Short Infusion Research Articles

Short versus continuous gemcitabine treatment of non-small cell lung cancer in an in vitro cell culture bioreactor system

Five-year survival for non-small cell lung cancer is 15%. Gemcitabine is a nucleoside analogue that inhibits ribonucleotide reductase and interferes with DNA replication. In this study, we sought to compare short versus continuous infusion gemcitabine in an in vitro bioreactor system using pharmacokinetic-guided dosing. Gemcitabine was infused over either 0.5 or 2.5h to produce concentration-time profiles that mimic those measured in biological samples (i.e., patient plasma). The effects of gemcitabine on the growth and survival of H2009 cells were examined using trypan blue staining, cell cycle analysis, TUNEL assay, and clonogenic assay. Data were analyzed with two ways analysis of variance. Maximum gemcitabine (Cmax) concentrations during the short infusion were 51.2+/-10.4 microM and for the continuous, 14.8+/-2.93 microM. Steady-state concentrations during the continuous infusions were 14.9+/-2.90 microM. Gemcitabine treatment resulted in a decrease for G1 fraction relative to controls. G2/M, subG1 and TUNEL were higher following gemcitabine relative to controls. Survival was approximately 20-fold higher following the short infusion compared with the continuous infusion (p = 0.0085). In conclusion, gemcitabine infused by this novel method induced apoptosis after both the short and continuous infusions, and long-term survival was significantly diminished following continuous compared with the short infusion.

Gemcitabine administered as a short infusion versus a fixed dose rate in combination with cisplatin for the treatment of patients with advanced non-small cell lung cancer

Previous studies have indicated that, in combination with cisplatin, fixed dose rate gemcitabine may be more efficacious than standard infusion gemcitabine. This open-label, randomised phase II study was aimed to compare the efficacy and safety of these regimens as treatment for advanced non-small cell lung cancer (NSCLC) in Latin American patients. Sixty-four patients were randomised to receive up to six cycles of treatment with cisplatin 75 mg/m(2) on Day 1 plus either gemcitabine 1000 mg/m(2) over 30 min on Days 1 and 8 of a 21-day cycle (standard arm, N=33) or gemcitabine 1000 mg/m(2) at a fixed dose rate of 10 mg/m(2)/min on Days 1 and 8 of a 21-day cycle (FDR arm, N=31). In the standard arm, 9 of 33 (27%) patients responded compared with 6 of 30 (20%) patients in the FDR arm (odds ratio: 0.67, 95% CI, 0.21-2.2; p=0.56). Median overall survival was 7.5 months in the standard arm and 9.9 months in the FDR arm. One-year survival rates were 35% and 37% in the standard arm and the FDR arm, respectively. Patients in the FDR arm experienced more grade 3/4 haematological toxicity than those in the standard arm (48% versus 21%). The results of this trial do not support FDR administration of gemcitabine in preference to the standard administration in Latin American patients with NSCLC.

Phase I clinical pharmacokinetics of RTA 744: A blood brain barrier penetrating anthracycline active against high-grade glioma

2045 Background: Preclinical studies demonstrated that RTA 744, a 4’-O benzyl anthracycline designed to circumvent P-gp and MRP1-mediated efflux, effectively crosses the BBB, is retained in brain & brain tumor tissue for >24 hrs, and has demonstrated in vivo activity against glioblastoma multiforme (GBM) in an orthotopic model. Methods: We designed a multicenter, phase I dose- escalation study of RTA 744 administered as a short intravenous infusion for 3 consecutive days, every 3 weeks. Patients enrolled in the study were adult patients with recurrent or refractory GBM, anaplastic astrocytoma, or other primary brain tumors. Peripheral blood samples for PK analysis were collected prior to and at selected timepoints from 5 min to 96 hrs after drug administration, and quantified by LC/MS/MS. PK parameters describing RTA 744 disposition were determined by fitting compartmental models to individual patient plasma concentration-time data. Results: Twenty patients have been enrolled at daily doses ranging from 1.2 to 9.6 mg/m2. Mean (range) population terminal half-life was 34.6 (20.5–89.2) hrs, plasma drug clearance was 45.0 (27.4–86.9) L/hr/m2, and Vss was 1942 (684.9–4721.7) L/m2; population PK values reported for doxorubicin are 20–32 hrs, 24–35 L/hr/m2, and 700–1100 L/m2, respectively. Regimen related toxicity has been minimal with the most common adverse event being myelosuppression. Percentage of unchanged parent drug renally eliminated was 2.4% (0.42–6.03%). Several partial responses and one complete response have been noted, even at dose levels below the observed MTD of 7.5 mg/m2/day. Conclusions: These results are similar to what we have observed in our preclinical studies, demonstrating increased lipophillicity and enhanced biodistribution of RTA 744 when compared to doxorubicin. Direct confirmation of drug penetration into the CNS has not been determined in this study, however this is the focus of an ongoing trial in patients with leptomenigeal malignancies. No significant financial relationships to disclose.

