Is generic rifaximin still a poorly absorbed antibiotic? A comparison of branded and generic formulations in healthy volunteers.

Rifaximin is an antibiotic, locally acting in the gastrointestinal tract, which may exist in different crystal as well as amorphous forms. The branded rifaximin formulation contains the polymorph rifaximin-α, whose systemic bioavailability is very limited. This study was performed to compare the pharmacokinetics of this formulation with that of a generic product, whose composition in terms of solid state forms of the active pharmaceutical ingredient was found to be different.

Development steps of pharmacokinetics: a perspective on bioanalytical methods and bioequivalence.

This paper describes the main development steps of pharmacokinetics that paralleled the development of analytical bioassay methods. From the first stirrings on 1950s, with very sensitive but not specific radiotracing measurements using 14C or 3H labelled drugs, to further developments with more specific methods like gas chromatography, high pressure liquid chromatography, to the last achievement with tandem mass spectrometry, pharmacokinetics has supported all the development procedures of both NDA (New Drug Application) and ANDA (Abridged New Drug Application). The discovery of new therapeutic active molecules is now concentrated in a few very big companies, and requires pharmacokinetic support from the first screening procedures to the last clinical developments.

Tandem mass spectrometry (LC-MS-MS): a predominant role in bioassays for pharmacokinetic studies.

Plasma concentrations of drugs and drug metabolites in bioavailability studies are routinely bioassayed with high performance liquid chromatography (HPLC), gas chromatography (GC), and liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) methods. In the 1980s and 1990s, HPLC had achieved a relevant role compared to GC and other techniques in pharmacokinetic bioassays. However, in the last few years the LC-MS-MS technique, known as tandem mass spectrometry, has attained a predominant role over all other techniques.

Endoscopic evaluation of the effects of indobufen and aspirin in healthy volunteers.

This is an outcomes pharmacodynamic study using Nonsteroidal antiinflammatory agents, particularly acetylsalicylic acid (ASA), have been shown useful in various cardiovascular disorders, but they can be a major cause of iatrogenic gastrointestinal injury. Newer NSAIDs such as indobufen, an inhibitor of platelet aggregation that acts by reversibly inhibiting the platelet cyclooxygenase enzyme, have proven to be as effective as the older NSAIDs and appear to have a better gastrointestinal tolerability profile. When the gastroduodenal tolerability of 10 days of oral treatment with indobufen or ASA was assessed in healthy adult volunteers using endoscopic evaluation and the modified score scale of Lanza, only 1 of 18 (6%) volunteers who received indobufen had an increased erosion score at the completion of therapy, compared with 6 of 18 volunteers who received ASA (33%).

Pharmacokinetic and pharmacodynamic comparative study of zofenopril and enalapril in healthy volunteers.

Zofenopril calcium (CAS 81938-43-4) is a new angiotensin converting enzyme (ACE) inhibitor, which in addition to the typical activity of the class, proved to possess a specific cardioprotective effect due also to the presence of the sulfhydryl group. In this trial zofenopril calcium and enalapril maleate (CAS 76095-16-4) were given to 20 healthy volunteers of both sexes in repeated dose regiment at two dose levels: 30 mg and 60 mg zofenopril calcium and 10 mg and 20 mg enalapril maleate. The study was conducted according to a two-period, two-sequence, crossover design, with washout.

Pharmacokinetic behaviour of antithrombin III following intravenous infusion in healthy volunteers.

Antithrombin III (CAS 52014-67-2) is produced from plasma of healthy donors and is purified from any detectable agent of transmissible infection. This drug is used in therapy by i.v.

Bioequivalence of endogenous substances facing homeostatic equilibria: an example with potassium.

Oral administration of endogenous substances in most cases results in negligible net increases in baseline plasma concentrations, associated with high variability. This poses the problem of their bioequivalence. Using the data obtained from a bioequivalence investigation of potassium aspartate (test vs reference formulation), the authors demonstrate the inconsistency of bioequivalence based on plasma concentrations and standard methods.

Amlodipine bioequivalence achieved with a very sensitive liquid chromatography tandem mass spectrometric bioassay.

