how to select appropriate drug doses for patients. In the era of oral and targeted therapy and in the adjuvant and prevention setting, when patients may be on daily continuous therapy, drug accumulation because of organ dysfunction can be severe and result in acute and long-term undesirable effects. The scenario is further complicated by the use of some agents that cause renal toxicity, such as cisplatin, zolandronic acid, and antibiotics.^5-7

In this issue of the Journal of Clinical Oncology, Mita et al⁸ report a study designed to define the dose of pemetrexed in advanced cancer patients with renal dysfunction. The study was a phase I, dose escalation, safety, and pharmacokinetic study to determine adequate pemetrexed starting dose in patients with compromised renal function. The study had four cohorts based on glomerular filtration rate (GFR) as a measure of renal function in the patients. GFR was measured by serum technetium-99m diethylenetriamine penta-acetic acid (^99mTc-DTPA) clearance. The GFR groupings were one through four with a GFR of 60 mL/min, 40 to 59 mL/min, 20 to 39 mL/min, and less than 20 mL/min, respectively; group 1 was subdivided, A and B, with GFRs 80 mL/min and 60 to 79 mL/min, respectively, and group 3 was subdivided, A and B, with GFRs of 30 to 39 mL/min and 20 to 29 mL/min, respectively. The patients were treated with a 10-minute infusion of 150 to 600 mg/m² pemetrexed dose once every 3 weeks. Dose escalations were performed within each GFR group and were independent from the other GFR groups.

The objective of the study was to assess the maximum-tolerated dose and recommend a starting dose for each GFR group. However, a change in the management of patients receiving pemetrexed occurred. In December 1999, patients were instructed to take folic acid and vitamin B₁₂ before starting the study and then as prescribed (folic acid daily and vitamin B₁₂ once every 9 weeks) while on study. This change was to reduce the more severe drug-related toxicities of the drug.

The study conducted by Mita el al⁸ illustrates the challenges encountered in the conduct of renal impairment study with a cytotoxic agent, pemetrexed, with a narrow therapeutic window. The study accrued 47 patients in over two years. Drug-associated death of the only patient treated with the starting dose of 150 mg/m² in group 4 (< 20 mL/min) resulted in closure of accrual to this subgroup. Although left open, there was no accrual of group 3A patients with GFR between 20 and 39 mL/min. Therefore, adequate dosing recommendation for patients with GFR less than 40 mL/min was not determined in this study. It seems that the study GFR groups were initially opened to all patients. Although this may be safe in the more normal GFR groups (ie, GFR 80 mL/min, GFR 60 to 79 mL/min, and possibly GFR 40 to 59 mL/min) this proved to be problematic for the one patient entered with a GFR less than 20 mL/min. A more prudent approach would have been to sequentially accrue patients to the more normal GFR groups first, determining safety and pharmacokinetics, followed by accrual to the GFR 30 to 39 mL/min group. The data obtained may have determined whether it was in the best interests of lower GFR patients to proceed further.

The toxicity assessment is also questionable since all patients did not receive folic acid and vitamin B₁₂ supplement in this study. In general, the dose-limiting toxicities of pemetrexed were myelosuppression (ie, neutropenia and thrombocytopenia). Patients also had fatigue and stomatitis as dose limiting adverse effects. In clinical studies,⁹ folic acid and vitamin B₁₂ reduce the level of cystathionine or homocysteine and helped to minimize lowering of ANC nadir associated with pemetrexed treatment. Neutropenia was the major dose- limiting toxicity in this study. As a result, the recommended treatment dose for renal impaired patients in this study appears to be without a sound rationale. Since no patients with GFR between 20 and 39 mL/min were treated with pemetrexed in this study and the number of patients between 40 and 45 mL/min was likely to be small, pemetrexed should be administered only to patients whose creatinine clearance is greater than 45 mL/min. This is in accordance with the approved label of pemetrexed.⁹

