BMS-354825: a novel drug with potential for the treatment of imatinib-resistant chronic myeloid leukaemia

The BCR-ABL tyrosine kinase inhibitor imatinib has greatly improved the outcome for patients with chronic myeloid leukaemia (CML). Unfortunately, mutations causing resistance to imatinib are leading to relapses in some patients. In addition to inhibiting the wild-type BCR-ABL, BMS-354825 inhibited 14 of 15 BCR-ABL mutants. BMS-354825 treatment of immunodeficient mice prevented the progression of the disease in mice treated with the most clinical common imatinib-resistant mutant Met351Thr. The safety and efficacy of BMS-354825 is presently being evaluated in a phase I/II clinical trial in CML patients with imatinib resistance. The frequency of clinical use of SMS-3548125 in CML patients will depend on its efficacy/safety profile in clinical trial.

The population pharmacokinetics of citalopram after deliberate self-poisoning: A Bayesian approach

Defining the pharmacokinetics of drugs in overdose is complicated. Deliberate self-poisoning is generally impulsive and associated with poor accuracy in dose history. In addition, early blood samples are rarely collected to characterize the whole plasma-concentration time profile and the effect of decontamination on the pharmacokinetics is uncertain. The aim of this study was to explore a fully Bayesian methodology for population pharmacokinetic analysis of data that arose from deliberate self-poisoning with citalopram. Prior information on the pharmacokinetic parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses. The data set included concentration-time data from 53 patients studied after 63 citalopram overdose events (dose range: 20-1700 mg). Activated charcoal was administered between 0.5 and 4 h after 17 overdose events. The clinical investigator graded the veracity of the patients' dosing history on a 5-point ordinal scale. Inclusion of informative priors stabilised the pharmacokinetic model and the population mean values could be estimated well. There were no indications of non-linear clearance after excessive doses. The final model included an estimated uncertainty of the dose amount which in a simulation study was shown to not affect the model's ability to characterise the effects of activated charcoal. The effect of activated charcoal on clearance and bioavailability was pronounced and resulted in a 72% increase and 22% decrease, respectively. These findings suggest charcoal administration is potentially beneficial after citalopram overdose. The methodology explored seems promising for exploring the dose-exposure relationship in the toxicological settings.

Assessing cost-effectiveness of drug interventions for schizophrenia

Objective: To assess from a health sector perspective the incremental cost-effectiveness of eight drug treatment scenarios for established schizophrenia. Method: Using a standardized methodology, costs and outcomes are modelled over the lifetime of prevalent cases of schizophrenia in Australia in 2000. A two-stage approach to assessment of health benefit is used. The first stage involves a quantitative analysis based on disability-adjusted life years (DALYs) averted, using best available evidence. The robustness of results is tested using probabilistic uncertainty analysis. The second stage involves application of 'second filter' criteria (equity, strength of evidence, feasibility and acceptability) to allow broader concepts of benefit to be considered. Results: Replacing oral typicals with risperidone or olanzapine has an incremental cost-effectiveness ratio (ICER) of A$48 000 and A$92 000/DALY respectively. Switching from low-dose typicals to risperidone has an ICER of A$80 000. Giving risperidone to people experiencing side-effects on typicals is more cost-effective at A$20 000. Giving clozapine to people taking typicals, with the worst course of the disorder and either little or clear deterioration, is cost-effective at A$42 000 or A$23 000/DALY respectively. The least cost-effective intervention is to replace risperidone with olanzapine at A$160 000/DALY. Conclusions: Based on an A$50 000/DALY threshold, low-dose typical neuroleptics are indicated as the treatment of choice for established schizophrenia, with risperidone being reserved for those experiencing moderate to severe side-effects on typicals. The more expensive olanzapine should only be prescribed when risperidone is not clinically indicated. The high cost of risperidone and olanzapine relative to modest health gains underlie this conclusion. Earlier introduction of clozapine however, would be cost-effective. This work is limited by weaknesses in trials (lack of long-term efficacy data, quality of life and consumer satisfaction evidence) and the translation of effect size into a DALY change. Some stakeholders, including SANE Australia, argue the modest health gains reported in the literature do not adequately reflect perceptions by patients, clinicians and carers, of improved quality of life with these atypicals.