Final report of a phase II trial of nimotuzumab in the treatment of refractory and relapsed high-grade gliomas in children and adolescents

2006 Background: Despite multimodal therapy most children with high grade gliomas (HGG), including glioblastoma multiforme (GM), anaplastic astrocytoma (AA) and intrinsic pontine glioma (PG) have an infaust prognosis if they relapse or are refractory to the primary treatment. Recently novel therapeutic approaches are investigated in order to improve the survival of these patients while preserving a good quality of life. This multicentre phase II trial was designed to explore the feasibility and efficacy of the h-R3 monoclonal anti-EGFR antibody (nimotuzumab) in the treatment of these patients. Patients and Methods: Pediatric patients with GM, AA or PG with radiologically proven progressive disease following primary or relapse treatment and a life expectancy of less than 4 weeks were eligible to the study. The treatment consisted of an induction therapy including a weekly short infusion of 150 mg/m2 nimotuzumab for six weeks, and in case of non-PD a consolidation therapy of 4 infusions in a 3 week interval. The response was documented by MRI in week 8 and 21 and only clinically in rapidly progresssive disease. Results: Between June 2004 and April 2006 47 patients aged 4 to 17 years (median 11 years) were enrolled in this study. 46 patients were evaluable for response. According to RECIST 14 out of 46 patients showed objective responses (PR n=4, SD n=10) in the MRI as the best response with a median change in the largest diameter of the index lesion of -11% (-50% to +16%). The PR/SD were seen in 2/13 patients with GM, 2/11 with AA and 10/22 with PG. Thirteen patients continued with the consolidation therapy and showed 4 PR, 3 SD and 6 PD in week 21. The median overall survival was 4.4 months (0.3–25.4 months) and was significantly better for repsonders (median 10 months) than for nonresponders (median 4.0 months). No severe side effects related to the study medication were observed. Conclusions: These data suggest that the repeated application of nimotuzumab is well tolerated and safe. Nimotuzumab has cytotoxic efficacy in heavily pre- treated relapsed HGG. Based on this data a phase III trial with nimotuzumab in newly diagnosed diffuse intrinsic pontine gliomas concomittent with radiotherapy was introduced in first quarter 2006. No significant financial relationships to disclose.

Phase I trial of gemcitabine (GEM) infused at fixed-dose rate (FDR) with high-dose docetaxel/melphalan/carboplatin (GEM-DMC) and autologous stem-cell transplant (ASCT)