The goals of the study were not completely achieved, particularly in the patients who were supplemented with folic acid and Vitamin B₁₂. For example, the following statement from the article, "Because fewer than six total patients were treated at the highest dose level in this group, 500 mg/m² was the recommended pemetrexed dose for the patients with GFR of 60 to 79 mL/min" suggested that protocol defined dose escalation was not followed in the study. As stated above, the study accrued 47 patients (34 nonsupplemented and 13 supplemented with vitamin B₁₂ and folic acid). Most of the patients were accrued in GFR groups 1 and 2. No patients were accrued in group 3, and one patient who was treated with 150 mg/m² pemetrexed dose in group 4 died from drug-related toxicities. The limited data demonstrated that with impaired renal function pemetrexed: (1) AUC increased; (2) plasma clearance decreased; (3) renal clearance decreased; and (4) plasma elimination half-life increased. Pemetrexed plasma clearance correlated with GFR and systemic exposure increased with decreased renal function. Complete escalation of pemetrexed was not performed in the GFR groups studied, particularly in the folic acid and B₁₂-supplemented patients. This was important because the drug was labeled to be given with vitamin supplementation. In GFR group 1A, only one vitamin-supplemented patient had dose-limiting toxicity at 500 mg/m²; and there was no vitamin-supplemented patients treated at 600 mg/m² who had dose-limiting toxicity. In GFR group 1B, only one of five vitamin-supplemented patients had dose-limiting toxicity at 600 mg/m²; and it was not reported that a sixth patient was accrued or whether there was additional dose escalation in GFR group 1B. Because fewer than six patients were accrued to this cohort, the authors recommended 500 mg/m² for GFR group 1B, which was the same recommendation for nonsupplemented patients. No vitamin-supplemented patients were accrued to GFR group 2, and a dose of 500 mg/m² was the recommendation for this GFR group. In general, these dose recommendations were problematic because there was no accounting for the potential negative effect on efficacy by the addition of folic acid and vitamin B₁₂ without an increase in the pemetrexed dose.¹³ In the entire study only two vitamin-supplemented patients had dose-limiting toxicities, suggesting that further dose escalation may be possible in the higher GFR groups.

According to the current label, the recommended pemetrexed dose is 500 mg/m² administered either as a single agent or in combination with cisplatin.^9-13 The recommended dose of pemetrexed is labeled with folic acid plus vitamin B₁₂ supplementation.⁹ It is unknown whether there is any increased benefit of a higher dose of pemetrexed in either lung cancer or mesothelioma. Moreover, for mesothelioma patients, pemetrexed is used with a nephrotoxic agent, cisplatin, and the effect of both agents administered together in subsequent cycles and in renal impaired patients at this time is not known.

In general, a number of oncology drugs are dosed based on the renal function of a patient. Caution is recommended, and renal function testing before and during drug treatment is suggested in the label of a number of cancer drugs. Specific dosing recommendation is also included in drug labels.^14-17 Renal elimination is the major route for carboplatin excretion from the body. Dosing of carboplatin is usually based on the renal status of a patient. Hematologic toxicities are associated with the renal function and the total carboplatin dose is calculated based on target exposure and GFR.^18,19 In cancer treatment, hematologic or nonhematologic toxicities of a number of drugs in renal impaired patients is well documented. Moreover, some anticancer agents are nephrotoxic. Urinary alkalinization and various types of hydration regimens are recommended for a number of nephrotoxic agents.^20-23 Methotrexate, a drug in the same class as pemetrexed, with extensive renal clearance, is generally limited to patients with creatinine clearance greater than 60 mL/min.²² Oral sodium bicarbonate and adequate hydration is recommended during methotrexate treatment. Dose-related and cumulative renal toxicity is the major cisplatin dose-limiting toxicity.²⁰ Pretreatment hydration is required and cisplatin is diluted in 2 L of 5% dextrose and infused over 6 to 8 hours.

In oncology, when the therapeutic window of a drug is narrow and the pharmacokinetic and pharmacodynamic relationship is not well established, the treating physician, lacking data, may choose to alter the starting dose of a patient with compromised organ function. This may compromise the small benefit that the drug may offer to the patient. Subsequently, the patient may receive a dose, with observation for toxicity, as the treating physician performs an individual dose-escalation or dose-de-escalation study.