Monitoring salivary lamotrigine concentrations

Lamotrigine concentrations were measured simultaneously (as far as was feasible) in stimulated and unstimulated saliva samples, and in plasma, from seven adult volunteers over a 32 h period following a single 50 mg dose of the drug, and in 20 children and adolescents during the course of routine antiepileptic therapy. In individuals there was a close correlation between the measurements at least 2 It after ingestion of the drug. Concentrations in stimulated and unstimulated saliva were similar; the stimulation produced little change in the saliva secretion rate. The saliva-to-plasma concentration ratio increased linearly by 0.78% for each 1 mg/L plasma lamotrigine concentration, with a mean value of 48.8% at a plasma lamotrigine concentration of 10 mg/L. With appropriate precautions as to the timing of saliva collections, and a single plasma lamotrigine concentration measurement to calibrate the salivary values in the individual, salivary lamotrigine concentration measurement appears to be a practicable approach to therapeutic drug monitoring. This has significant implications for the elucidation of the pharmacokinetics of lamotrigine in the paediatric population.

A DHA14 drug efflux gene from Xanthomonas albilineans confers high-level albicidin antibiotic resistance in Escherichia coli

Aims: Identification of a gene for self-protection from the antibiotic-producing plant pathogen Xanthomonas albilineans, and functional testing by heterologous expression. Methods and Results: Albicidin antibiotics and phytotoxins are potent inhibitors of prokaryote DNA replication. A resistance gene (albF) isolated by shotgun cloning from the X. albilineans albicidin-biosynthesis region encodes a protein with typical features of DHA14 drug efflux pumps. Low-level expression of albF in Escherichia coli increased the MIC of albicidin 3000-fold, without affecting tsx-mediated albicidin uptake into the periplasm or resistance to other tested antibiotics. Bioinformatic analysis indicates more similarity to proteins involved in self-protection in polyketide-antibiotic-producing actinomycetes than to multi-drug resistance pumps in other Gram-negative bacteria. A complex promoter region may co-regulate albF with genes for hydrolases likely to be involved in albicidin activation or self-protection. Conclusions: AlbF is the first apparent single-component antibiotic-specific efflux pump from a Gram-negative antibiotic producer. It shows extraordinary efficiency as measured by resistance level conferred upon heterologous expression. Significance and Impact of the Study: Development of the clinical potential of albicidins as potent bactericidial antibiotics against diverse bacteria has been limited because of low yields in culture. Expression of albF with recently described albicidin-biosynthesis genes may enable large-scale production. Because albicidins are X. albilineans pathogenicity factors, interference with AlbF function is also an opportunity for control of the associated plant disease.

Optimal crossover designs for logistic regression models in pharmacodynamics

Pharmacodynamics (PD) is the study of the biochemical and physiological effects of drugs. The construction of optimal designs for dose-ranging trials with multiple periods is considered in this paper, where the outcome of the trial (the effect of the drug) is considered to be a binary response: the success or failure of a drug to bring about a particular change in the subject after a given amount of time. The carryover effect of each dose from one period to the next is assumed to be proportional to the direct effect. It is shown for a logistic regression model that the efficiency of optimal parallel (single-period) or crossover (two-period) design is substantially greater than a balanced design. The optimal designs are also shown to be robust to misspecification of the value of the parameters. Finally, the parallel and crossover designs are combined to provide the experimenter with greater flexibility.

Impact of mycophenolate mofetil loading on drug exposure in the early posttransplant period

Achieving adequate therapeutic levels of immunosuppressive medications is important in rejection prevention. This study examined exposure to mycophenolic acid (MPA) in kidney transplant patients within the first 5 days posttransplantation. Methods. This single-center, nonrandomized study of first solitary kidney allograft recipients receiving cyclosporine (n = 116) or tacrolimus (n = 50) included patients who received either 1 g or 1.5 g of mycophenolate mofetil twice daily starting postoperatively. Exposure to MPA was measured at days 3 and 5 posttransplant using published limited sampling time equations. Results. There were no significant differences in exposure in the cyclosporine-treated patients receiving 3-g (n = 22) compared to 2-g (n = 94) daily doses (AUC([0-12]) 33.8 +/- 10.0 mg*h/L versus 30.1 +/- 9.7 mg*h/L, P =.20, respectively). About half the patients in both groups had AUC([0-12]) < 30 mg*h/L on days 3 and 5 posttransplant. On the other hand, there was significantly greater exposure on day 3 in the tacrolimus-treated patients receiving 3 g (n = 21) compared to 2 g (n = 29) daily (AUC([0-12]) 43.1 +/- 9.0 mg*h/L versus 36.8 +/- 11.1 mg*h/L, P =.016, respectively). On day 3 one (4.8%) patient receiving 3 g had an AUC([0-12]) of < 30 mg*h/L; whereas, eight (27.5%) receiving 2 g were below this level (P =.068). The AUC([0-12]) levels were not different on day 5. Conclusions. Loading with higher doses of mycophenolate mofetil results in greater exposure and a trend toward more patients in the therapeutic window within the first week for tacrolimus- but not for cyclosporine-treated patients.