17500 Background: More active ASCT regimens are needed. We combined GEM, which inhibits DNA damage repair, with the potent DMC regimen (BBMT 11:297–306,2005). GEM infusions at FDR of 10 mg/m2/min, targeting steady-state concentrations (Css) <20 μM, which in vitro do not saturate its intracellular activation to GEM-triphosphate (GEM-TP), result in greater activity but more myelotoxicity than its usual short infusions. Methods: Pts with advanced, refractory tumors and normal organ function were eligible. Study endpoints: to define the maximum tolerated duration (MTD) of GEM at FDR with ASCT, dose-limiting toxicity (DLT) and regimen-related toxicity (RRT) of GEM-DMC, and pharmacokinetics (PK) of high-dose GEM and docetaxel. Daily GEM FDR infusions (d-5 to d-2) were extended in sequential cohorts (total length: 9 to 20 hr), followed on d-5 by docetaxel (350 mg/m2), on d-4 to d-2 by melphalan (50 mg/m2/d) and carboplatin (333 mg/m2/d), and ASCT on d0. Results: 52 pts accrued (breast ca [N=31], Ewing's [5], germ-cell [4], lymphoma [4], Hodgkin's [3], sarcoma [5]), median age 40 (6–66), 3 median prior chemo regimens and 3 organs involved. GEM MTD: 5 hr/d x 4 (total 20 hr, 12 g/m2). Neutrophils engrafted on d+8 (6–10) and platelets on d+11 (8–33). There were 3 non-RRT deaths (1 aspiration, 2 catheter-related sepsis). At the MTD (N=25), enteritis (20% G3) was DLT; all other RRT were = G3 and reversible (28% stomatitis, 8% ileus, 8% rash). The response rate was 97% (60% complete). At median follow-up of 18 (7–27) months, 58% EFS (median 22 mo) and 85% OS rates (median not reached). All pts had GEM Css <20 μM. The infusion length correlated linearly with the AUC of GEM (r2= 0.65, p<10-5) but not with its clearance (r2=0.03) or t1/2 (r2= 0.02). GEM AUC was associated with G3 RRT (p<10-3). The AUCs of GEM and GEM-TP (/106 mononuclear cells) correlated on d-5 (r2=0.5, p=0.01), but not on d-2 (r2= 0.05) due to late GEM-TP accumulation. Docetaxel had 3–4 fold higher AUC and peak levels and similar clearance compared to its standard-dose population PK. Conclusions: GEM-DMC, markedly extending GEM infusions at FDR, is tolerable and highly active, without saturating the activation of GEM to GEM-TP. High-dose GEM and docetaxel show adequate linear PK. No significant financial relationships to disclose.

Low doses of humanized anti-CD20 antibody, IMMU-106 (hA20), in refractory or recurrent NHL: Phase I/II results

8032 Background: An open-label, multicenter study has shown that the humanized anti-CD20 antibody, IMMU-106 (hA20), which has framework regions of epratuzumab, has a good safety and efficacy profile in NHL pts when administered once-weekly × 4 at different doses. The trial is now focused on confirming the efficacy of lower doses (80–120 mg/m2/wk × 4). Methods: A total of 68 pts (35 male, 33 female; age 34–84) received hA20 at 750 (N=3), 375 (N=27), 200 (N=11), 120 (N=21), or 80 mg/m2 (N=6). They had follicular (FL, N=47) or other (N=21) B-cell NHL, were predominantly stage III/IV (N=47) at study entry, and had received 1–8 prior treatments (median, 2), including 1 (N=40) or more (N=21) rituximab regimens (without progression within 6 months). Results: Sixty- six pts completed all 4 infusions; 1 pt progressed during treatment and withdrew, while another pt with hives and chills after prior rituximab discontinued treatment after a similar episode at 1st infusion. hA20 was generally well tolerated, with shorter infusion times (typically 2 h initially and 1 h subsequently) at lower doses. Drug-related adverse events were transient, Grade 1–2, most occurring only at 1st infusion, and there was no evidence of HAHA in 54 pts now evaluated. Mean antibody serum levels increased with dose and infusions; serum clearance at 375 mg/m2 appears similar to rituximab. Currently, 48 pts with at least 12 wks follow-up were evaluated by Cheson criteria: 32 FL pts had 15 (47%) OR's with 7 (22%) CR/CRu's, even after 2–4 prior rituximab-regimens, and 17 non-FL pts had 6 (38%) OR's, with 1 CRu in a marginal zone NHL pt. At a median follow-up of 11 mo., 9/21 pts with ORs are continuing responses, including 4 long-lived responses (15–20 mo). The evaluated pts include 17 pts at 120 mg/m2 who had 5 (29%) ORs with 3 (17%) CR/CRu's. Responses at 80 mg/m2 remain to be evaluated, but B-cell depletion occurs after the 1st infusion even at this low dose. Conclusions: hA20 appears well-tolerated, with no evidence of significant adverse events other than minor infusion reactions, even at short infusion times. B-cell depletion and responses have occurred at all doses evaluated, with no clear-cut evidence of a dose-response. As such, the study is continuing to confirm the efficacy of lower doses. No significant financial relationships to disclose.

