This in vivo cytogenetic test is a short-term mutagenicity test for the detection of structural chromosomal aberrations.

In vivo gene mutation test

The micronucleus test is a mammalian short-term in vivo test for the detection of chromosomal damage or damage of the mitotic apparatus by chemicals.

Mutagenicity (in vivo mammalian bone-marrow cytogenetic test, chromosomal analysis)

MUTAGENICITY (' IN VIVO ' MAMMALIAN BONE-MARROW CYTOGENETIC TEST, CHROMOSOMAL ANALYSIS)

an in vivo procedure (the micronucleus test or the metaphase analysis of bone marrow cells) is also acceptable.

the number of animals needed for the positive control when testing mutagenicity in vivo is also lowered (methods B.11 and B.12)

- Testing with irrelevantly high doses is avoided by the introduction of limit tests, not only in the acute toxicity tests (methods B.1, B.2 and B.3) but also in the in vivo tests for mutagenicity (methods B.11 and B.12).

A compound known to produce chromosomal aberrations in vivo is employed as a positive control and a negative (solvent) control group is also included in the design of each experiment.

In order to ensure that efficacy of the product is reproducible from batch to batch and to demonstrate conformity with specifications, potency tests based upon in vitro or in vivo methods, including appropriate reference materials whenever available, shall be carried out on each final bulk or each batch of finished product, with appropriate confidence limits;

The assessment of the efficacy and safety of an advanced therapy medicinal product must include the careful description and evaluation of the therapeutic procedure as a whole, including special ways of administration, (such as transfection of cells ex vivo, in vitro manipulation, or use of interventional techniques), and testing of the possible associated regimens (including immuno-suppressive, antiviral, cytotoxic treatment).

a test for chromosomal aberrations in-vitro and in-vivo.

a test for chromosomal damage in vitro and in vivo.

In vivo somatic cell mutation assay, the mouse spot test, (Method B.24)

* Antibody titre obtained according to the in vivo potency test in chickens.

The genotoxic potential of deferiprone was evaluated in a set of in vitro and in vivo tests.

Mutagenicity (in vivo mammalian bone-marrow cytogenetic test, chromosomal analysis) //151

MUTAGENICITY ('IN VIVO` MAMMALIAN BONE-MARROW CYTOGENETIC TEST, CHROMOSOMAL ANALYSIS)

The battery of tests suggested above does not imply, however, that other tests are inappropriate or that other tests, in particular in vivo tests, would not be acceptable as alternatives.

In vitro and in vivo tests on genetic toxicology did not provide any evidence for a clinically relevant genotoxic potential.

With somatropins, in vitro and in vivo genotoxicity studies on gene mutations and induction of chromosome aberrations have been negative.

The test can be an in vivo study or an in vitro study using a different metabolising system from that/those previously used.

The battery of tests suggested above does not imply, however, that other tests are inappropriate or that other tests, in particular in-vivo tests, would not be acceptable as alternatives.

Atorvastatin did not demonstrate mutagenic or clastogenic potential in 4 in vitro tests with and without metabolic activation and in 1 in vivo assay.

Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames assay) and in vivo micronucleus assay in mice.

Acceptable are also in vivo procedures, e.g. the micronucleus test (Method B.12) or the metaphase analysis of bone marrow cells, (Method B.11).

When any result of an in vivo study in somatic cells is positive, in vitro testing for germ cell effects may be justified.

Porcine Circovirus type 2 ORF2 subunit antigen: at least 4.5 log2 ELISA units as determined in the in vivo potency test in chickens Adjuvants:

19 which are not considered to have biological relevance for humans. There was no indication of genotoxic potential in three in vivo rat studies (micronucleus tests in bone marrow and liver and liver comet assay).

If positive in 6.6.1, 6.6.2 or 6.6.3, then an in-vivo mutagenicity study will be required (bone marrow assay for chromosomal damage or a micronucleus test)

When a test or both tests were positive in the base set, a supplementary study should include the same or different end points in other in vivo test methods.

If this result is obtained at concentrations below 10 µg/ml, the test chemical is also likely to act as phototoxin also under various exposure conditions in vivo.

Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations.

In contrast, if no toxicity was demonstrated (+ UV and - UV) and if aqueous solubility limited concentrations to values less than 100 µg/ml, then compatibility of the test substance with the assay may be questioned and confirmatory testing should be considered (e.g. using an in vitro skin model, or an ex vivo skin model or an in vivo test).

If negative in 6.6.4 but positive in-vitro tests then undertake a second in-vivo study to examine whether mutagenicity or evidence of DNA damage can be demonstrated in tissue other than bone marrow

In cases where the chemical could be tested up to the highest concentration of 100 µg/ml, a negative result indicates that the chemical has no phototoxic potential, and phototoxicity in vivo may be considered unlikely.

The in vitro 3T3 NRU phototoxicity test was developed and validated in a joint EU/COLIPA project from 1992-1997 (1) (2) (3), to establish a valid in vitro alternative to the various in vivo tests in use.

Results from the in vitro 3T3 NRU phototoxicity test were compared with acute phototoxicity/photoirritation effects in vivo in animals and humans, and the test has been shown to give excellent predictivity for these effects.

Lapatinib was not clastogenic or mutagenic in a battery of assays including the Chinese hamster chromosome aberration assay, the Ames assay, human lymphocyte chromosome aberration assay and an in vivo rat bone marrow chromosome aberration assay.

Whereas the use of metabolising systems is a general requirement for all in vitro tests for the prediction of genotoxic and carcinogenic potential, up to now, in the case of phototoxicology, no chemical is known for which metabolic transformation is needed for the chemical to act as a phototoxin in vivo or in vitro.

In vivo resistance (Therapy naïve patients) Isolates from most patients experiencing virological failure with a regimen containing abacavir in pivotal clinical trials showed either no NRTI-related changes from baseline (45 %) or only M184V or M184I selection (45 %).

Since the toxicological endpoint of the in vitro test is determination of photocytotoxicity, induced by the combined action of a chemical and light, compounds that are phototoxic in vivo after systemic application and distribution to the skin, as well as compounds that act as photoirritants after topical application to the skin, can be identified by the test.

Overall, the in vitro characterisation of phenotypic cross-resistance between lopinavir and other protease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreased susceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility to amprenavir, saquinavir, and nelfinavir.

Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.