Standard 30-minute Infusion Research Articles

Safety and efficacy of a 5-minute infusion versus the standard 30-minute infusion for antibiotics in an outpatient setting

The National University Hospital Outpatient Parenteral Antibiotic Therapy (OPAT) centre was established in 2004 and now provides for over 350 patients yearly. OPAT refers to the administration of intravenous (IV) antibiotics for the management of infections in the outpatient setting without requiring hospital admission, or as a transition following hospitalization. It is a cost-effective and safe alternative to inpatient care. Depending on the pharmacokinetic profile, antibiotics are generally administered either via 24-hour infusion devices or once-daily infusions (Fisher et al., 2017).

A Randomized Trial of Prophylactic Extended Carboplatin Infusion to Reduce Hypersensitivity Reactions in Recurrent Ovarian Cancer.

Hypersensitivity with repeated exposure to platinum agents is common and can preclude continued treatment, even in patients with disease that remains platinum sensitive. We sought to compare the effects of prophylactic, extended carboplatin infusion versus standard infusion on the rate of carboplatin hypersensitivity reactions (HSRs) in women with recurrent ovarian cancer. This was a single-institution, randomized, nonblinded trial comparing a graded, 3-hour extended infusion of carboplatin with a standard 30-minute infusion in patients with recurrent ovarian cancer who were enrolled from January 2011 to April 2015. The study was designed to detect a decrease in the HSR rate from 20% (standard infusion) to 5% (extended infusion) assuming a type 1 error of 10% and power of 80% using a 1-sided test. Of 146 enrolled patients, 114 were evaluable. Fifteen (13%) had an HSR-11% (6/56) in the extended-infusion and 16% (9/58) in the standard-infusion groups (P = 0.582). Planned treatment completion was achieved in 50 (89%) of 56 patients and 49 (84%) of 58 patients, respectively. Of 25 patients who received single-agent carboplatin, 8 (32%) had an HSR (53% of all patients who had an HSR [8/15]). Of 23 patients who received carboplatin with gemcitabine, 4 (17%) had an HSR (27% of all patients who had an HSR [4/15]). Of 8 patients who received carboplatin with paclitaxel, 3 (38%) had an HSR (20% of all patients who had an HSR [3/15]). There were no HSRs with pegylated liposomal doxorubicin, the most commonly given concurrent chemotherapy (46% of all patients). A prophylactic, extended carboplatin infusion was not associated with a decreased HSR rate. The overall low HSR rate suggests that premedication may help reduce HSRs.

Comparative Pharmacokinetics, Pharmacodynamics, and Tolerability of Ertapenem 1 Gram/Day Administered as a Rapid 5‐Minute Infusion versus the Standard 30‐Minute Infusion in Healthy Adult Volunteers

To compare ertapenem pharmacokinetics, pharmacodynamics, and tolerability when administered as a rapid 5-minute infusion to the standard 30-minute infusion. Prospective, randomized, crossover pharmacokinetic study. Clinical research center. Twelve healthy adult volunteers. Each subject received ertapenem 1g intravenously, administered either as a rapid 5-minute infusion or the standard 30-minute infusion, every 24hours for 3days (first phase); after a 4-day washout period, each subject then received the other infusion every 24hours for 3days (second phase). Plasma samples were collected after the first and third (steady-state) doses of each study phase, and protein binding was assessed by use of ultrafiltration. Pharmacokinetic analyses were conducted using noncompartmental and compartmental methods. A 5000-subject Monte Carlo simulation was used to assess the probability of target attainment for free drug concentration remaining above the minimum inhibitory concentration (MIC) for 40% or greater of the dosing interval (40% fT>MIC) over an MIC range. Ertapenem was well tolerated and adverse events were similar for both infusions. The ertapenem steady-state mean±SD maximum concentrations were 193.3±43.3 and 165.7±20.4mg/L for the 5- and 30-minute infusions, respectively; the mean±SD areas under the concentration-time curves from 0-24hours were 561.2±77.0 and 531.3±56.9μg · hr/ml (geometric mean ratio 1.008, 90% confidence interval 0.999-1.017), respectively. Protein binding was concentration dependent (range 87.9-98.9%). A two-compartment model best described ertapenem pharmacokinetics with the following parameter estimates: clearance 1.89±0.19L/hr, volume of central compartment 5.04±0.56L, and transfer constants k12 0.43±0.08/hr and k21 0.44±0.07/hr. The probabilities of target attainment for 5- and 30-minute infusions were 97.0% and 97.9% at an MIC of 0.25 mg/L and 1.7% and 2.8% at an MIC of 0.5mg/L, respectively. Ertapenem administered as a rapid 5-minute infusion provides a well tolerated, bioequivalent, and pharmacodynamically equivalent regimen to the 30-minute infusion at clinically relevant MICs.

