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Therapeutic Drug Monitoring of 21-Day Oral Etoposide in Patients with Advanced Non-Small Cell Lung Cancer’

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Therapeutic Drug Monitoring of 21-Day Oral Etoposide in Patients with Advanced Non-Small Cell Lung Cancer’ Vol. 4, 1705-1710, July /998 Clinical Cancer Research 1705 Therapeutic Drug Monitoring of 21-Day Oral Etoposide in Patients with Advanced Non-Small Cell Lung Cancer’ Antonius A. Miller,2 Elizabeth A. Tolley, and but poor in patients whose dosages were increased. The Harvey B. Niell actual observed ANC was compared with the predicted ANC based on the pharmacodynamic model. The predic- Department of Veteran Affairs Medical Center [A. A. M., H. B. N.] and University of Tennessee [A. A. M., E. A. I., H. B. N.], Memphis, tion was considered accurate if the predicted and actual Tennessee 38163 ANC values were within 500/pt of each other. Using this margin, the ANC was accurately predicted in 10 of 22 patients. Etoposide concentrations >0.3 pig/ml on this ABSTRACT schedule were significantly correlated with combined grades The purpose of this study was to prospectively test a 3 and 4 neutropenia (P < 0.0001). In conclusion, the phar- pharmacodynamic model for therapeutic drug monitoring macodynamic model is statistically sound when applied to a of 21-day oral etoposide. In our previous studies, etoposide population of patients. However, when applied to individual trough concentrations on this schedule were related to the patients for therapeutic drug monitoring, the model lacks hematological toxicity, expressed as WBC and neutrophil precision and accuracy. counts at the nadir. The following pharmacodynamic model estimated the absolute neutrophil count at the nadir (ANC) based on the etoposide concentration (Er) and the pretreat- INTRODUCTION ment count (ANC): Measurements of drugs like aminoglycosides, digoxin, phenytoin, or theophylline for making decisions during treat- ANC = 0.32(1 + ANC x e 2.47 X Ec) ment are accepted practice in internal medicine. Useful strate- Patients were treated with 40 mg/m2/day etoposide p.o. x 21 gies exist for these drugs such that concentrations can be deter- days and 100 mg/m2 cisplatin i.v. on day 1. All patients had mined at steady-state (i.e., theophylline) or at specified times non-small cell lung cancer stage 11111 or IV, had a perfor- (i.e., peak and trough for arninoglycosides) and doses adjusted, mance status of 0-2, and had a median age of 66 (range, depending on how far off the measured concentration is from 42-80). Etoposide was measured in the plasma on day 8 by the target (1). In cancer therapy, however, therapeutic drug high-performance liquid chromatography, and dosage ad- monitoring has not found a standard role except for methotrex- justments were made for the remainder of the course. We ate measurements to guide leucovorin rescue after high-dose targeted for grade 3 neutropenia (ANC, 500 to 999/pI) and therapy (2). Clinical oncologists are well aware of the narrow attempted to avoid grade 4 neutropenia (ANC0, <500/pA). therapeutic index of antineoplastic drugs and make dose adjust- of 25 patients entered, 22 were evaluable for therapeutic ments after toxicity is encountered. The problem of making drug monitoring in the first course. Three patients devel- correct dosing decisions is at least in part attributed to our oped grade 3 neutropenia, and seven patients developed incomplete clinical assessment of the pharmacokinetic variabil- grade 4 neutropenia. Etoposide concentrations were signif- ity between patients, which in turn determines the pharmacody- icantly correlated with ANC in the first course (r -0.50, name variability (3). Pharmacodynamics is defined as the rela- P < 0.02). For those patients whose dosages were not tionship between drug concentrations and therapeutic or toxic changed, the estimated correlation between predicted and responses. The problem of interpatient variability and the in- ability to predict the severity of toxicity cannot be overcome actual ANC was 0.77 (P < 0.01). No evidence of significant bias of the pharmacodynamic model was detected. The eto- unless the relationships between pharmacological measurements poside dosages were increased in 12 patients and were not and clinical effects are explored. The toxicity of anticancer changed in the remaining patients. The precision of the chemotherapy is mainly due to growth inhibition of rapidly model was good in patients whose dosages were not changed dividing normal tissues exemplified by bone marrow suppres- sion. Troublesome consequences of myelosuppression are neu- tropemic fever and sepsis. These adverse consequences of chem- otherapy are not immediately apparent, and the time interval and degree of toxicity are poorly predictable. Received 1/16/98; revised 4/3/98; accepted 4/10/98. Lung cancer is the leading cause of death from cancer in The costs of publication of this article were defrayed in part by the the United States (4). The majority of patients have non-small payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to