This article is available online at http://dmd.aspetjournals.org ABSTRACT:Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.Drug-drug interactions can lead to severe side effects and have resulted in early termination of development, refusal of approval, severe prescribing restrictions, and withdrawal of drugs from the market. Regulators, including the U.S. Food and Drug Administration (FDA 1 ) have therefore issued guidances for in vitro and in vivo drug interaction studies to be conducted during development. These guidances, however, do not address the specific designs of the studies, and there is a desire by regulatory authorities to harmonize approaches and study designs to allow for a better assessment and comparison of different drugs. In addition, the existing guidances cover mainly cytochrome P450 (P450)-mediated drug interactions and the importance of other mechanisms, such as transporters, has been recognized only recently. To address these issues, workshops have been held in

Two hundred and eighty-eight subjects with a history of allergy to penicillin were studied for objective proof of their allergy. On the basis of skin tests, specific IgE antibody measurements and direct challenge tests. 64 patients (22%) were shown objectively to be allergic to one or more penicillins. The following tests were carried out: skin tests to benzyl-penicilloyl poly-L-lysine (BPO-PLL), minor determinant mixture (MDM), amoxycillin (AX) and ampicillin (AMP), in-vitro IgE antibody measurement to benzyl-penicilloyl (BPO) and AX and challenge with benzylpenicillin (BP), phenoxy-methyl-penicillin (PV) and amoxycillin. Forty-four cases were found to respond to benzyl or phenoxymethyl-penicillin, however, 20 were shown to be sensitive to amoxycillin and unresponsive to tests with other penicillins. The contribution that any individual test gave for establishing the diagnosis was 21.8% for skin testing with BPO-PLL, 9.3% with MDM and 12.5% with AX. Nine point three per cent were RAST positive to BPO and 1.5% to AX; 7.8% developed a positive response after challenge to BP, 7.8% to PV and 14% to AX. In 16% of the 64 positive cases more than one test was found to be positive. The challenge tests suggested that not all the penicillin-sensitive subjects had IgE-mediated reactions implying other immunological mechanisms. These results clearly demonstrate the importance of side chain-specific diagnostic reagents and challenge tests. Thirty-one per cent of the positive group or 6.9% of the total group would have been missed in this study using benzyl or phenoxymethyl-penicillin diagnostic reagents alone.

Carotenoids are the most common pigments in nature and are synthesized by all photosynthetic organisms and fungi. Carotenoids are considered key molecules for life. Light capture, photosynthesis photoprotection, excess light dissipation and quenching of singlet oxygen are among key biological functions of carotenoids relevant for life on earth. Biological properties of carotenoids allow for a wide range of commercial applications. Indeed, recent interest in the carotenoids has been mainly for their nutraceutical properties. A large number of scientific studies have confirmed the benefits of carotenoids to health and their use for this purpose is growing rapidly. In addition, carotenoids have traditionally been used in food and animal feed for their color properties. Carotenoids are also known to improve consumer perception of quality; an example is the addition of carotenoids to fish feed to impart color to farmed salmon.

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Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.