Implementation of an extended-infusion piperacillin–tazobactam program at an urban teaching hospital

The development and implementation of an extended-infusion piperacillin-tazobactam program at an urban teaching hospital are described. A multidisciplinary team was formed to address the feasibility of converting from the standard 30-minute infusion to an extended infusion of piperacillin- tazobactam. Before hospitalwide implementation, feasibility studies were performed in a subset of patients to identify potential barriers to program implementation. On the day of hospitalwide conversion, the orderables for piperacillin-tazobactam were reprogrammed in the computerized prescriber-order-entry system to allow separate options for the 30-minute infusion (for pediatric patients) and the extended-infusion regimen. After selecting the orderable for the extended-infusion regimen, an electronic message appeared to remind prescribers of the rationale for this change and recommended indications for piperacillin-tazobactam. Program success was prospectively evaluated on 11 weekdays after hospitalwide conversion for all 96 adult inpatients receiving piperacillin-tazobactam. Of the 194 piperacillin-tazobactam doses observed, 90% were appropriate, with compliance increasing to 100% by the end of the observation period. There was near-complete cessation of the every-6-hour dosage interval and a marked increase in the every-8-hour and every-12-hour dosage intervals. The number of piperacillin-tazobactam doses per 1000 patient-days significantly decreased during the postimplementation period. During the postimplementation period, pharmacy expenditures related to piperacillin-tazobactam decreased by 18% and the total number of grams of piperacillin-tazobactam purchased decreased by 24%. A hospitalwide program for the administration of extended-infusion piperacillin-tazobactam was safely and successfully implemented using a multi-disciplinary approach in an urban teaching hospital.

Pharmacokinetics of Gemcitabine at Fixed-Dose Rate Infusion in Patients with Normal and Impaired Hepatic Function

Gemcitabine (2,2-difluorodeoxycytidine [dFdC]) can be administered in a standard 30-minute infusion or in a fixed-dose-rate (FDR) infusion to maximize the rate of accumulation of triphosphate, its major intracellular metabolite. The standard 30-minute infusion requires dose adjustment in patients with organ dysfunction, especially in patients with elevated baseline serum bilirubin levels. On the other hand, the FDR infusion is burdened by increased haematological toxicity. The primary aim of this study was to evaluate the pharmacokinetics of dFdC and its metabolite difluorodeoxyuridine (dFdU) in patients with normal and impaired hepatic function. In this prospective study, patients with pancreatic or biliary tract carcinoma and normal or impaired hepatic function tests were considered eligible for recruitment. Patients were recruited according to the following criteria: (i) serum bilirubin <1.6 mg/dL and AST and ALT <2 times the upper the limit of normal (ULN) [cohort I]; and (ii) serum bilirubin >1.6 mg/dL and/or AST/ALT >2 times the ULN (cohort II). An FDR infusion of gemcitabine 1000 mg/m2 was administered on days 1, 8 and 15 every 4 weeks. The pharmacokinetic analysis of gemcitabine and dFdU was performed with high-performance liquid chromatography-tandem mass spectrometry assay in cycles 1 and 2. Thirteen patients were enrolled, four in cohort I and nine in cohort II. All patients were assessable for toxicity and pharmacokinetic analysis. The grade and rate of toxicities were similar in both groups, and patients with elevation of bilirubin and/or transaminases did not require dose reduction of gemcitabine. Pharmacokinetic analysis revealed a reduction of the experimental area under the plasma concentration-time curve for gemcitabine and dFdU in patients with hepatic dysfunction when compared with patients with normal hepatic function. All other pharmacokinetic parameters were similar in the two cohorts. No statistical difference was demonstrated for all parameters evaluated between cycle 1 and cycle 2 in the two groups. Gemcitabine 1000 mg/m2 can be administered as an FDR infusion in patients with altered hepatic function without causing additional toxicity compared with patients with normal hepatic function.

