Aim and objectives The objective of this study was to perform a preliminary pharmacokinetic (PK) model of adalimumab to evaluate covariates potentially responsible for the PK variability in paediatric patients with IBD. Material and methods A 3 year retrospective multicentre study was performed including children and adolescent (£ 18 years) diagnosed with IBD and treated with adalimumab. Demographic and clinical data were collected, including serum albumin, C reactive protein and faecal calprotectin. Pre-dose serum samples were carried out before administration. Adalimumab concentrations and anti-adalimumab antibodies (AAA) were determined by ELISA. The model was developed in NONMEM V.7.4 by approximating the non-linear mixed effects models. The first order conditional estimation method with interaction (FOCEI) was used for model building. Concentrations below the lower limit of quantification (LLOQ) were set to LLOQ/2. Body weight (WGT) was included in the PK parameters following an allometric relationship. Results Twenty-three paediatric patients (10 women) were included, 3 were diagnosed with ulcerative colitis and 20 with Crohn disease. Median age (range) was 14.0 (5-18) years and weight 55.9 (20.4-80) kg. A total of 75 concentrations (2< LLOQ) were determined, with a medium concentration of 10.72 (0.1-24.7) mg/mL. Median (range) serum albumin level was 4.0 (2.8-5.0) g/dL. Only one patient developed AAA. Population PK model (PopPK): a one compartment with first order absorption and elimination described adequately the serum adalimumab concentration-time data. The absorption rate constant was fixed (Ka=0.008/hour) according to Sharma et al. Among the clinical variables analysed, only albumin was significant on the apparent clearance (CL/F). The final PopPK model in the absence of AAA was as defined as: V/ F=11.30×(WGT/56 kg) and CL/F (L/day)=0.42×(albumin/4 g/ dL)-2.32 × (WGT/56 kg) 0.75. Covariate analysis reduced the interindividual variability associated with CL (IIVCL) from 34.1% to 21.3%. Proportional residual error estimated was 28.4%. Conclusion and relevance Adalimumab PK in paediatric patients with IBD was best described by a one compartment model with first order absorption and elimination. WGT was included in the PK parameters following an allometric relationship. Albumin showed statistically significant differences on adalimumab CL/F, explaining 62.5% of its variability.
Aim and objectives The objective of this study was to describe the current status of clinical trials (CT) for AD in our hospital pharmacy service and to analyse the investigational drugs. Material and methods An observational descriptive retrospective study was carried out in a tertiary academic hospital. All active CT in the neuropsychology service from 1 January 2014 to 31 March 2019 were reviewed. Collected data were total number of CT; total number of included patients; demographic data; total number of CT classified by CT status (active/closed); clinical trial phase; therapeutic targets (reduction of amyloid plaques (AP)/precursor amyloid peptide (PAP) attack/inhibition of GLYT1 transporter/selective antagonism of 5-HT6 receptor/partial selective agonism of a 7 nicotinic receptor); administration route (oral/intravenous/subcutaneous); clinical trials with results; and type of result (positive/negative). Results Twelve CT were analysed involving a total of 59 patients (mean 5 patients per clinical trial (rank 0-8)), 34 (57.6%) women with a mean age of 77.4 years (95% CI 71.5-84.7). Six (50.0%) CT were active; 3 (25.0%) CT were phase II trials and 9 (75.0%) were phase III trials. Therapeutic targets were reduction in AP 5 (41.7%), attack of PAP 3 (25.0%), inhibition of GLYT1 transporter 1 (8.3%), selective antagonism of 5-HT6 receptor 2 (16.7%), partial selective agonism of a 7 nicotinic receptor 1 (8.3%); route of administration oral 7 (58.3%), intravenous 1 (8.3%) or subcutaneous 4 (33.3%); and 3 (25.0%) CT had results, all of which were negative (3 (100%)). Conclusion and relevance. The highest number of active CT were phase III trials.. Only 25% of CT had results and all were negative.. Almost 60% of CT studied oral administration, which was patients' preference.. There were a total of five therapeutic targets but more than 40% of the CT evaluated the reduction in APs.. Based on these results, we should rethink the research on Alzheimer's disease before continuing to develop clinical trials with the same therapeutic target.
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