Phase I Trial and Pharmacokinetics of Gemcitabine in Children With Advanced Solid Tumors

2004 ◽  
Vol 22 (12) ◽  
pp. 2445-2451 ◽  
Author(s):  
Joel M. Reid ◽  
Wenchun Qu ◽  
Stephanie L. Safgren ◽  
Matthew M. Ames ◽  
Mark D. Krailo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase I Trial ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Time Data ◽  
Serious Adverse Events ◽  
Concentration Time ◽  
Major Toxicity ◽  
Life Values ◽  
Dose Limiting Toxicity

Purpose To determine the maximum tolerated dose, toxicity, and pharmacokinetics of gemcitabine in children with refractory solid tumors. Patients and Methods Gemcitabine was given as a 30-minute infusion for 2 or 3 consecutive weeks every 4 weeks, to 42 patients aged 1 to 21 years. Doses of 1,000, 1,200 and 1,500 mg/m2 were administered for 3 weeks. Subsequently, gemcitabine was given for only 2 consecutive weeks at 1,500, 1,800, and 2,100 mg/m2. Plasma concentrations of gemcitabine and its metabolite, 2′2′-difluorodeoxyuridine, were measured in 28 patients. Results Forty patients who received 132 courses of gemcitabine were assessable for toxicity. The maximum tolerated dose of gemcitabine given weekly for 3 weeks was 1,200 mg/m2. Dose-limiting toxicity was not seen in one-third of children treated at any doses given for 2 weeks. The major toxicity was myelosuppression in three of five patients at 1,500 mg/m2 for 3 weeks, and one of seven patients at 1,800 mg/m2 for 2 weeks. Other serious adverse events were somnolence, fever and hypotension, and rash in three patients. Gemcitabine plasma concentration–time data were fit to a one- (n = 5) or two-compartment (n = 23) open model. Mean gemcitabine clearance and half-life values were 2,140 mL/min/m2 and 13.7 minutes, respectively. One patient with pancreatic cancer had a partial response. Seven patients had stable disease for 2 to 17 months. Conclusion Gemcitabine given by 30-minute infusion for 2 or 3 consecutive weeks every 4 weeks was tolerated well by children at doses of 2,100 mg/m2 and 1,200 mg/m2, respectively.

Phase I study of oral etoposide in children with refractory solid tumors.

1994 ◽  
Vol 12 (7) ◽  
pp. 1452-1457 ◽  
Author(s):  
P Mathew ◽  
R C Ribeiro ◽  
D Sonnichsen ◽  
M Relling ◽  
C Pratt ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Plasma Concentrations ◽  
Rest Period ◽  
Maximum Tolerated Dose ◽  
Oral Etoposide ◽  
Daily Dose ◽  
Dose Levels ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and plasma concentrations of orally administered etoposide (VP-16) in pediatric oncology patients. PATIENTS AND METHODS In a phase I study, 20 children with refractory solid tumors received oral VP-16 (the intravenous preparation diluted with sodium chloride) three times daily for 21 days. Daily dose levels studied were 50 mg/m2 (n = 5), 60 mg/m2 (n = 7), and 75 mg/m2 (n = 8). VP-16 concentrations were measured in blood samples collected on days 1, 7, 14, and 21. RESULTS Grade 3 to 4 thrombocytopenia and/or neutropenia causing interruption of the 21-day course or persisting for more than 7 days after the last day of chemotherapy was seen at all dose levels, but was not dose-limiting. One patient treated at the 50-mg/m2 daily dose died of sepsis. At the 75-mg/m2 dose level, diarrhea was dose-limiting. Estimated plasma VP-16 concentrations were greater than 1 micrograms/mL for median periods of 9.4, 15.4, and 13.5 hours per day at daily doses of 50, 60, and 75 mg/m2, respectively. Responses were observed in seven of 14 patients who received at least one additional course of etoposide after a rest period of 7 days. There was one complete and two objective responses. Four patients were considered to have stable disease. CONCLUSION The intravenous preparation of VP-16 administered orally appears to be well tolerated by heavily pretreated pediatric patients. On the three-times daily, 21-day schedule, a daily dose of 75 mg/m2 exceeds the MTD, with diarrhea as the dose-limiting toxicity. The recommended dose for oral etoposide is 60 mg/m2/d administered every 8 hours.

Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: a collaborative pediatric branch, National Cancer Institute and Children's Cancer Group trial.

1997 ◽  
Vol 15 (4) ◽  
pp. 1538-1543 ◽  
Author(s):  
S M Blaney ◽  
N L Seibel ◽  
M O'Brien ◽  
G H Reaman ◽  
S L Berg ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Intravenous Infusion ◽  
Phase I Trial ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Cancer Group ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Dose Limiting Toxicity

PURPOSE A phase I trial of docetaxel was performed to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities, and the incidence and severity of other toxicities in children with refractory solid tumors. PATIENTS AND METHODS Forty-four children received 103 courses of docetaxel administered as a 1-hour intravenous infusion every 21 days. Doses ranged from 55 to 150 mg/m2, MTD was defined in heavily pretreated and less heavily pretreated (< or = 2 prior chemotherapy regimens, no prior bone marrow transplantation [BMT], and no radiation to the spine, skull, ribs, or pelvic bones) patients. RESULTS Dose-related neutropenia was the primary dose-limiting toxicity. The MTD in the heavily pretreated patient group was 65 mg/m2, but the less heavily pretreated patients tolerated a significantly higher dose of docetaxel (maximum-tolerated dose, 125 mg/m2). Neutropenia and constitutional symptoms consisting of malaise, myalgias, and anorexia were the dose-limiting toxicities at 150 mg/m2 in the less heavily pretreated patients. Thrombocytopenia was not prominent, even in patients who experienced dose-limiting neutropenia. Common nonhematologic toxicities of docetaxel included skin rashes, mucositis, and mild elevations of serum transaminases. Neuropathy was uncommon. Peripheral edema and weight gain were observed in two of five patients who received more than three cycles of docetaxel. A complete response (CR) was observed in one patient with rhabdomyosarcoma, a partial response (PR) in one patient with peripheral primitive neuroectodermal tumor (PPNET), and a minimal response (MR) in two patients with PPNET. Three of the four responding patients were treated at doses > or = 100 mg/m2. CONCLUSION The recommended phase II dose of docetaxel administered as a 1-hour intravenous infusion in children with solid tumors in 125 mg/m2. Because neutropenia was the dose-limiting toxicity and thrombocytopenia was mild, further escalation of the dose should be attempted with granulocyte colony-stimulating factor (G-CSF) support.

scholarly journals A Bayesian dose-finding design for outcomes evaluated with uncertainty

2021 ◽  
pp. 174077452110015
Author(s):  
Matthew J Schipper ◽  
Ying Yuan ◽  
Jeremy MG Taylor ◽  
Randall K Ten Haken ◽  
Christina Tsien ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Data Augmentation ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Number Of Patients ◽  
Continual Reassessment ◽  
Partially Observed ◽  
Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

1998 ◽  
Vol 16 (7) ◽  
pp. 2494-2499 ◽  
Author(s):  
A M Langevin ◽  
D T Casto ◽  
P J Thomas ◽  
S D Weitman ◽  
C Kretschmar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Malignant Tumors ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Recommended Phase Ii Dose

PURPOSE A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Phase I and Pharmacokinetic Study of the Camptothecin Analog DX-8951f Administered as a 30-Minute Infusion Every 3 Weeks in Patients With Advanced Cancer

2000 ◽  
Vol 18 (23) ◽  
pp. 3986-3992 ◽  
Author(s):  
Valérie Boige ◽  
Eric Raymond ◽  
Sandrine Faivre ◽  
Michel Gatineau ◽  
Kathleen Meely ◽  
...  
Keyword(s):  
Phase I ◽  
Intravenous Infusion ◽  
Topoisomerase I ◽  
High Performance ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Phase Ii Studies ◽  
Heavily Pretreated ◽  
Dose Limiting Toxicity