There is uncertainty about the appropriate drug exposure-response relationship and the acceptance of blood drug level or overall drug exposure as a surrogate for drug activity at the target site. Therefore, a phase I dose escalation study with toxicity or pharmacodynamic end points rather than drug pharmacokinetics alone may be preferred for cytotoxic agents. However, an appropriate dose escalation study in renal impaired patients is difficult to perform, mostly because of lack of understanding of the starting dose in the impaired cohort and the number of patients required for reliable assessment of maximum-tolerated dose or dose-limiting toxicity in this patient population. Drug levels may be a more sensitive measure for effectiveness and toxicity rather than traditional toxicity end points (myelosuppression or nonhematologic toxicities). The toxicity end point measurements usually have more variability than the variability in drug exposure, requiring a large number of patients for reliable toxicity estimate. Traditional drug development programs include assessment of the effectiveness of the phase I selected dose in a phase II or phase II/III study in normal organ function patients. The effectiveness of the phase I selected dose for each impaired group (mild, moderate, and severe renal impaired) is not tested or established in a phase II study.

In oncology drug labels, the statement, "insufficient data available in renal and hepatic impaired patients, caution should be exercised when treating patients with compromised organ function" presents a challenge for providing personalized medicine for cancer patients. Inadequate information in the drug label or in the scientific literature about the starting dose for organ dysfunction patients provide a greater concern to the treating physician, managing the risk-benefit of cytotoxic agents in cancer patients with serious comorbidities. The study by Mita et al⁸ demonstrates the issues in designing and executing renal impairment study with cytotoxic agent. The study also demonstrates that the toxicity end points may not be reliable because of individual patient’s sensitivity to the drug and variability in the measured toxicity end points.

Where do we go from here? Should we conduct a study with pharmacokinetic assessment as the primary end point and recommend a starting dose based on drug exposure equivalent to exposure in normal organ function patients? Is that a rational approach? If we consider blood drug level as a surrogate for pharmacologic effect at the target site, the dose that provides, in organ dysfunction patients, an equivalent exposure compared to normal organ function patients should be the starting dose. This corroborates the reliance on exposure measurements in pivotal trials as the drug exposure that provides for maximum benefit of the drug and balances for effectiveness and toxicity. The perfect scenario will be a significant relationship between the organ function and drug clearance; and toxicity and/or effectiveness and drug clearance. In the absence of that type of relationship, the drug exposure or the drug clearance should be a reliable estimate for dose adjustment in organ dysfunction patients treated with cytotoxic agents.

In assessing an appropriate starting dose in organ dysfunction patients, a formal dose escalation phase I study, with a complete pharmacokinetic profile as the primary end point and toxicity as the secondary end point may be conducted. The pharmacokinetics of the major pharmacologic agents (ie, either the parent drug or the active metabolite[s]) should be assessed in the study. Patient accrual and dose selection in each cohort should proceed after an appropriate dose is defined in the less impaired patient cohort. Modeling and simulation may be conducted to predict a safe starting dose for severe organ dysfunction patients. Both preclinical and clinical data of the drug and knowledge from a similar class of drug should be utilized in the design and conduct of a formal renal impairment study. The primary goal of the recommended study is to determine if the pharmacokinetics are altered to such an extent that the dosage should be adjusted from that established in phase III efficacy and safety trials. Alternatively, based on the human disposition pathways of the drug, a population pharmacokinetic study with sparse blood sampling can be designed to assess the safety and effectiveness of the drug in phase III trial. The trial is expected to enroll patients with mild and moderate renal impairment. Also, a concentration-controlled study may be designed to determine the starting dose of a cytotoxic agent in renal impaired patients.

Cancer patients in the real world frequently have compromised organ function. Based on the principle of drug accumulation in the body because of less effective drug elimination pathways, chemotherapeutic agents are likely to cause severe toxicity in organ dysfunction patients. The challenge is to treat the patient with organ dysfunction with a safe starting dose that provides drug exposure equivalent to the exposure in the normal organ function patients. This level of exposure is expected to offer an optimum benefit with minimum risk to a patient. Any dose adjustment subsequent to the first dose will follow the dosing algorithms based on drug toxicity. Organ dysfunction studies are essential to establish a safe starting dose in this patient population. Absence of such information does not help the treating physician and subjects a patient to unnecessary harm with minimal benefit. We need to do better.

Note: The views expressed in this article are those of the authors and do not necessarily reflect the official views of the United States Food and Drug Administration.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Author Contributions

Conception and design: Atiqur Rahman Collection and assembly of data: Atiqur Rahman Data analysis and interpretation: Atiqur Rahman, Robert M. White Manuscript writing: Atiqur Rahman, Robert M. White

 

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