Adapting therapy with repeated short-infusions to inter individual variability between patients

Because of the wide inter individual variability between patients and their marked differences in drug response, one of the major issues that arises is adapting the therapy in question to the particular patient. In hospital, it is possible to vary the conditions of intravenous (i.v.) drug delivery by means of short infusions repeated at certain intervals. In this study, review of this process has been presented, and a therapeutic method described. It essentially consists of two stages. The first concerns the time of the first infusion, and the course of drug elimination: from two analyses of the drug concentrations in the blood made at two different times, the pharmacokinetic parameters of the patient are determined. Stage 2 consists of repeated short infusions and the therapy is adapted to the particular patient by varying the conditions involved. Thus, either the amount of the dose based on the rate of infusion or the time interval between the repeated infusions are varied. In order to reach a general solution, master curves are built by using dimensionless numbers as co-ordinates, such as time expressed in terms of the half-life t0.5 of the drug, and the drug concentration at the peaks defined as a fraction of the first unchanged peak concentration.

A Comparison of Pharmacokinetic/Pharmacodynamic versus Mass-Balance Measurement of Brain Concentrations of Intravenous Anesthetics in Sheep

There are two recognized methods of estimating the brain concentrations of IV anesthetic drugs: (i) use of pharmacokinetic/pharmacodynamic (PK/PD) modeling of drug effect, from arterial concentrations and electroencephalogram changes, and (ii) direct measurement of the uptake of drug in the brain, by simultaneously measuring arterial and jugular concentrations and cerebral blood flow (mass-balance method). These two methods have not been directly compared. Because an accurate estimate of the time taken for transfer of anesthetic drug from arterial blood to its effect-compartment in the brain is critical for accurate effect-compartment dosing in IV anesthesia, we compared the PK/PD and mass-balance methods for propofol, methohexital, and ketamine in a sheep model. After instrumentation with arterial and sagittal-sinus cannulae, electrocorticogram, and sagittal sinus Doppler flow measurement seven adult sheep were given a random sequence of short anesthetic infusions with methohexital, ketamine, and propofol. Multiple blood samples were taken for measurement of the time course of the drug concentrations, and the electrocorticogram processed (approximate entropy, for propofol and methohexital and percentage high frequency time, for ketamine) to numerically quantify drug effect. Using the PK/PD method the t(1/2)K(eo) was 2.0 +/- 0.4 min for ketamine, 2.7 +/- 1.1 min for propofol, and was significantly shorter (0.3 +/- 0.1 min) for methohexital. PK/PD and the mass-balance methods did not differ in the times to peak effect. Both methods of calculating the delay in transfer of drug from arterial blood to brain give similar values. Methohexital crosses into the brain much faster than either propofol or ketamine.

Population pharmacokinetics and pharmacodynamics of short term etomidate infusion in healthy volunteers

Population pharmacokinetics and pharmacodynamics of short term etomidate infusion in healthy volunteers

A phase I study of bendamustine hydrochloride administered once every 3 weeks in patients with solid tumors

The present phase I trial was planned to assess the maximum tolerated dose, the dose-limiting toxicity and the pharmacokinetics of bendamustine hydrochloride in a once every 3 weeks schedule, and to recommend a safe dose for future phase II studies. Included were patients with refractory solid tumors. Bendamustine hydrochloride was administered as a short intravenous infusion over 30 min. The starting dose was defined at 160 mg/m2 and dose escalation used increments of 20 mg/m2. Plasma and urine samples were analyzed using validated high-pressure liquid chromatography/fluorescence assays. Twenty-six patients (14 men, 12 women) were enrolled for the study. At 280 mg/m2, one out of four patients developed a thrombocytopenia grade 4, two experienced grade 3 fatigue and three experienced cardiac toxicity (grade 2). The latter toxicity was considered dose limiting also and further dose escalation was stopped. Plasma pharmacokinetics parameters of bendamustine hydrochloride and its metabolites were assessed in 15 patients. Mean pharmacokinetic parameters of bendamustine hydrochloride were a tmax of 32.3 min, a t1/2 of 37.8 min, a volume of distribution of 14.2 l/m and a clearance of 287.8 ml/min/m2. No dose dependency of bendamustine hydrochloride was observed within the used dose range. The metabolites comprised only 23% of the overall area under the concentration-time curve. The maximum tolerated dose of bendamustine hydrochloride on day 1 q 3 weeks is 280 mg/m2. Fatigue and cardiac toxicity were dose limiting. The plasma pharmacokinetics data of bendamustine and its metabolites were in accordance with previous reports. The recommended dose for future trials is 260 mg/m2 every 3 weeks.