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

Gemcitabine is frequently used in the treatment of patients with solid tumors. Gemcitabine is taken up into the cell via human nucleoside transporters (hNTs) and is intracellularly phosphorylated by deoxycytidine kinase (dCK) to its monophosphate and subsequently into its main active triphosphate metabolite 2',2'-difluorodeoxycytidine triphosphate (dFdCTP), which is incorporated into DNA and inhibits DNA synthesis. In addition, gemcitabine is extensively deaminated to 2',2'-difluorodeoxyuridine, which is largely excreted into the urine. High expression levels of human equilibrative nucleoside transporter type 1 were associated with a significantly longer overall survival duration after gemcitabine treatment in patients with pancreatic cancer. Clinical studies in blood mononuclear and leukemic cells demonstrated that a lower infusion rate of gemcitabine was associated with higher intracellular dFdCTP levels. Prolonged infusion of gemcitabine at a fixed dose rate (FDR) of 10 mg/m2 per minute was associated with a higher intracellular accumulation of dFdCTP, greater toxicity, and a higher response rate than with the standard 30-minute infusion of gemcitabine in patients with pancreatic cancer. In the current review, we discuss the molecular pharmacology of nucleoside analogues and the influence of hNTs and dCK on the activity and toxicity of gemcitabine, which is the basis for clinical studies on FDR administration, and the results of FDR gemcitabine administration in patients. These findings might aid optimal clinical application of gemcitabine in the future.

Questions About Gemcitabine Dose Rate: Answered or Unanswered?

Even before 2 ,2 -difluorodeoxycytidine (dFdC) was given the name gemcitabine, laboratory studies were investigating the biochemical feature of its phosphorylation to demonstrate that the rate of accumulation of its triphosphate (dFdCTP, gemcitabine triphosphate) was saturated by 10 to 20 mol/L of exogenous gemcitabine. The first investigation that established the saturability for gemcitabine triphosphate accumulation was done in a cell line. This was extended to primary cells in vitro and in peripheralblood mononuclear cells (PBMCs) during therapy. In the clinic, when gemcitabine was administered at different doses during a standard 30-minute infusion, the rate of intracellular accumulation of gemcitabine triphosphate was highest when plasma gemcitabine was about 20 mol/L. Pharmacokinetic studies during therapy further established that such gemcitabine levels (20 mol/L) were achieved in plasma with a dose rate of 10 mg/m/ min, hence coining the term fixed dose rate (FDR) of gemcitabine. At this dose rate, a continuous increase in gemcitabine triphosphate concentration was observed for up to 18 hours. For the FDR delivery, generally 1,000 or 1,500 mg/m is infused during 100 or 150 minutes, respectively. In contrast, a phase I dose escalation trial established that the maximum tolerated dose of gemcitabine was 2,200 mg/m/wk for 3 weeks when administered as a 30-minute infusion. This half-hour administration has been the most used schedule and has been termed the standard (STD) dose schedule of gemcitabine. Saturation kinetics that led to a defined dose rate have been observed for cytarabine, a prototype of nucleoside analogs. The reason that phosphorylated moieties of cytarabine (cytarabine triphosphate) and gemcitabine (gemcitabine diphosphate, gemcitabine triphosphate) are the active and cytotoxic metabolites of these nucleoside analogs further underscored the importance of the dose rate of infusion during clinical trials. Although several clinical trials have been performed with gemcitabine, either with STD doses or with FDR schedules, only a few were designed to ask two specific questions: First, is there a greater accumulation of gemcitabine triphosphate with a FDR of gemcitabine; and, second, does this result in a better clinical outcome (Table 1).

