Population pharmacokinetics of NNZ-2566 in healthy subjects

NNZ-2566 is a novel, small molecule being developed as a treatment for cognitive impairment in different CNS conditions, including Rett and Fragile-X syndrome, both of which are associated with moderate to severe neurodevelopmental disorder. In current study we characterise the population pharmacokinetics of NNZ-2566 after administration of single and repeated ascending doses to healthy subjects. A meta-analytical approach was used to analyse pharmacokinetic data from 3 different studies, in which a total of 61 healthy subjects (median age 23years, range 19 to 38) were treated with NNZ-2566. Doses of NNZ-2566 ranged from 6.0 to 100mg/kg after oral administration and from 0.1 to 30mg/kg after intravenous administration. A two-compartment model with first order absorption and elimination was found to best describe the pharmacokinetics of NNZ-2566. Inter-individual variability was identified in clearance, absorption rate, central volume of distribution, peripheral volume of distribution and inter-compartmental clearance. Population predicted clearance and central volume of distribution were 10.35L/h and 20.23L, respectively. No accumulation, metabolic inhibition or induction was observed during the course of treatment. Dose proportionality was observed across the dose range evaluated in healthy subjects. In addition, oral bioavailability appeared to vary with food intake. The relatively short half-life of 1.4h suggests the need for a twice or three times daily regimen to maintain relevant systemic levels of NNZ-2566 in plasma

Population pharmacokinetics of raxibacumab in healthy adult subjects

AIM: Raxibacumab is a fully humanized monoclonal antibody that blocks the interaction of Bacillus anthracis toxins, thereby protecting target cells from its effects. Raxibacumab is approved in the USA for the treatment of adults and children with inhalational anthrax in combination with antibiotics, and for prophylaxis of inhalational anthrax. The aim of this investigation was to characterise the population pharmacokinetics and assess the effect of baseline demographic covariates on the disposition of raxibacumab. METHODS: The data used for this analysis were obtained from 3 clinical trials and include 2229 blood samples from 322 healthy subjects who were randomized to receive a 40 mg/kg intravenous dose of raxibacumab over a period of 2.25 hours. Population pharmacokinetic modelling was performed using a nonlinear mixed effects approach. Secondary parameters of interest were the area under the curve, maximum concentration and the time of serum raxibacumab concentrations greater than or equimolar to the highest serum protective antigen concentrations observed for at least 28 days in any monkey challenged with B. anthracis that died. RESULT: Raxibacumab exposure in healthy subjects was described by a 2-compartment model. Inter-individual variability (IIV) was estimated for all model parameters, whilst residual variability was described by a proportional and additive error model. Weight was the only influential covariate with significant effect on disposition parameters. CONCLUSION: A dose of 40 mg/kg provided comparable exposure across the overall healthy subject population. IIV in raxibacumab versus time profiles could partially be accounted for by differences in body weight

Extrapolation and dosing recommendations for raxibacumab in children from birth to < 18 years of age

AIM: The US Food and Drug Administration's Animal Rule allows for the approval of drugs when human efficacy studies are not ethical. While the therapeutic doses of raxibacumab, a monoclonal antibody for the prophylaxis and treatment of inhalational anthrax, have been based on pharmacokinetic data from adult subjects, its disposition in children has not been evaluated in clinical trials. Here we evaluate the effect of demographic covariates on the pharmacokinetic disposition of raxibacumab and explore opportunities for the optimization of the paediatric doses. METHODS: A population pharmacokinetic model was used as basis for the extrapolation of raxibacumab disposition from adults to children. Different extrapolation scenarios, including weight-banded dosing regimens, were considered to assess the effect of growth and maturation processes on the pharmacokinetic parameters of interest. AUC, Cmax , and the time of serum raxibacumab concentrations greater than or equimolar to the highest serum protective antigen concentrations observed for at least 28 days in any monkey challenged with Bacillus anthracis that died were derived and compared with the currently approved US doses. RESULTS: Based on practical considerations, a weight-banded dosing regimen consisting of four dose levels (75 mg/kg for individuals ≤ 1.5 kg, 55 mg/kg for individuals 50 kg) was necessary to optimize target exposure across the paediatric population. CONCLUSION: Age-related maturation processes may affect raxibacumab clearance in young patients. The proposed dosing regimens take into account effects of body weight and maturation processes on the elimination of raxibacumab