Mario Del Tacca

In the past 20 years, an increased discrepancy between new available antibacterials and the emergence of multidrug-resistant strains has been observed. This condition concerns physicians involved in the treatment of central nervous system (CNS) infections, for which clinical and microbiological success depends on the rapid achievement of bactericidal concentrations. In order to accomplish this aim, the choice of drugs is based on their disposition toward the cerebrospinal fluid (CSF), which is influenced by the physicochemical characteristics of antibacterials. A reduced distribution into CSF has been documented for beta-lactams, especially cephalosporins and carbapenems, on the basis of their hydrophilic nature. However, they represent a cornerstone of the majority of combined therapeutic schemes for their ability to achieve bactericidal concentrations, especially in the presence of inflamed meninges. The good tolerability of beta-lactams makes possible high daily dose intensities, which may be associated with increased probability of cure. Furthermore, the adoption of continuous infusion seems to be a fruitful option. Fluoroquinolones, namely moxifloxacin, and antituberculosis drugs, together with the agents such as linezolid, reach the highest CSF/plasma concentration ratio, which is greater than 0.8, and for most of these drugs it is near 1. For all drugs that are currently used for the treatment of CNS infections, the evaluation of pharmacokinetic/pharmacodynamic parameters, on the basis of dosing regimens and their time-dependent or concentration-dependent pattern of bacterial killing, remains an important aspect of clinical investigation and medical practice.

The main goal of early phase trials is to gain knowledge about the clinical suitability of novel compounds, without pursuing specific therapeutic purposes. Healthy volunteers usually represent the ideal model for conducting phase I clinical trials, in order to investigate pharmacokinetics and pharmacodynamics as well as to document safety and tolerability without interference by concomitant pathological conditions. The increasing cost of novel drug development, in conjunction with ethical considerations, has fostered a new procedure for first-in-man trials, designated as “phase 0,” which is conducted very early on a limited number of healthy volunteers who are exposed to low drug levels. The present review discusses issues concerning the enrollment of healthy volunteers in the early phase of drug development from different points of view, with some focus on the Italian experience. From the ethical standpoint, much discussion revolves around payments to healthy volunteers. Most authors agree that an adequate remuneration must be provided to healthy subjects, while avoiding coercion and excessive psychological pressure. Pending the lack of international and national guidelines, our center for clinical drug experimentation has implemented an operative procedure to estimate payments for healthy volunteers based on specific items, including restriction, time spent, discomfort, and risk. Other unresolved issues about the recruitment of healthy volunteers are represented by the lack of international consensus on the definition of healthy status and the need for guidelines about advertisement on clinical trials addressed to potential participants.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Generic medicinal products are ‘copies’ of patented drugs and can be marketed at low cost following patent expiration of the brand‐name preparations.• Although the development of generic medicinal products is regulated by specific guidelines, a number of issues and concerns continue to undermine the confidence of physicians and patients in generic drugs. WHAT THIS STUDY ADDS • The present findings open interesting perspectives for the discussion of the quality of generic drugs in the postmarketing setting.• In particular, our trial shows that postmarketing evaluation of bioequivalence between branded amoxicillin and its generic copies might result in lack of interchangeability.AIMS: There are concerns about the quality of generic drugs in the postmarketing setting. The aim was to establish whether two generic formulations of amoxicillin, available on the Italian market, fulfil the criteria for clinical pharmacokinetic bioequivalence vs. the branded drug.METHODS: Two generic amoxicillin products (generic A and B) were selected among four fast‐release tablet formulations available on the Italian market. Twenty‐four healthy adult volunteers of either sex participated to a single‐dose, randomized, three‐treatment, crossover, single‐blind bioequivalence study designed to compare generic A and B with branded amoxicillin. Plasma samples were collected at preset times for 24 h after dosing, and assayed for amoxicillin levels by high‐performance liquid chromatography.RESULTS: Ninety percent confidence intervals of AUC ratios were 0.8238, 1.0502 (ratio 0.9302) and 0.8116, 1.1007 (ratio 0.9452) for generic A and B vs. branded amoxicillin, respectively. Ninety percent confidence intervals of C_max ratios were 0.7921, 1.0134 (ratio 0.8960) and 0.8246, 1.1199 (ratio 0.9610) for generic A and B vs. branded amoxicillin, respectively. The mean pharmacokinetic profiles showed that the AUC value of branded amoxicillin was 8.5 and 5.4% greater than that estimated for generic A and B, respectively. Few adverse events were recorded; these were not serious and occurred without apparent relationship to any specific amoxicillin formulation.CONCLUSIONS: These results indicate that one of the two marketed amoxicillin generics analysed in the present study is not bioequivalent to the brand leader product for C_max on the basis of single‐dose pharmacokinetic assessment.

Biliary tract carcinoma (BTC) is a rare highly malignant neoplasia. Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross-complementing group-1 (ERCC1) and X-ray repair cross complementing group 1 (XRCC1) genes were evaluated and correlated with clinical outcome. Thirty-three patients with BTC were treated with intravenous or intra-arterial cisplatin and epirubicin and oral capecitabine. The ERCC1-C118T, XPD-Asp312Asn, XPD-Lys751Gln and XRCC1-Arg399Gln polymorphisms were studied. A partial response (PR) occurred in 6 patients. The median progression-free (PFS) and overall survival (OS) were 4.8 and 18.9 months, respectively. No significant correlations were observed between response, PFS and OS in patients grouped according to all the studied polymorphisms. The analysis of survival starting from diagnosis resulted in a significant association of the XRCC1-Arg399Arg variant with a shorter survival. A role of the XRCC1-Arg399Gln polymorphism as a possible prognostic factor in patients affected by BTC is suggested.