Lessons Learned in the Management of Advanced Pancreatic Cancer

The treatment of patients with advanced pancreatic cancer remains a major challenge. The outcome for this condition is extremely poor, with the median survival of patients treated with best supportive care within approximately 3 to 4 months. Patients treated with gemcitabine have a median survival of approximately 6 months and a 1-year survival rate of approximately 20%. Gemcitabine has been widely accepted as the standard treatment based on a relatively small study showing a modest, but statistically significant, improvement in overall survival as well as improved clinicalbenefitcomparedwithbolusfluorouracilplusleucovorin. 1 Although a pharmacokinetic rationale exists for administering gemcitabineoveraprolongedinfusedover150minutes(fixeddose rate [FDR]), with a small clinical study suggesting high activity, a randomized phase III study comparing the FDR regimen and the standard 30-minute infusion failed to show superiority for FDR gemcitabine. 2,3 Gemcitabine has been combined with a variety of cytotoxic agents and targeted agents (Tables 1, 2, and 3). 3-17 Most phase III studies, however, have failed to show improved survival comparedwithgemcitabinealone. 3-8 OnephaseIIIstudycomparingthecombinationofgemcitabineandcapecitabinewithgemcitabine monotherapy has shown a significantly improved median and 1-year survival in favor of the combination arm: 7.4 months versus 6.0 months and 26% versus 19%, respectively, with a favorable safety profile. 9 This study of 533 patients used a different regimen of gemcitabine plus capecitabine than a smaller study, in 319 patients that showed a trend, but no significant difference, compared with gemcitabine monotherapy. 9,10 This latter study was underpowered to show a survival difference. Other studies with gemcitabine, with or without intravenous fluorouracil all failed to show a difference between gemcitabine monotherapy and combination treatment. 11-13

Prolonged infusion of gemcitabine in patients with platinum resistant or refractory recurrent ovarian carcinoma: A phase II study Of GEICO (Spanish Group for investigation on ovarian cancer)

5101 Background: Preclinical and clinical evidence suggests that a prolonged infusion may be more effective than the standard 30-minute infusion of gemcitabine. To investigate the activity and toxicity of gemcitabine infused over 2 hours in patients with platinum resistant or refractory recurrent ovarian carcinoma. Methods: A multi-center phase II study was conducted in patients with recurrent platinum-resistant or refractory ovarian carcinoma. Patients were to receive gemcitabine 1000 mg/m2 over 2 hours on days 1 and 8 every 21 days for at least 6 cycles unless disease progression or unacceptable toxicity occurs. Results: From August, 2003 to October, 2004, 39 patients have been included. Toxicity and efficacy data from first 20 patients are presented. Median age was 64 (range: 30–77). Median platinum-free interval was 3.65 months. 77 cycles have been administered (median of 3 cycles per patient, range: 1–10). Dose delay was required in 27% of cycles and dose reduction was indicated in 2 pts. Dose on day 8 was reduced in 26% of cycles and missed in 11.6% of cycles according to protocol dose modifications. Grade 3–4 haematological toxicities were (% of pts): anemia 20%, neutropenia 15%, and thrombocytopenia 5%. 2 pts had low-risk neutropenic fever. The most frequent non-haematological grade 2–3 toxicities were (% of pts): asthenia 25% (2 pts G2 and 3 pts G3) and nausea 15% (3 pts G2). There were 3 partial responses (15%; 95% CI: 0–30%) and no complete responses observed. Two patients had stable disease (10%) and 15 pts progressed on therapy (75%). Median time to progression was 2 months. Conclusions: These preliminary data suggest that the activity of a prolonged infusion of gemcitabine is comparable with the standard 30-min infusion. The recruitment will continue until the endpoint of 41 patients. Mature data of toxicity and efficacy will be presented. No significant financial relationships to disclose.