Intracisternal versus intracarotid infusion of L-arginine in experimental cerebral vasospasm

Aim The effect of short term intracisternal and intracarotid L-arginine infusion on experimental cerebral acute phase vasospasm in a rabbit subarachnoid haemorrhage model is investigated, and the two groups compared. Materials and Method Subarachnoid haemorrhage was produced by intracisternal injection of autologous blood in New Zealand rabbits. On the fourth day after subarachnoid haemorrhage, cerebral blood flow was monitored using transcranial Doppler ultrasonography during intracisternal and intracarotid saline and L-arginine infusions. Result Cerebral blood flow measurements revealed resolution of vasospasm with short-term intracisternal and intracarotid L-arginine infusion. No significant difference was found between the effects of intracisternal and intracarotid L-arginine infusions, however intracarotid L-arginine infusion created a more potent vasodilatation towards the end of infusion. Conclusion Both intracisternal and intracarotid short term L-arginine infusion significantly improve acute phase cerebral vasospasm after experimental subarachnoid haemorrhage. Intracarotid L-arginine infusion is more potent and safer as large amounts of intracisternal L-arginine may lead to overproduction of nitric oxide by inducible nitric oxide synthase with the production of free radicals.

Short duration testosterone infusions maintain male sex behavior in Syrian hamsters

In most mammalian species, reduced androgen availability is associated with marked reductions in male sexuality; conversely, androgen replacement in castrated males restores sex behavior within a few weeks. Testosterone (T) pulse duration, amplitude, frequency, and inter-pulse interval may be as important as total amount of hormone in determining target tissue responsiveness. We remain ignorant of the number and duration of daily T pulses necessary and sufficient to sustain male mating behavior. An in-dwelling infusion system was employed to vary T-pulse frequencies and durations. Daily 4 h infusions of aqueous T (100 μg/0.064 ml) and twice daily 4 h pulses of T (each 50 μg/0.064 ml) were sufficient to maintain ejaculatory behavior of sexually experienced castrated hamsters for 11 weeks post-castration; castrated hamsters infused with vehicle ceased to display the ejaculatory pattern 3 weeks after gonadectomy. Circulating T concentrations of hormone-infused hamsters declined markedly 7 h after the termination of each infusion. These results establish that male sex behavior can be sustained with infusions of relatively low T concentrations for 4 h/day and suggests that the basal concentrations of T sustained by the gonad during inter-pulse intervals may not be necessary for maintenance of sex behavior. 4 h T infusions were sufficient to maintain penile and seminal vesicles weights, but not ventral prostate weights or flank gland dimensions; the threshold for maintaining male sex behavior is lower than that for some androgen-dependent peripheral structures. Development of effective androgen replacement regimens that sustain sex behavior in castrated animals may be useful in the design of androgen replacement therapy for hypogonadal men.

A phase I study of bi-weekly administration of 24-h gemcitabine followed by 24-h irinotecan in patients with solid tumors

To determine the maximal tolerated doses (MTD) and dose-limiting toxicities (DLT) of combination of 24-h infusions of gemcitabine and irinotecan in patients with advanced solid tumors. Twenty-four patients with advanced solid tumors received gemcitabine as a 24-h IV infusion followed by a 24-h infusion of irinotecan every 2 weeks. Pharmacokinetic parameters of both drugs and their metabolites were estimated by using non-compartmental methods. Twenty-four patients were fully evaluable for toxicity. DLT was observed in two of six patients at irinotecan/gemcitabine 110/150 mg/m(2) (grade 3 diarrhea and grade 3 GI bleeding). No patient developed acute cholinergic symptoms at any dose. Other toxicities were < or =grade 2 nausea, vomiting, and fatigue. Tumor responses were observed in three patients (one CR: cholangiocarcinoma; two PR: SCLC, gastric neuroendocrine tumor). Stable disease >3 months was found in six patients including five patients who had failed short infusions of either drug. Pharmacokinetic analysis showed that C (max) of each drug and active metabolites were dose-dependent. High dose of gemcitabine increased C (max), AUC, and T(1/2) of irinotecan. However, gemcitabine had minimal effects on SN-38. The recommended dose for Phase II studies is gemcitabine 125 mg/m(2) given as a 24-h IV infusion on D1 and D15, followed by a 24-h IV infusion of irinotecan 110 mg/m(2) on D2 and D16. Both pretreated patients and chemo-naive patients seem to tolerate higher doses of this combination without significant toxicities. Objective responses among patients with solid tumors, in particular cholangiocarcinoma and small cell lung cancer merits further investigation.

