The new generation of intravenous iron: chemistry, pharmacology, and toxicology of ferric carboxymaltose.

An ideal preparation for intravenous iron replacement therapy should balance effectiveness and safety. Compounds that release iron rapidly tend to cause toxicity, while large molecules can induce antibody formation and cause anaphylactic reactions. There is therefore a need for an intravenous iron preparation that delivers appropriate amounts of iron in a readily available form but with minimal side effects and thus with an excellent safety profile. In this paper, a review is given on the chemistry, pharmacology, and toxicology of ferric carboxymaltose (FCM, Ferinject), a stable and robust complex formulated as a colloidal solution with a physiological pH. The complex is gradually taken up mainly from the hepatic reticulo-endothelial system (RES), followed by effective delivery of iron to the endogeneous transport system for the haem synthesis in new erythrocytes, as shown in studies on the pharmacodynamics and pharmacokinetics with radio-labelled FCM. Studies with radio-labelled FCM also demonstrated a barrier function of the placenta and a low transfer of iron into the milk of lactating rats. Safety pharmacology studies indicated a favourable profile with regard to cardiovascular, central nervous, respiratory, and renal toxicity. A high maximum non-lethal dose was demonstrated in the single-dose toxicity studies. Furthermore, based on the No-Observed-Adverse-Effect-Levels (NOAELs) found in repeated-dose toxicity studies and on the cumulative doses administered, FCM has good safety margins. Reproductive and developmental toxicity studies did not reveal any direct or indirect harmful effects. No genotoxic potential was found in in vitro or in vivo studies. Moreover, antigenicity studies showed no cross-reactivity of FMC with anti-dextran antibodies and also suggested that FCM does not possess sensitizing potential. Lastly, no evidence of irritation was found in local tolerance studies with FCM. This excellent toxicity profile and the high effectiveness of FCM allow the administration of high doses as a single infusion or bolus injection, which will enhance the cost-effectiveness and convenience of iron replacement therapy. In conclusion, FCM has many of the characteristics of an ideal intravenous iron preparation.

Understanding and applying regulatory guidance on the nonclinical development of biotechnology-derived pharmaceuticals.

Biotechnology-derived pharmaceuticals are a well established and growing part of the therapeutic armamentarium. Beginning with recombinant versions of products such as insulin that were previously manufactured by extraction from animal and human sources, licensed biotechnology drugs and those in development now span an ever-increasing range of product types and therapeutic categories. As a consequence of this diversity, both general and product class-specific scientific guidelines have been developed on a regional (e.g. EU/US) or international (e.g. ICH - International Conference on Harmonization) basis. The current portfolio of nonclinical guidelines, particularly ICH S6, emphasizes flexibility and adaptability to the specific circumstances of the individual biotechnology product and its intended indication, taking into account factors not generally applicable to small-molecule drugs, such as pharmacodynamic responsiveness of safety and efficacy models, species specificity, and antibody formation. Guidelines developed principally with small-molecule drugs in mind may, nevertheless, have some applicability to biotechnology drugs on issues such as safety pharmacology, as well as on regulatory, procedural and dossier submission requirements. Scientific guidelines, such as those providing nonclinical guidance, are just one, albeit important, component of an increasingly complex legal/scientific environment in drug development.

Non-clinical development of cancer vaccines: regulatory considerations.

This paper discusses regulatory requirements essential during the non-clinical development of cancer vaccines. DNA vaccines and vaccines containing monoclonal antibodies are specifically addressed. ICH, CHMP, FDA, and WHO guidance documents in addition to scientific literature are reviewed and the regulatory framework, including respective EMEA and the FDA divisions responsible for review and assessment of cancer vaccines, is described. Selection criteria for an appropriate animal model for efficacy and/or toxicity studies are discussed.

Justification for routine screening of pharmaceutical products in immune function tests: a review of the recommendations of Putman et al. (2003).

In a recent publication by Putman et al. (2003), salmeterol, morphine/methadone and buprenorphine were quoted as examples of pharmaceutical drugs whose immunotoxicity has only been revealed by conduct of specific immune function tests in non-clinical studies. Review of the published non-clinical data for these drugs has shown that there is no clear evidence of immunotoxicity of salmeterol in these studies, and in addition, there are no clinical issues regarding adverse immunological effects of this drug. Of the opioid drugs, only very minor evidence of immunosuppression by morphine, and marginal evidence of slight immunostimulation by buprenorphine were detected in the non-clinical immune function assays performed at high doses. Methadone showed no effects on immune function assays in animals. As some immunomodulation by opioid drugs might have been expected based on the known pharmacological properties of this drug class, the marginal effects, or lack of effects observed in the immune function tests does raise a question about the sensitivity and specificity of the assays to detect clinically relevant changes. This review has suggested that, based on the cited examples, there is no strong case for routine non-clinical immune function testing of all new pharmaceutical products. A more rigorous evaluation of non-clinical immune function tests, and their ability to discriminate between clinically relevant and non-clinically relevant immunosuppression, is needed before definitive regulatory guidance in this area can be finalized.