The role of population PK-PD modelling in paediatric clinical research

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child

Crusted (Norwegian) scabies in a patient with dystrophic epidermolysis bullosa

A 13-year-old girl with severe non-mutilating recessive dystrophic epidermolysis bullosa (EB) was admitted to hospital because of a Staphyloccus aureus sepsis, deterioration of her general condition and worsening of her sl;in disease, which itched severely, In addition to the blisters and erosions normally seen, she was covered from head to toe with scales and hyperkeratotic crusts. Despite intensive topical therapy, her skin condition did not improve significantly until scabies was detected. and treated 1 week after admission, Because of the huge number of mites found and the crusted appearance, a diagnosis of crusted (Norwegian) scabies was made. She was successfully treated with two doses of ivermectin orally and one application of lindane ointment. Permethrin cream was not tolerated. In this patient crusted scabies may have developed because of: (i) a modified host response due to malnourishment; (ii) inability to scratch because of the absence of fingernails; and (iii) abnormal scratching behaviour because of the vulnerability of EB skin, or a combination of these factors. Limited isolation measures were taken on admission and full measures were taken immediately after the diagnosis of crusted scabies was made. Prophylactic treatment of ward personnel was not undertaken. Fortunately, there was not an outbreak of scabies in the hospital

RAPID DETECTION OF RESPIRATORY VIRUSES USING MIXTURES OF MONOCLONAL-ANTIBODIES ON SHELL VIAL CULTURES

Eleven hundred and thirty-three clinical specimens submitted to the laboratory for diagnosis of respiratory virus infections were tested by direct immunofluorescence (DIF) for respiratory syncytial virus (RSV), by shell vial culture, and by conventional cell culture. The shell vial cultures were stained with 8 different monoclonal antibodies both 1 day and 3-7 days after inoculation. In order to limit the cost and the workload, mixtures of monoclonal antibodies were used. Coverslips with HEP-2 cells were incubated with a mixture of FITC-labeled monoclonal antibody to RSV and nonlabeled monoclonal antibody to adenovirus. When no RSV positive IF staining was observed after the first incubation step, the same coverslip was incubated once more with FITC-labeled anti-mouse antibody. A positive reaction at this stage indicated the presence of adenovirus. Similarly, cultures of tertiary monkey kidney cells were investigated with a mixture of two FITC-labeled monoclonals to the influenza viruses A and B and three nonlabeled monoclonals to the parainfluenza viruses 1, 2 and 3. If influenza virus or parainfluenza virus was detected, the exact type was determined by staining different parts of a duplicate coverslip. Shell vial cultures for cytomegalovirus (CMV) were always performed separately on human embryonic lung fibroblasts. Using this approach, we detected RSV (n = 248), CMV (n = 42), parainfluenza virus (n = 31), influenza virus (n = 28), and adenovirus (n = 6), in most cases after only one day of culture. For RSV, the sensitivity of the shell vial method was too low (74%) to allow omission of DIF (sensitivity 95%). For the other viruses, the "shell vial/monoclonal antibody mixture" approach was very attractive, being rapid, very specific (greater-than-or-equal-to 97%), and also very sensitive (probably >95%)