Amlodipine (CAS 88150-42-9) is a 1,4-dihydropyridine derivative, one of the most widely used drugs for the management of essential hypertension. In developing manidipine (CAS 120092-68-4), a new antihypertensive drug, amlodipine was selected as the reference comparator drug in a Phase III double blind clinical trial. However, manidipine is formulated in hard gelatin capsules, whereas amlodipine is presented as a tablet.

Pharmacokinetics of diclofenac after oral administration of its potassium salt in sachet and tablet formulations.

This paper reports the results of a pharmacokinetic study involving 24 healthy volunteers and designed to characterise the rate and extent of diclofenac absorption after the administration of a single dose of diclofenac (CAS 15307-86-5) potassium salt 50 mg in sachet (Voltfast) and tablet (Cataflam) formulations. Timed plasma concentrations of diclofenac during a 12-h-period after dosing were measured by means of HPLC with UV detection at 275 nm and a quantification limit of 10 ng/ml; the method was fully validated for pharmacokinetic purposes. These plasma concentrations were used to calculate Cmax, tmax, trapezoidal AUC0-t and AUC0-infinity and t1/2 by means of noncompartmental analysis.

Pharmacokinetics and pharmacodynamics of zofenopril in healthy volunteers.

This study was carried out to investigate the pharmacokinetics of zofenopril (CAS 81938-43-4) and zofenoprilat, the behaviour of the angiotensin converting enzyme (ACE) (pharmacodynamics) following the administration of zofenopril calcium at the single oral dose of 60 mg in eighteen healthy volunteers. This open label, one-way study was carried out in a single centre on 18 healthy volunteers. The volunteers received an oral single 60 mg dose of zofenopril calcium following an overnight fast.

Bioavailability, food effect and tolerability of S-naproxen betainate sodium salt monohydrate in steady state.

S-Naproxen betainate sodium salt monohydrate (naproxen-beta Na, CAS 104124-26-7, Aprenin) in 550 mg capsules (corresponding to 327 mg of naproxen) was administered to 24 healthy volunteers (12 males and 12 females) b.i.d.

Toxicokinetics of endogenous substances: a neglected issue.

Some specific problems related to the pharmacokinetics and toxicokinetics of endogenous substances are reviewed in this paper with specific reference to baseline and its variation, reversible dynamic pools, saturable tubular reabsorption, the stability of the parent compound, poorly absorbed substances, analytical procedures and statistical analysis. Compared to xenobiotics, endogenous substances require special care in planning pharmacokinetic and toxicokinetic investigations as they possess homeostatic equilibria. The presence of a baseline, its variation according to specific rhythms, age, sex or simple fluctuation, active absorption and passive diffusion, saturable enzyme processes, renal threshold, the distribution of the exogenous drug in relation to that already present in the body and a possible balance between endogenous synthesis and dietary intake are the main mechanisms which allow homeostatic equilibria to be preserved and restored when impaired.

Bioequivalence. An updated reappraisal addressed to applications of interchangeable multi-source pharmaceutical products.

This paper reviews study procedures for bioequivalence trials, mainly addressed to the New Drug Application (NDA) of generic drugs, strictly referring to EU and USA guidelines on this matter. Specific attention is devoted to the most appropriate experimental designs, the size of the volunteer sample, the ethical issues involved, statistics to assess bioequivalence and the accepted standard format for final research reports. Some aspects which create serious problems in bioequivalence trials, most of which not fully covered by the EU and USA specific guidelines, are comprehensively discussed.

The body of a trial master file for a pivotal phase I study.

This paper describes in detail the documentation which would form the body of a Trial Master File for Phase I pivotal investigations filed to render easily and totally auditable all the documentation. The body of a Trial Master File is formed by formal documents (study protocol, research report), by documents to be attached to the research report (clinical report, analytical validation report, statistical report, blank case report form, blank consent form, approval from Ethics Committee), by documents to be kept in file (investigator's brochure, clinical source documentation, clinical trial supplies, filled case report forms, monitoring reports, auditing reports, letters, contracts, faxes, phone notes) and by confidential documents that must be filed in the Clinical Unit only (signed consent forms which contain the subjects' identification).