A Comparison of the Haemodynamic Effects of 4% Succinylated Gelatin, 6% Hydroxyethyl Starch (200/0.5) and 4% Human Albumin after Cardiac Surgery

The goal for volume replacement therapy is to maintain stable haemodynamics after cardiac surgery. We hypothesized that a short term infusion of hydroxyethyl starch results in better haemodynamic response than an infusion of lower molecular weight gelatin. 45 patients received a predetermined fixed dose of 15 ml kg(-1) of either 4% succinylated gelatin (GEL) or 6% hydroxyethyl starch (HES) or 4% human albumin (HA) after cardiac surgery. Pulmonary capillary wedge pressure was more increased in GEL and HES groups [mean (SD) 153% (54) and 168% (57) of pre-infusion value] than in HA group [122% (23)] (P = 0.031) after completion of infusion, but no differences in cardiac index (CI) and stroke volume index (SVI) were observed. At 2 and 18 hours after end of study infusions SVI was more increased in HES [143% (38) and 148% (41) of pre-infusion values] and HA [143% (35) and 163% (42) of pre-infusion values] groups than in GEL [116% (23) and 125% (30)] group (P = 0.047 at 2 hours and P = 0.033 at 18 hours). In early postoperative phase after cardiac surgery, HES and HA infusions improve haemodynamics more and longer period than GEL infusion.

Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients

To develop a population pharmacokinetic model for melphalan in children with malignant diseases and to evaluate limited sampling strategies for melphalan. Melphalan concentration data following a single intravenous dose were collected from 59 children with malignant diseases aged between 0.3 and 18 years. The data were split into two sets: the model development dataset (39 children, 571 concentration observations) and the model validation dataset (20 children, 277 concentration observations). Population pharmacokinetic modelling was performed with the NONMEM software. Stepwise multiple linear regression was used to develop a limited sampling model for melphalan. A two-compartment model was fitted to the concentration-vs.-time data. The following covariate population pharmacokinetic models were obtained: (i) Clearance (l h(-1)) = 0.34.WT - 3.17.CPT + 0.0377.GFR, where WT = weight (kg), CPT = prior carboplatin therapy (0 = no, 1 = yes), and GFR = glomerular filtration rate (ml min(-1) 1.73 m(-2)); (ii) Volume of distribution (l) = 1.12 + 0.178.WT. Interpatient variability (coefficient of variation) was 27.3% for clearance and 33.8% for volume of distribution. There was insignificant bias and imprecision between observed and model-predicted melphalan concentrations in the validation dataset. A three-sample limited sampling model was developed which adequately predicted the area under the concentration-time curve (AUC) in the development and validation datasets. A population pharmacokinetic model for melphalan has been developed and validated and may now be used in conjunction with pharmacodynamic data to develop safe and effective dosing guidelines in children with malignant diseases.

Population Pharmacokinetics and Proton Pump Inhibitory Effects of Intravenous Lansoprazole in Healthy Japanese Males