PURPOSE: DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks. PATIENTS AND METHODS: Twelve patients with refractory solid malignancies were treated with DX-8951f at dose levels ranging from 4 to 7.1 mg/m2. All but one patient had received previous chemotherapy, and eight patients were considered heavily pretreated. Total DX-8951f plasma concentrations were assayed using high-performance liquid chromatography. RESULTS: Thirty-six cycles of DX-8951f were administered. Neutropenia was the dose-limiting toxicity, and it was dose-related, reversible, and noncumulative. Other toxicities included nausea and vomiting, alopecia, asthenia, fever, and anemia. Grade 1 or 2 diarrhea was observed in seven patients but was transient and resolved without requiring treatment. Pharmacokinetic analysis showed that DX-8951f had a half-life of 7.15 hours and a clearance rate of 1.65 L/h·m2. The DX-8951f area under the plasma-concentration curve increased linearly with the dose. We defined the MTD of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks as 7.1 mg/m2. CONCLUSION: The dose-limiting toxicity of DX-8951f is neutropenia. The recommended dose for phase II studies is 5.33 mg/m2 every 3 weeks in patients previously treated with chemotherapy.

scholarly journals Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e000870
Author(s):  
Aung Naing ◽  
Joseph P Eder ◽  
Sarina A Piha-Paul ◽  
Claude Gimmi ◽  
Elizabeth Hussey ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Ex Vivo ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Antitumor Effects ◽  
Dual Inhibitor ◽  
Indoleamine 2,3 Dioxygenase

BackgroundM4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors.MethodsIn preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsIn mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%).ConclusionsThere were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.Trial registration numberNCT03306420.

Phase I study of CPT-11 and etoposide in patients with refractory solid tumors.

1993 ◽  
Vol 11 (10) ◽  
pp. 2030-2035 ◽  
Author(s):  
A Karato ◽  
Y Sasaki ◽  
T Shinkai ◽  
K Eguchi ◽  
T Tamura ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Topoisomerase I ◽  
Phase Ii Trial ◽  
Supportive Therapy ◽  
Maximum Tolerated Dose ◽  
Granulocyte Colony Stimulating Factor ◽  
Small Cell Lung ◽  
Dose Levels ◽  
Stimulating Factor ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) and acceptable dose level of a cytotoxic regimen of CPT-11, a new camptothecin derivative, in combination with etoposide (VP-16) and to describe the principal toxicities associated with it. PATIENTS AND METHODS Patients with refractory solid tumors received VP-16 and CPT-11 daily for 3 consecutive days (days 1 through 3) every 3 or 4 weeks. Groups entered the trial at escalating CPT-11/VP-16 dose levels of 40/60, 60/60, 60/80, and 80/60 mg/m2. Thirty-four patients entered this study, of whom 33 were assessable for toxicity and 22 for therapeutic efficacy. RESULTS Granulocytopenia was so severe that this regimen required supportive therapy with recombinant human granulocyte colony-stimulating factor (G-CSF). The majority of the patients experienced a 5% weight loss and diarrhea was the dose-limiting toxicity. The MTDs were 60/80 and 80/60 mg/m2 administered on days 1 through 3. Five of seven previously untreated patients with non-small-cell lung cancer (NSCLC) achieved partial responses (PRs) to this therapy, as did two with NSCLC who had received prior chemotherapy, two with head and neck cancer, and one with an adenocarcinoma (primary tumor unknown). CONCLUSION The recommended dose of CPT-11/VP-16 for this regimen with G-CSF is 60/60 mg/m2 on days 1 through 3 every 3 to 4 weeks. We suggest that the combination of topoisomerase I and II inhibitors is likely to be an effective treatment strategy. The activity of this regimen against NSCLC is particularly encouraging and should be evaluated in a phase II trial.

Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group Study.

1998 ◽  
Vol 16 (3) ◽  
pp. 945-952 ◽  
Author(s):  
R L Saylors ◽  
C F Stewart ◽  
W C Zamboni ◽  
D A Wall ◽  
B Bell ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Pediatric Patients ◽  
Wilms Tumor ◽  
Systemic Exposure ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
Phase Ii Trials ◽  
Pediatric Solid Tumors ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity of topotecan when combined with cyclophosphamide in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS A total of 33 patients received cyclophosphamide (250 mg/m2/dose) followed by topotecan in escalating doses (0.6 to 0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. A total of 154 fully assessable treatment courses were given to these patients. RESULTS Neutropenia was the dose-limiting toxicity of the therapy at both topotecan dose levels. The addition of filgrastim allowed escalation of the topotecan dose to the 0.75-mg/m2 level with acceptable neutropenia. Other significant toxicities were anemia and thrombocytopenia. Nonhematopoietic toxicity of grades > or = 3 was not observed. Responses were reported in patients with Wilms' tumor (one complete response [CR], one partial response [PR]), neuroblastoma (one CR, one PR), rhabdomyosarcoma (one PR), and osteosarcoma (one PR). Pharmacokinetic studies indicate that cyclophosphamide administered on the schedule used in this study did not alter topotecan disposition on day 5. As with previous studies, a pharmacodynamic relation between systemic exposure and myelosuppression was noted. CONCLUSION The combination of topotecan and cyclophosphamide shows activity in a wide variety of pediatric solid tumors and can be given with acceptable hematopoietic toxicity with the use of filgrastim support. We recommend that pediatric phase II trials use cyclophosphamide 250 mg/m2 followed by topotecan 0.75 mg/m2 daily for 5 days with filgrastim for amelioration of neutropenia.

