Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first-in-human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 μg) [(14) C]-hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs.
BackgroundDrug disposition in children may vary from adults due to age-related variation in drug metabolism, but paediatric pharmacokinetic (PK) studies are challenging. Microdose studies present an innovation to study PK in paediatrics, and can only be used when the PK of a microdose are dose-linear to a therapeutic dose. We aimed to assess dose-linearity of [14C]midazolam (MDZ), a marker for the activity of the developmentally regulated CYP3A enzyme, by comparing the PK of an intravenous (IV) [14C]MDZ microtracer given simultaneously with therapeutic MDZ, with the PK of a single IV [14C]MDZ microdose.MethodsPreterm to 2-year-old infants admitted to the intensive care unit received [14C]MDZ IV either as a microtracer during therapeutic MDZ infusion or as an isolated microdose. Dense blood sampling was done up to 36 hours after dosing. Plasma concentrations of [14C]MDZ and [14C]1-OH-MDZ were determined by accelerator mass spectrometry. A population PK model was developed with NONMEM 7.4 to study whether there was a difference in the PK of the microtracer versus those of a microdose [14C]MDZ.ResultsOf fifteen children (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), nine received a microdose and six a microtracer [14C]MDZ (111 Bq/kg; 37.6 ng/kg). In a two-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the [14C]MDZ microdose or microtracer, suggesting the PK of MDZ to be linear within the range of the therapeutic doses and microdoses.ConclusionOur data supports the dose-linearity of an IV [14C]MDZ microdose in children, thus a [14C]MDZ microdosing approach can be used to study developmental changes in hepatic CYP3A activity.Disclosure(s)This project was funded by the ZonMw ERA-NET PRIOMEDCHILD programme (projectnumber 113205022). * both authors contributed equally
(SD 0.06) mmol/L, p = 0.001). There were no important adverse effects. However, accelerated failure time analysis showed a nonsignificantly shortened time to medical readiness for discharge of 14% favouring the magnesium sulfate group, OR=1.14, 95% CI 0.93 to 1.40, p = 0.20. Mean times until readiness for discharge were 14.6 h [SD 9.7] vs 15.6 h [SD 11.3] for the investigational and placebo groups, respectively, p = 0.9. Conclusions Adding nebulized magnesium sulfate to combined nebulized bronchodilator and systemic steroid therapy fails to provide evident benefit for patients with moderate or severe status asthamticus. Rationale Microdosing is a promising new method to obtain pharmacokinetic data in children with minimal burden and minimal risk. The use of a labelled oral microdose offers the added benefit to study intestinal and hepatic drug disposition in children already receiving an intravenous therapeutic drug dose for clinical reasons. Background and aim Preterm birth has been associated with myocardial remodelling, arrested vascular growth, higher blood pressure and ventricular hypertrophy later in life. The aim of this study was to evaluate arterial dimensions and intima media thickness in 6-year-old children born extremely preterm. Method Children born extremely preterm (EXP; <27 weeks of gestation) in Sweden 2004 to 2007 and matched controls born at term were included. The end-diastolic diameter of the abdominal aorta (AAD) and common carotid artery (CCAD) and carotid intima media thickness (CIMT) were determined by ultrasonography. Blood pressure, weight and height were also measured. Results EXP-children (n = 88; mean GA 25.1 w; BW 817 g) were significantly shorter than controls (mean heights 117.8 and 122.8 cm, p < 0.001). AAD was 8.8 mm in EXP and 8.9 mmin controls (n.s). CCAD was larger (5.5 mm) in EXP than in controls (5.2 mm; p < 0.01) after adjusting for body surface area (BSA). CIMT was 0.62 mm in EXP and 0.54 mm in controls (p < 0.001) adjusted for BSA. Unadjusted systolic blood pressure was 2.2 mmHg lower in EXP compared to controls (p < 0.05) but this difference disappeared after taking length into account. Conclusion The CCAD but not the AAD was significantly wider and the carotid intima media was thicker in 6-year-old children born extremely preterm as compared to age matched controls at term. O-203b EAP -Investigators PresentationsFurther vascular follow-up at older age is warranted and analyses of carotid strain using two dimensional speckle tracking are underway.Abstract O-203a Figure 2 Oral abstracts A102Arch Dis Child 2014;99(Suppl 2):A1-A620
Background and aims To examine the ethical, legal, and social implications (ELSI) of microdosing in exploratory paediatric research where there is exposure to background radiation and no therapeutic benefit to participants. Methods The ethical and regulatory issues encountered in the ERA-NET PRIOMEDCHILD project ‘Paediatric Accelerator Mass Spectrometry Evaluation Research Study (PAMPER)’ were analysed. These included the project design, scientific and ethical reviews, informed consent and recruitment processes. Infants 0–2 years were recruited in Estonia and the UK to study the pharmacokinetics (PK) of acetaminophen using accelerator mass spectrometry (AMS) bioanalysis. The study was considered in the context of the scientific, regulatory, and ethical frameworks guiding Phase 0 studies in adults and children. Results The science and ethics were developed in the protocol design and informed consent process, which resulted in approval of the study by research ethics committees in the UK and Estonia. Fifty-two babies were recruited into the study, with an acceptance rate of 50% among the parents approached. The study results demonstrated PK comparability between microdosing and therapeutic dosing in young children. Conclusions The PAMPER study showed the feasibility and validity of microdosing AMS PK studies in children, This methodology may provide a safer and more ethically robust approach for paediatric PK studies in certain drug models than more traditional PK study designs. The parameters and validation methods for microdosing AMS PK studies need to be reflected in regulatory guidance from the EMA, FDA and other authorities.
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