A total of 56 healthy Japanese males were enrolled in single- or multiple- dose pharmacokinetic trials of intravenous lansoprazole administration. The population pharmacokinetics of the drug was evaluated using nonlinear mixed effects model (NONMEM) software. In addition, the effect of CYP2C19 polymorphism on proton pump inhibition by lansoprazole was investigated using 24-h intragastric pH monitoring in the 32 subjects. Time course of serum lansoprazole concentration following intravenous short infusion was well described by a 2-compartment model. The mean volume of the central and peripheral compartments was 0.110 and 0.201 l/kg, respectively. The mean inter-compartment clearance was estimated to be 0.0882 l/h/kg. The population mean value of systemic clearance in the homoEM (CYP2C19 1/ 1), heteroEM (CYP2C19 1/2 and 1/3), and PM (CYP2C19 2/2, 2/3, and 3/3) groups was 0.179, 0.109, and 0.038 l/h/kg, respectively. The mean intragastric pH following twice-daily doses of 30 mg lansoprazole was approximately 6, 5, and 4 in the PM, heteroEM, and homoEM groups, respectively. These findings indicate that large interindividual variability exists in the pharmacokinetics of intravenously administered lansoprazole, but that twice-daily infusion of a 30 mg dose leads to significant and sustained proton pump inhibition, even in the homoEM group, despite the short elimination half-life of the drug.

Plasma and cerebrospinal fluid pharmacokinetics of intravenously administered ABT-751 in non-human primates

ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine binding site on beta-tubulin and inhibits microtubule polymerization. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of ABT-751, after a short intravenous infusion, were evaluated in a non-human primate (Macaca mulatta) model that is highly predictive of the CSF penetration of drugs in humans. Plasma and CSF samples were collected over 24 h after 7.5 mg/kg (150 mg/m2) ABT-751 infused over 0.25-0.70 h, and ABT-751 concentrations in plasma and CSF were quantified using a validated HPLC-MS/MS assay. Pharmacokinetic parameters in plasma and CSF were derived using non-compartmental methods. Plasma disappearance was bi-exponential with a terminal half-life of 13 h. The mean +/- SD clearance was 100 +/- 18 ml/min m2, the mean +/- SD volume of distribution at steady state was 1.3 +/- 0.5 l/kg, and the mean +/- SD mean residence time was 4.6 +/- 1.8 h. The mean +/- SD peak ABT-751 concentration in CSF was 0.26 +/- 0.08 microM, and the mean +/- SD CSF half-life of 1.3 +/- 0.3 h. CSF penetration was limited (mean +/- SD AUC(CSF):AUC(plasma), 1.1 +/- 0.3%) relative to total (protein-bound + free) plasma drug concentrations, but the CSF concentrations approximated the estimated free drug concentrations in plasma.

Subacute cardiotoxicity caused by anthracycline therapy in children: can dexrazoxane prevent this effect?

Anthracyclines are potent cytostatic drugs, but their use may be limited by cardiac toxicity. In the study reported here, we investigated the incidence and outcome of anthracycline-induced cardiotoxicity and the possible preventive role of dexrazoxane. A total of 108 patients with the diagnosis of osteosarcoma, Ewing-sarcoma, soft tissue sarcoma and leukemia were studied between 1991 and 2003. Of these, 41 children (treated from 1996) received dexrazoxane (Group D) as chemotherapy from the beginning of their treatment (mean follow-up: 8.2±3.9 years). The dose of dexrazoxane was 20-fold higher than the anthracycline dose and was administered as a 20-min sodium-lactate infusion. The control (Group C) cohort comprised 67 children (all treated before 1996) who did not receive any cardioprotection (mean follow-up: 12.3±3.2 years). All patients in the C and D groups received anthracyclines in the form of short infusions (1–3 h). The cumulative dose of anthracycline did not differ between the two groups (Table 1). Supportive treatment did not change during the investigated period. Cardiac ultrasound examinations were performed regularly, and fractional shortening (FS) for detecting left ventricular function was measured. The incidence of acute cardiotoxicity was 13.4% in Group C patients and 7.3% in Group D patients, a nonsignificant difference. Cardiac function, expressed as FS, was abnormally low (<30%) 2 years after therapy in 13.7% of the Group C patients and in 0% of the Group D patients (p=0.034) (Fig. 1a) and was still abnormally low 3 years after therapy in 19.3% of the Group C patients and 0% of the Group D patients (p=0.008) (Fig. 1b). At the 5year follow-up, FS was under 30% in 14.9% of the Group C patients and 2.4% of the Group D patients (Fig. 1c). Seven patients in Group C needed heart-protective drugs (digitalis, furosemide, angiotensine converting enzyme inhibitors) for congestive heart failure for at least 6 months. Only one patient in Group D received cardiac drugs. Dilatative cardiomyopathy is a severe complication of anthracycline therapy, and even in children, lower cumulative doses (<300 mg/m 2 ) may cause irreversible congestive heart failure [3]. The incidence of slight cardiotoxicity has been reported to vary between 12 and 32% and mortality or severe dysfunction to vary between 2 and 7%, depending

