Objectives The objectives of this study were to investigate the population pharmacokinetics of posaconazole in immunocompromised children, evaluate the influence of patient characteristics on posaconazole exposure and perform simulations to recommend optimal starting doses. Methods Posaconazole plasma concentrations from paediatric patients undergoing therapeutic drug monitoring were extracted from a tertiary paediatric hospital database. These were merged with covariates collected from electronic sources and case-note reviews. An allometrically scaled population-pharmacokinetic model was developed to investigate the effect of tablet and suspension relative bioavailability, nonlinear bioavailability of suspension, followed by a step-wise covariate model building exercise to identify other important sources of variability. Results A total of 338 posaconazole plasma concentrations samples were taken from 117 children aged 5 months to 18 years. A one-compartment model was used, with tablet apparent clearance standardised to a 70-kg individual of 15 L/h. Suspension was found to have decreasing bioavailability with increasing dose; the estimated suspension dose to yield half the tablet bioavailability was 99 mg/m 2 . Diarrhoea and proton pump inhibitors were also associated with reduced suspension bioavailability. Conclusions In the largest population-pharmacokinetic study to date in children, we have found similar covariate effects to those seen in adults, but low bioavailability of suspension in patients with diarrhoea or those taking concurrent proton pump inhibitors, which may in particular limit the use of posaconazole in these patients. Key PointsPosaconazole is unlicensed for children under 13 years of age and its pharmacokinetics have not widely been reported in this population group; our study provides a large cohort in this age group receiving both tablets and an oral suspension A population-pharmacokinetic model has revealed saturable suspension bioavailability, and reduced bioavailability in patients taking proton pump inhibitors and those with diarrhoea Based on simulations from our model, dosing and therapeutic drug monitoring guidelines are provided
BackgroundWe previously described an endogamous Pakistani kindred in whom we identified a novel homozygous missense mutation in the PRKCD gene encoding for protein kinase C δ (PKCδ) as a cause of monogenic systemic lupus erythematosus (SLE). PKCδ has a role in the negative regulation of B cells. Given the nature of the disease, a logical targeted therapeutic approach in these patients is B cell depletion. Indeed, the 3 siblings all had a marked clinical response and resolution of symptoms with rituximab, although 2 of the siblings had severe reactions to rituximab thus precluding further treatment with this. We therefore describe the first successful use of ofatumumab for this rare form of monogenic SLE.Case presentationAll three affected siblings presented with SLE before the age of 3-years with lethargy, intermittent fever, thrombocytopenia, cutaneous involvement, alopecia, and hepatosplenomegaly. Tubulointerstitial nephritis was also present in 1 of the siblings. Homozygosity mapping followed by whole exome sequencing identified a homozygous missense mutation in PRKCD (p.Gly432Trp), subsequently confirmed by Sanger sequencing to be present in all 3 siblings. All 3 patients were initially treated with rituximab, however 2 of the siblings developed severe infusion-related reactions. For subsequent disease flare in these individuals we therefore used an alternative B cell depleting agent, ofatumumab (300 mg/1.73m2 on day 1; 700 mg/1.73m2 on day 15). This resulted in marked clinical improvement in both patients. To the best of our knowledge, this is the first report describing the successful use of ofatumumab for PKCδ deficiency.ConclusionsPKCδ deficiency causes a monogenic form of SLE which responds well to B cell depletion. Ofatumumab is also likely to have a therapeutic role for sporadic juvenile SLE (jSLE) patients intolerant of rituximab.
Aims Rituximab is a chimeric IgG‐1 monoclonal antibody that depletes B cells, aiding in the treatment of several conditions including autoimmune diseases. It is not licensed for use in children. This study aimed to quantify the B cell‐related pharmacodynamics of rituximab in children with autoimmune disease. Methods Routine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2 × 750 mg/m2 intravenous infusions of rituximab on days 1 and 15, or 4 × 375 mg/m2 infusions on days 1, 8, 15 and 22. Rituximab pharmacokinetics (PK) were not measured but CD19+ lymphocyte counts were taken before and after rituximab treatment. A dose–response model was constructed describing the life cycle of CD19+ lymphocytes, with rituximab assumed to increase the death rate. Rituximab effect was assumed to decay by first‐order kinetics. Results In total, 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (% relative standard error) of rituximab effect decay was 0.036 (22.7%) days−1 and CD19+ turnover was 0.02 (41%) days−1 corresponding to half‐lives of 19 and 35 days respectively. Rituximab increased CD19+ death rate 35‐fold, with methotrexate and cyclophosphamide associated with further increases. Simulations suggested that a single infusion of 750 mg/m2 provides similar 6‐month suppression of CD19+ lymphocytes to current dosing. Conclusions Rituximab pharmacodynamics (PD) in paediatric autoimmune diseases has been described. Compared with rituximab alone, the additional effect of methotrexate or cyclophosphamide was statistically significant but small.
Knowledge of the basic principles of parenteral nutrition is essential for any clinician working in paediatric and neonatal intensive care units. This article aims to give a brief review of the up-to-date recommendations for the paediatric population together with practical tips and considerations about current challenges and issues we believe are still open for debate, particularly with regard to neonates.
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