Phase I trial of paclitaxel in children with refractory solid tumors: a Pediatric Oncology Group Study.

1993 ◽  
Vol 11 (12) ◽  
pp. 2324-2329 ◽  
Author(s):  
C A Hurwitz ◽  
M V Relling ◽  
S D Weitman ◽  
Y Ravindranath ◽  
T J Vietti ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Phase I ◽  
Solid Tumors ◽  
Plasma Concentrations ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clonic Seizure ◽  
Fine Motor ◽  
Phase Ii Trials

PURPOSE A phase I study was performed to describe the principal toxicities and identify the maximum-tolerated dose (MTD) of Taxol (paclitaxel; Bristol-Myers Squibb Co, Wallingford, CT) in children with therapy-resistant solid tumors. Additionally, the pharmacokinetic disposition of Taxol in children was studied, and preliminary evidence of the activity of Taxol against pediatric solid tumors was assessed. PATIENTS AND METHODS Twenty-four-hour continuous infusions of Taxol were administered every 21 days to children (median age, 12 years; range, 2 to 22) with refractory solid tumors. Doses ranged from 200 to 420 mg/m2, there was no intrapatient dose escalation. RESULTS A total of 62 courses of Taxol were administered to 31 patients. Two patients developed acute anaphylaxis during their second infusion of taxol at doses of 200 mg/m2 and 350 mg/m2, respectively. No other allergic reactions were documented. Myelosuppression occurred at all dose levels, but was of short duration (< or = 7 days) and did not appear to increase with consecutive courses or at higher dosage levels. A stocking-and-glove peripheral neuropathy became evident at doses > or = 290 mg/m2. Dose-limiting neurotoxicity occurred at 420 mg/m2 and comprised a significant fine-motor and peripheral neuropathy in one patient, and a tonic-clonic seizure in another. End-of-infusion plasma concentrations ranged from 0.40 to 6.4 mumol/L, and were not found to be dose-dependent over the range of doses studied. A complete response was documented in one patient, partial response in two, and minimal response in one for an overall response rate of 13%. CONCLUSION Neurotoxicity was dose-limiting when Taxol was administered by 24-hour continuous infusion to pediatric patients with relapsed solid tumors. In this population, the recommended dose for phase II trials is 350 mg/m2/d.

scholarly journals Daptomycin Pharmacokinetics in Adult Oncology Patients with Neutropenic Fever

2008 ◽  
Vol 53 (2) ◽  
pp. 428-434 ◽  
Author(s):  
Joseph S. Bubalo ◽  
Myrna Y. Munar ◽  
Ganesh Cherala ◽  
Brandon Hayes-Lattin ◽  
Richard Maziarz
Keyword(s):  
Median Time ◽  
Intravenous Infusion ◽  
Plasma Concentrations ◽  
Neutropenic Fever ◽  
Time Data ◽  
Bacteriostatic Effect ◽  
Oncology Patients ◽  
Time Zero ◽  
Concentration Time ◽  
Free Plasma

ABSTRACT Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means ± standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (C max) was 49.04 ± 12.42 μg/ml (range, 21.54 to 75.20 μg/ml), the 24-h plasma concentration was 6.48 ± 5.31 μg/ml (range, 1.48 to 29.26 μg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 ± 523.53 μg·h/ml (range, 164.64 to 3155.11 μg·h/ml), the volume of distribution at steady state was 0.18 ± 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 ± 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 ± 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 ± 20.66 h (range, 7.00 to 121.73 h), and the median time to C max was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 ± 0.02. All patients achieved C max/MIC and AUC from time zero to 24 h (AUC0-24)/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a C max/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC0-24/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.

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