Neonatal Infusion Therapy: Preventing Complications and Improving Outcomes

Infusion therapy is one of the most common procedures performed in the hospitalized patient. Particularly in the neonatal intensive care unit, almost 100% of the patients receive infusion therapy. The process becomes very routine and many patients do not suffer obvious complications. However, some complications are very common and often accepted as part of the treatment. There are measures that can help to decrease the incidence or seriousness of these complications. This article will focus on the process of initiation and maintenance of short peripheral infusion therapy, the most common type administered. Common complications and how they may be prevented or minimized in the neonatal patient are presented. Standards and guidelines currently in place are discussed as they apply to the neonatal population.

Rituximab-Relapsing Patients with Non-Hodgkins Lymphoma Respond Even at Lower Doses of Humanized Anti-CD20 Antibody, IMMU-106 (hA20): Phase I/II Results.

Background: An open-label, multicenter, dose-escalation study in patients with recurrent NHL was initially undertaken to establish the safety, tolerance, PK, and immunogenicity (HAHA) of humanized anti-CD20 antibody, IMMU-106 (hA20), administered once-weekly for 4 weeks at different doses. Additional patients have now been entered to confirm the efficacy of 120 and 375 mg/m2 dosing, and to determine the feasibility of using even lower hA20 doses.Methods: A total of 55 patients (23 male, 32 female; 51 Caucasian; 40–84 years old) received hA20 at 120 (N=21), 200 (N=6), 375 (N=25) or 750 mg/m2 (N=3). They had follicular (FL, N=37) or other (N=18) B-cell lymphomas, were predominantly stage III/IV (N=44) at study entry, and had received 1–7 prior treatments (median, 2), including 1 (N=34) or more (N=14) rituximab regimens (without progression within 6 months).Results: Fifty-two patients completed all 4 infusions, 2 are currently being treated, and one patient with hives and chills after prior rituximab discontinued treatment after similar NCI CTC v.3 grade 1–2 reactions at 1st hA20 infusion. hA20 was generally well tolerated with a median infusion time at the lowest dose of 120 mg/m2 of 2.2 h for 1st infusion and 1.2 h for subsequent infusions. Twenty-one patients had drug-related adverse events; these were all transient, mild-to-moderate (Grade 1–2) events, most occurring only at first infusion. No consistent pattern of abnormal laboratory changes occurred, and there was no evidence of immunogenicity in 29 patients now evaluated for HAHA. Mean antibody serum levels increased with dose and with repeated infusions, and limited post-treatment data indicate the serum clearance at 375 mg/m2 dosing is similar to rituximab. Even at 120 mg/m2, peripheral blood B-cell depletion occurred after the first infusion and persists after 4th infusion, with analysis continuing > 6 mo. Thirty-nine patients with at least 12 wks follow-up had one or more responses evaluated by Cheson criteria (Table), with all CR/CRu occurring in follicular lymphoma except for one patient with marginal zone lymphoma; 6 pts progressed by week 4. Of 18 pts with OR's, 9 have continuing responses (median follow-up, 9 mos post-treatment), including 4 with long-lived responses (12–18 mos).Conclusions: hA20 is well tolerated, with no evidence of significant toxicity or pattern of adverse events other than minor infusion reactions, even at short infusion times. All dose levels studied so far, including the lowest dose of 120 mg/m2, resulted in B-cell depletion and objective responses (including CR/CRu), with no clear-cut evidence of dose response in efficacy. As such, further dose de-escalation is ongoing.Treatment ResponsehA20 DoseORCR/CRuAll patients (n = 39)46% (18/39)21% (8/39)120 mg/m2 (n = 11)36% (4/11)27% (3/11)200 mg/m2 (n = 6)67% (4/6)33% (2/6)375 mg/m2 (n =19)42% (8/19)11% (2/19)750 mg/m2 (n = 3)67% (2/3)33% (1/3)