A randomized phase II study of gemcitabine/cisplatin, gemcitabine fixed dose rate infusion, gemcitabine/docetaxel, or gemcitabine/irinotecan in patients with metastatic pancreatic cancer (CALGB 89904)

4011 Background: In the treatment of advanced pancreatic cancer, chemotherapy regimens utilizing prolonged infusions of gemcitabine or combinations of gemcitabine and other agents have been associated with higher objective tumor response rates and, in some cases, improvements in progression-free survival when compared with gemcitabine administered as a standard 30-minute infusion. Comparisons between these novel regimens have been limited. We therefore performed a randomized phase II study of four investigational chemotherapy regimens in pts with documented metastatic pancreatic cancer. Methods: Pts were randomized to receive one of the following four treatments: gem 1000 mg/m2 d 1, 8, 15 with cisplatin 50 mg/m2 d1, 15 q 28d (Arm A); gem 1500 mg/m2 at a fixed dose rate of 10 mg/m2/minute d1, 8, 15 q 28d (Arm B); gem 1000 mg/m2 d1, 8 with docetaxel 40 mg/m2 d1, 8 q 21d (Arm C); or gem 1000 mg/m2 d1, 8 with irinotecan 100 mg/m2 d1, 8 q 21d (Arm D). Planned follow up per pt is 6 months. Results: Two hundred and fifty-one pts (61–65 per arm) were enrolled, with the following characteristics: median age 60.7 (range (31–84); M/F = 157/94; ECOG PS 0/1/2 = 49/86/18. Median follow-up time is 4.8 months. Pts were followed for overall survival, tumor response, time to tumor progression, and toxicity. The major toxicities experienced by 198 enrolled pts for whom data is currently available are shown in Table 1. Three pts experienced treatment related deaths: 1 (2%) in Arm A and 2 (4%) in Arm B. Conclusions: While the specific toxicities differ to some degree between regimens, all four regimens have acceptable toxicity profiles. Accrual to the trial has been completed. Updated toxicity data, as well as preliminary data for survival, response, and time to tumor progression will be presented at the annual meeting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Pharmaceuticals

Phase I trial of gemcitabine and epirubicin in patients with solid malignancies

4190 Background: Gemcitabine (G) given as a standard 30-minute infusion is well tolerated with modest clinical activity, but new data suggest prolonged exposure may improve response. In vitro studi...

A randomized phase II study of gemcitabine/cisplatin, gemcitabine fixed dose rate infusion, gemcitabine/docetaxel, or gemcitabine/irinotecan in patients with metastatic pancreatic cancer (CALGB 89904)

4011 Background: In the treatment of advanced pancreatic cancer, chemotherapy regimens utilizing prolonged infusions of gemcitabine or combinations of gemcitabine and other agents have been associated with higher objective tumor response rates and, in some cases, improvements in progression-free survival when compared with gemcitabine administered as a standard 30-minute infusion. Comparisons between these novel regimens have been limited. We therefore performed a randomized phase II study of four investigational chemotherapy regimens in pts with documented metastatic pancreatic cancer. Methods: Pts were randomized to receive one of the following four treatments: gem 1000 mg/m2 d 1, 8, 15 with cisplatin 50 mg/m2 d1, 15 q 28d (Arm A); gem 1500 mg/m2 at a fixed dose rate of 10 mg/m2/minute d1, 8, 15 q 28d (Arm B); gem 1000 mg/m2 d1, 8 with docetaxel 40 mg/m2 d1, 8 q 21d (Arm C); or gem 1000 mg/m2 d1, 8 with irinotecan 100 mg/m2 d1, 8 q 21d (Arm D). Planned follow up per pt is 6 months. Results: Two hundred ...