cell lung cancer. Patients with advanced non-small cell lung indicate this fact. cancer commonly receive chemotherapy for palliation of their Supported by a Merit Review Grant from the Office of Research and disease. Our previous Phase II study demonstrated that a 2 1 -day Development, Medical Research Service, Department of Veteran Af- schedule of oral etoposide in combination with iv. cisplatin was fairs. active in patients with advanced non-small cell lung cancer (5, 2 To whom requests for reprints should be addressed, at University of Tennessee, 3 North Dunlap, Memphis, IN 38163. Phone: (901) 448- 6). Etoposide was administered at a dosage of 50 mg/rn2 for 21 5157; Fax: (901) 448-5033; E-mail: [email protected]. days, and 100 mg/rn2 cisplatin were given on day 1 of a 28-day Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 1998 American Association for Cancer Research. 1706 Therapeutic Drug Monitoring of Etoposide cycle. Etoposide plasma concentrations were measured weekly PATIENTS AND METHODS just before the daily dose (trough levels). The etoposide con- Patients had biopsy-proven non-small cell lung cancer centrations on this schedule were related to the hematological stage IIIB or IV, measurable or evaluable disease, and a per- toxicity, expressed as WBC and neutrophil counts at the nadir formance status of 0-2 (Eastern Cooperative Oncology Group). (5). The following pharmacodynamic model was developed to Staging procedures were the same as in our previous studies estimate the absolute neutrophil count at the nadir (ANC) based (5-7). Prior chemotherapy and bone marrow or brain metastases on the etoposide concentration (Er) and the pretreatment count were reasons for exclusion. Required laboratory values for entry (ANC): on study were: ANC l500/i.l; hemoglobin 10 g/dl, platelets l00,000/iil; serum creatinine 1.5 mg/dl; and bilirubin 1 .5 X normal. Patients had to be able to swallow capsules so ANC = 0.32(1 + ANC X e247 X EC) they could comply with the oral etoposide regimen. Patients with another malignancy and other serious medical or psychi- Subsequently, this model was tested prospectively and per- atric disease were excluded. All patients gave written informed formed reliably (7). consent. A similar regimen consisting of 21-day oral etoposide (50 The treatment consisted of 40 rng/m2/day etoposide p.o. X mg/m2/day) with cisplatin given at a dosage of 33 mg/rn2 i.v. on 21 days and ]00 mg/rn2 cisplatin iv. on day 1. Treatment cycles days 1, 2, and 3 was used by the CALGB3 for extensive stage were repeated every 28 days. Up to three cycles of therapy were small-cell lung cancer (8). Multiple linear regression analysis of given with therapeutic drug monitoring. After that, patients were this CALGB trial led to the following pharrnacodynamic model off protocol but could receive a maximum of six cycles. Therapy (9): was given in the outpatient clinic. Bristol-Myers Oncology (Princeton, NJ) provided 10-mg capsules of etoposide, which log10(ANC) = - 0.153 - 0.017 X age - 0.363 were similar in formulation to the marketed 50-mg capsules x E + 0.530 x log10 (alkaline phosphatase) (VePesid). The trial was conducted under Investigational New Drug 43,71 1 from the Food and Drug Administration (Rock- ville, MD). The commercially available formulation of cisplatin However, this latter pharmacodynamic equation was not avail- was used. able at the beginning of the trial that is described here. It is All patients had laboratory studies performed before study important to note that the above equations were derived from entry and before each treatment cycle: complete blood cell count groups of patients (population pharmacology), and that their with differential; electrolytes (including calcium and magnesi- performance when applied to individual patients (therapeutic urn); liver and renal function chemistries; lactate dehydrogem- drug monitoring) remained unknown. ase; total protein; and albumin. While on treatment, patients In previous studies of 50 mg/m2/day X 21 days, we ob- returned weekly to clinic for monitoring of compliance with oral served grades 3 and 4 neutropenia in 73- 83% of all patients etoposide, complete blood cell counts, and etoposide plasma (5-9). Therefore, the starting dose was reduced from 50 to 40 concentrations. For therapeutic drug monitoring, weekly etopo- mg/m2/day X 21 days for this trial. Etoposide is marketed in the side samples were obtained just before the daily dose (trough United States only as a 50-mg capsule. This capsule size was used in the previous studies (5-9). For therapeutic drug moni- concentrations). The etoposide concentration on day 8 of cycle toting, the 50-mg capsules were not useful because dose adjust- 1 was used to predict the neutrophil count at the nadir based on ments were not feasible. For the sake of prospective therapeutic the following equation: ANC, 0.32 (1 + ANC X e247 X Ec) dose adjustments, 10-mg capsules were obtained from Bristol- Based on this prediction, the dose of etoposide was adjusted for Myers Oncology.
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