Therapeutic exposure

It has been known for many years that homolytic fusion of the 0-0 bond in H2O2 will yield the hydroxyl free radical OH. This may be produced by exposure of H2O2 solutions to heat or ionising radiation and hence may be formed, for example, after accidental or therapeutic exposure to radiation (e.g. during cancer therapy) ... 

From a purely pragmatic perspective, it is clear that reactive metabolites are linked with toxicity and that a circumstantial link can be made to idiosyncratic toxicides. Consequently, even though the mechanism of this toxicity is not fully understood, since assays are available to measure the potential for bioactivation in an ideal world one would not carry this liability forward. Conversely, it is not an ideal world, all drug molecules have challenges and the definition of therapeutic index (i.e., the ratio between the toxic exposure and the therapeutic exposure) is critical. Covalent binding of reactive metabolites to macromolecules is a crude measure and not a full predictor of toxicity and it is well known that toxicity can be ameliorated by a lower dose. Furthermore, the so-called definitive assays require radiolabeled drug material which is expensive and generally slow to produce. 

The site as well as timing of therapeutic exposure to immunomodulatory cytokines can present an important issue. The cytokine gene therapy strategies predominantly but not exclusively involve... 

Typically these studies cost from 1.5 to 3 million to conduct. Based on the perceived probability of a significant QT interval effect (based on preclini-cal studies, class effects, and ECG data from phase 1 studies) a decision must be made whether to conduct the definitive QT study prior to proceeding with a proof-of-concept study in patients, or whether to delay this study until the proof of concept (POC) has been demonstrated. Of note, for many biophar-maceutical products it would not be possible nor ethical to dose to steady state in healthy volunteers, to dose at two to four times anticipated therapeutic exposures, or to use a crossover design with reasonable washout periods. Thus a QT study performed with a biopharmaceutical may need to vary from the usual design and the E14 guidance, and may present great challenges for subject or patient recruitment. 

Titanium is also a constituent of some anticancer compounds (6). Titanium dioxide is used in sunscreens. Non-therapeutic exposure to the metal also occurs. 

Therapeutic exposure Total daily dose of acetaminophen should not exceed 4g. Dosages of acetaminophen over 4-8 g day over long periods of time may be associated with higher risk of liver toxicity. Acetaminophen should not be administered for... 

Immunotoxicology can be defined as the study of adverse effects on the immune system resulting from occupational, inadvertent, or therapeutic exposure to drugs, environmental chemicals, and, in some instances, biological materials [16]. 

Dose A high, supratherapeutic dose of the NCE, which results in plasma levels in excess of what would be observed in patients with impaired clearance of the drug, should be used in the TQT study. The E14 states If not precluded by consideratimis of safety or tolerability due to adverse effects, the drug should be tested at substantial multiples of the anticipated maximum therapeutic exposure. The overriding principle is that plasma levels achieved with the supratherapeutic dose should exceed the worst-case scenario in patients, taking into account both intrinsic (e.g., renal impairment) and extrinsic factors (e.g., drug interactions). As an example, for NCEs that are CYP 3A4 or 2D6 substrates, the achieved exposure must exceed that observed with concomitant administration with potent 3A4 inhibitors, and in 2D6 poor metabolizers (Abbas et al. 2012 Boyce et al. 2012 Chaikin et al. 2005 Dalen et al. 2010 Malhotra et al. 2007 Robert et al. 2007 Tyl et al. 2012 Zhu et al. 2010). For a renally cleared drug, plasma levels that are only... 

Souliotis, V.L., Dimopoulos, M.A., and Sfikakis, P.P. (2003) Gene-specific formation and repair of DNA monoadducts and interstrand cross-links after therapeutic exposure to nitrogen mustards. Clin. Cancer Res., 9 (12), 4465 -4474. 

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