Effect of Renal Dysfunction on Toxicity in Three Decades of Cancer Therapy Evaluation Program–Sponsored Single-Agent Phase I Studies

Purpose Alterations in renal clearance of anticancer drugs can affect the occurrence of toxicities related to drug exposure. The National Cancer Institute and the US Food and Drug Administration (FDA) use different criteria to classify renal dysfunction. We examined those discrepancies and their potential association with the incidence of toxicities in patients enrolled onto Cancer Therapy Evaluation Program–sponsored single-agent phase I studies over three decades (1979 to 2010). Methods Data to estimate creatinine clearance according to the Cockcroft-Gault and Jelliffe formulas were available from 10,236 patients, and data to estimate creatinine clearance according to the six- and four-variable Modification of Diet in Renal Disease formulas were available from a subset (n = 4,084). Patients were classified according to National Cancer Institute and FDA criteria, and the rates of clinically relevant toxicities were evaluated within groups and compared among groups. Results Cockcroft-Gault estimated renal function improved over time, which may be attributed to an increase in weight of patients in the same time frame. Approximately 36% of patients enrolled onto phase I trials had mild renal dysfunction by FDA criteria. Relative to normal function, mild renal dysfunction was associated with a statistically significant but small increase in grade 3 or 4 nonhematologic toxicity and any relevant toxicities. Conclusion Patients with mild renal dysfunction by FDA criteria have routinely been enrolled onto phase I studies of antineoplastics without clinically meaningful increase in the risk of toxicity. In future oncology renal dysfunction trials based on the FDA classification, the FDA mild group may only need to be activated when the moderate and normal groups differ substantially in tolerability or pharmacokinetics.

Predictive Performance of Equations to Estimate Creatinine Clearance in Hospitalized Elderly Patients

OBJECTIVE: To ascertain the clinical accuracy of equations that estimate creatinine clearance to predict the correct drug doses in hospitalized elderly patients DESIGN: Single 24-hour creatinine clearance measurement compared with estimated creatinine clearances derived from eight equations using total and modified ideal body weight SETTING: Nonintensive care medical and surgical units at a county hospital PATIENTS: 15 patients with urethral catheters were enrolled in each of three age groups: 65–75, 76–85, and ≥86 years MAIN OUTCOME MEASUREMENTS: Drug–dose predictions, bias, precision, and absolute errors RESULTS: The bias for all equations was −4.0−42.0 mL/min (–0.07–0.70 mL/s) and the precision was 10.8−47.4 mL/min (0.18–0.88 mL/s). The Jelliffe 1973, Hull et al., and Mawer et al. equations were the least biased and the Jelliffe 1973 was the most precise, followed by the Mawer et al., Hull et al., and Cockcroft-Gault equations. The percent of patients with absolute percent errors >20 percent were 38 percent for Jelliffe 1973, 36 percent for Mawer et al., 40 percent for Hull et al., and >50 percent for the other equations. The percent of patients receiving correct drug doses was 67 percent for Jelliffe 1973, 58 percent for Gates, 51 percent for Mawer et al. and Hull et al., and <50 percent for the other equations. Within various age, renal function, serum creatinine, and albumin subgroups, the Jelliffe 1973 estimates were least biased and most precise, followed by the Cockcroft-Gault estimates. Generally, estimates using modified lean body weight performed better than did those using total body weight. CONCLUSIONS: The Jelliffe 1973 equation with modified lean body weight was the best equation, followed by the Cockcroft-Gault equation. Even with the best equation, 33 percent of the patients would have received an incorrect drug dose. Therefore, some elderly patients may still require a measured creatinine clearance.

Predictability of Serum Digoxin Concentrations in Clinical Practice

A study was conducted to clarify the reliability of serum digoxin concentration (SDC) predictions in the absence of concurrent quinidine administration. The effects of age, sex, congestive heart failure (CHF), and the method used to estimate creatinine clearance were investigated. Data were collected from patients who were representative of those seen in clinical practice. Patients admitted to the study were required to have not received quinidine, to have stable renal function, to have been taking digoxin for ten consecutive days—the same dose and route of administration, and to have been categorized as having or not having CHF at the time of the SDC determination. There were 44 patients who qualified for admission to the study. SDCs were predicted on the basis of four methods for estimating creatinine clearance and four methods for estimating serum concentrations. After simple linear regression analysis, one method was found to have correlation coefficients ranging from 0.72 to 0.79, regardless of the method used to estimate creatinine clearance. In addition, analysis determined that age and presence of CHF were not factors affecting the reliability of predicted SDCs. Female patients had, on the average, a greater difference between measured and predicted SDCs; however, this was not statistically significant. Thus, in the absence of concurrent quinidine administration, SDCs may be estimated as long as the limitations of the method are acknowledged. Age, CHF, and the common methods used to estimate creatinine clearance do not significantly affect the reliability of predicted SDC values.