Translation strategy for the qualification of drug-induced vascular injury biomarkers.

Drug-induced vascular injury (DIVI) is a common preclinical toxicity usually characterized by hemorrhage, vascular endothelial and smooth muscle damage, and inflammation. DIVI findings can cause delays or termination of drug candidates due to low safety margins. The situation is complicated by the absence of sensitive, noninvasive biomarkers for monitoring vascular injury and the uncertain relevance to humans. The Safer And Faster Evidence-based Translation (SAFE-T) consortium is a public-private partnership funded within the European Commission's Innovative Medicines Initiative (IMI) aiming to accelerate drug development by qualifying biomarkers for drug-induced organ injuries, including DIVI. The group is using patients with vascular diseases that have key histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) in common with those observed in DIVI, and has selected candidate biomarkers associated with these features. Studied populations include healthy volunteers, patients with spontaneous vasculitides and other vascular disorders. Initial results from studies with healthy volunteers and patients with vasculitides show that a panel of biomarkers can successfully discriminate the population groups. The SAFE-T group plans to seek endorsement from health authorities (European Medicines Agency and Food and Drug Administration) to qualify the biomarkers for use in regulatory decision-making processes.

Pharmacokinetics and pharmacodynamics of a new formulation of recombinant human growth hormone administered by ZomaJet 2 Vision, a new needle-free device, compared to subcutaneous administration using a conventional syringe.

The objective of the present study was to investigate the applicability of a new human growth hormone (Zomacton) formulation, administered both by a conventional syringe and by a new needle-free device (ZomaJet 2 Vision). The study was performed according to a randomized, controlled, three-period crossover design. On 3 separate days, all subjects received in a random order a single subcutaneous injection of 1.67 mg hGH as follows: Zomacton 4 mg/ml conventional syringe administration (Treatment A), Zomacton 10 mg/ml conventional syringe administration (Treatment B), or Zomacton 10 mg/ml ZomaJet 2 Vision administration (Treatment C). The pharmacokinetic parameters were assessed for the individual subjects in each group by noncompartmental methods. Bioequivalence was assessed based on log-transformed AUC and C(max) values. To investigate the effectiveness of two formulations and the different administration methods, the pharmacodynamic parameters (insulin-like growth factor-1 [IGF-1] and free fatty acids [FFA]) were also evaluated. No subjects were withdrawn due to adverse events. The local tolerance assessment (assessed by inspection)revealed no differences between ZomaJet2 Vision application and conventional injections by syringe. Administration of the new hGH formulation by syringe was found to be bioequivalent with the reference treatment, both based on AUC and C(max) values; the new formulation administered by use of ZomaJet 2 Vision was found to be bioequivalent based on AUC values only. When using the ZomaJet 2 Vision, the absorption of hGH was faster, resulting in higher C(max) values. The maximum hGH serum concentration of around 20 ng/ml was observed 3.5 to 4 hours after drug administration. The terminal half-life was found to be around 2.5 hours. Comparison of the pharmacodynamic profiles (both IGF-1 and FFA) demonstrated bioequieffectiveness. These results support the use of jet injectors as a viable alternative to the traditional injection pens.

A generic operational strategy to qualify translational safety biomarkers.

The importance of using translational safety biomarkers that can predict, detect and monitor drug-induced toxicity during human trials is becoming increasingly recognized. However, suitable processes to qualify biomarkers in clinical studies have not yet been established. There is a need to define clear scientific guidelines to link biomarkers to clinical processes and clinical endpoints. To help define the operational approach for the qualification of safety biomarkers the IMI SAFE-T consortium has established a generic qualification strategy for new translational safety biomarkers that will allow early identification, assessment and management of drug-induced injuries throughout R&D.

Pharmacokinetics of tilidine and naloxone in patients with severe hepatic impairment.

The objective of the present study was to evaluate the pharmacokinetics of tilidine (CAS 20380-58-9), naloxone (CAS 465-65-6) and tilidine metabolites after administration of a single oral dose of a solution containing 100 mg tilidine hydrochloride and 8 mg naloxone hydrochloride (equivalent to 1.44 ml Valoron N solution) to patients with severe hepatic impairment. The investigation was carried out as an open single-dose study in 8 patients suffering from liver cirrhosis. Patients qualified for study enrollment if they had a Child-Pugh score of > or = 7 and a mono-ethyl-glycine-xylidide (MEGX) 15-min test value < 50 ng/ ml. Blood samples were taken over a period of 28 h and analyzed for the prodrug tilidine, its active metabolite nortilidine, bisnortilidine, and naloxone (total and non-glucuronidated fraction). Pharmacokinetic parameters were compared with data from a previous study performed in healthy volunteers. Tilidine, nortilidine and unconjugated naloxone pharmacokinetic parameters showed a high variability between patients. Compared to previous results obtained in healthy volunteers, maximum plasma concentration (Cmax) of nortilidine was reduced by 44%, whereas elimination half-life (t1/2) was prolonged by factor 2. The area under the curve (AUC) showed a slight reduction of approximately 20%. For total naloxone, no relevant change was observed. However, in contrast to the results obtained in healthy subjects, unconjugated naloxone could be measured in plasma from patients with cirrhosis, possibly due to a reduced glucuronidation capacity of the liver in these patients. In conclusion, severe hepatic impairment has a relatively minor influence on the exposure (AUC) to the active metabolite of tilidine (i.e., nortilidine). However, a straightforward interpretation of the results was confounded by pronounced variability in nortilidine pharmacokinetics. In individual patients with severely affected liver function, satisfactory analgesia with tilidine/naloxone oral solution might not be achieved because of insufficient formation of nortilidine and insufficient inactivation of naloxone.