A randomised controlled trial of a novel tramadol chewable tablet: pharmacokinetics and tolerability in children.

Tramadol is a bitter atypical opioid analgesic drug and is prescribed to treat postoperative pain in children. However, in many countries there is no licensed paediatric tramadol formulation available. We have formulated a novel chewable chocolate-based drug delivery system for the administration of tramadol to children. This pilot, single-centre, open-label, randomised clinical study assessed the taste tolerability and comparative population pharmacokinetics of the novel tramadol chewable tablet against a compounded tramadol hydrochloride oral liquid, at a dose of 1 mg.kg-1 . A 5-point facial hedonic scale was used by the children, parents and nurses to assess tolerability. One hundred and forty-one children aged 3-16 years were given tramadol 30 min before general anaesthesia. Blood samples were taken following the induction of anaesthesia and for up to 5 h following tramadol administration. Tramadol and its active metabolite O-desmethyltramadol were analysed using reversed-phase high-performance liquid chromatography. A population pharmacokinetic model was built using non-linear mixed effects modelling. The relative bioavailability for the tablet was 1.25 times higher (95%CI 1.16-1.35) than for tramadol hydrochloride oral liquid, while the absorption rate constant for the tablet was significantly lower (1.97 h-1 vs. 3.34 h-1 , p < 0.001). Larger inter-individual variability in absorption rates were observed with the liquid tramadol. The tramadol chewable tablet was more acceptable in taste to children when assessed by the children, parents and nurses (all p < 0.001). We conclude that the novel tramadol chewable tablet has favourable acceptability and more reliable relative bioavailability in children compared with tramadol hydrochloride oral liquid.

HPLC-UV assay of tramadol and O-desmethyltramadol in human plasma containing other drugs potentially co-administered to participants in a paediatric population pharmacokinetic study.

Multimodal analgesia is employed in paediatric pain management to maximise analgesia and minimise side effects. Tramadol is dosed at 1-1.5 mg/kg to treat severe pain in children but the assay for tramadol in plasma samples for pharmacokinetic and toxicology studies does not often consider concurrently administered medications. In this study we developed and validated an HPLC-UV method to quantify tramadol and its main metabolite (O-desmethyltramadol) in human plasma in the presence of seven potentially interfering drugs. Sample preparation method was developed by combining liquid-liquid extraction and protein precipitation. Chromatographic separation was achieved on a BDS-Hypersil-C18 column (5 µm, 250 × 4.6 mm) using a double gradient method. The limit of quantification was 6.7 ng/ml for both tramadol and ODT. The precision and accuracy were in compliance with ICH guidelines. This method was successfully employed to analyse the blood samples of 137 paediatric participants in a tramadol pharmacokinetic trial.

A novel, palatable paediatric oral formulation of midazolam: pharmacokinetics, tolerability, efficacy and safety.

Midazolam is one of many bitter drugs where provision of a suitable oral paediatric formulation, particularly in the pre-anaesthetic setting, remains a challenge. To overcome this problem, a novel chocolate-based tablet formulation has been developed with positive pre-clinical results. To further investigate the potential of this formulation, 150 children aged 3-16 years who were prescribed midazolam as a premedication were randomly assigned to receive 0.5 mg.kg-1 either as the novel formulation or an intravenous solution given orally, which is the current standard at our institution. Tolerability was assessed by each child, parent and nurse using a 5-point facial hedonic scale and efficacy was determined as the time to onset of sedation. Blood samples for midazolam and 1-hydroxymidazolam levels were analysed using high-performance liquid chromatography. Population pharmacokinetics were evaluated using non-linear mixed effects modelling. The novel formulation had significantly improved tolerability scores from children, parents and nurses (all p < 0.001). Time to effect was not different between the groups (p = 0.140). The pharmacokinetics of midazolam and 1-hydroxymidazolam were able to be modelled simultaneously. The novel formulation was subject to a higher estimated first-pass metabolism compared with the intravenous solution (8.6% vs. 5.0%) and a significantly lower relative bioavailability of 82.1% (p = 0.013), with no other significant differences. Exposure relative to dose was in the range previously reported for midazolam syrup. We conclude that the novel chocolate-based formulation of midazolam provides improved tolerability while remaining efficacious with suitable pharmacokinetics when used as a premedicant for children.

Caspase-8 activation by TRAIL monotherapy predicts responses to IAPi and TRAIL combination treatment in breast cancer cell lines.

The discovery of cancer cell-selective tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis generated broad excitement and development of TRAIL receptor agonists (TRA) as potential cancer therapy. Studies demonstrating the synergistic combination effect of SMAC mimetics and TRA further suggested potentially effective treatment in multiple tumour settings. However, predictive biomarkers allowing identification of patients that could respond to treatment are lacking. Here, we described a high throughput combination screen conducted across a panel of 31 breast cancer cell lines in which we observed highly synergistic activity between TRAIL and the inhibitors of apoptosis proteins (IAP) inhibitor (IAPi) AZD5582 in ~30% of cell lines. We detected no difference in the expression levels of the IAPi or TRAIL-targeted proteins or common modulators of the apoptotic pathway between the sensitive and resistant cell lines. Synergistic combination effect of AZD5582 and TRAIL correlated with sensitivity to TRAIL, but not to AZD5582 as a single agent. TRAIL treatment led to significantly greater activity of Caspase-8 in sensitive than in resistant cell lines (P=0.002). The majority (12/14) of AZD5582+TRAIL-resistant cell lines retained a functional cell death pathway, as they were sensitive to AZD5582+TNFα combination treatment. This suggested that failure of the TRAIL receptor complex to transduce the death signal to Caspase-8 underlies AZD5582+TRAIL resistance. We developed a 3D spheroid assay and demonstrated its suitability for the ex vivo analysis of the Caspase-8 activity as a predictive biomarker. Altogether, our study demonstrated a link between the functionality of the TRAIL receptor pathway and the synergistic activity of the IAPi+TRA combination treatment. It also provided a rationale for development of the Caspase-8 activity assay as a functional predictive biomarker that could allow better prediction of the response to IAPi+TRA-based therapies than the analysis of expression levels of protein biomarkers.