Phase dose-response relationship

Natural and synthetic chemicals affect every phase of our daily Hves ia both good and noxious manners. The noxious effects of certain substances have been appreciated siace the time of the ancient Greeks. However, it was not until the sixteenth century that certain principles of toxicology became formulated as a result of the thoughts of Philippus Aureolus Theophrastus Bombastus von Hohenheim-Paracelsus (1493—1541). Among a variety of other achievements, he embodied the basis for contemporary appreciation of dose—response relationships ia his often paraphrased dictum "Only the dose makes a poison."... 

Dose-response assessment is the process of obtaining quantitative information about the probability of human illness following exposure to a hazard it is the translation of exposure into harm. Dose-response curves have been determined for some hazards. The curves show the relationship of dose exposure and the probabihty of a response. Since vahdated dose-response relationships are scarce, various other inputs are used to underpin the hazard characterization phase of risk assessment. 

Therapeutic confirmatory (Phase III) Demonstrate/confirm efficacy Establish safety profile Provide an adequate basis for assessing the benefit/risk relationship to support licensing Establish dose-response relationship Adequate and well controlled studies to establish efficacy Randomized parallel dose-response studies Clinical safety studies Studies of mortality/morbidity outcomes Large simple trials Comparative studies... 

Ginical testing starts with Phase I studies on healthy subjects and seeks to determine whether effects observed in animal experiments also occur in humans. Dose-response relationships are determined. In Phase n, potential drugs are first tested on selected patients for Ltillmann, Color Atlas of Pharmacology... 

There is evidence that dose-response relationships exist for both skin sensitization and respiratory hypersensitivity, although these are frequently less well defined in the case of respiratory hypersensitivity (EC 2003). The dose of a substance required to induce sensitization in a previously naive subject or animal is usually greater than that required to elicit a reaction in a previously sensitized individual therefore, the dose-response relationship for these two phases will differ. Elicitation responses depend on several factors, among which are potency of the allergen and exposure conditions. Appropriate dose-response data can provide important information on the potency of the substance under evaluation. For sensitizers it is considered prudent to assume that a threshold cannot be identified, i.e., it is not possible to identify an elicitation dose or concentration of a sensitizing substance below which adverse effects are unlikely to occur in people already sensitized to a substance (EC 2003). 

Dose-escalation studies performed in an early phase of drug development provide preliminary information to explore pharmacodynamic parameters at different dose levels up to the MTD. If the focus of a study is on the relationship between the pharmacokinetic and pharmacodynamic parameters (rather than on dose response relationships), then the term PK PD studies is used. 

Phase III studies represent the confirmatory phase of drug development, which takes several years and usually involves several thousand patients at multiple trial centers. Large patient numbers are required in these trials to provide convincing documentation of clinical efficacy and safety, a more complete adverse event profile and covariates and estimates of variability in dose response relationship due to individual differences in pharmacokinetics and pharmacodynamics. They are aimed at definitively determining a drug s effectiveness and side-effect profile. Most of these studies are double-blind and placebo-controlled, sometimes with the option of open-label long-term extensions. 

A typical feature of Phase [lb are dose response trials regarding a drug s safety, efficacy and side effects. No single study design can address all aspects of dose response relationships for a new drug, and so a number of different... 

The disease appeared after a latent period of at least one to two weeks, longer in some cases, and an apparent relationship between the extent of use of the oil and the effect (a dose-response relationship) was noted in one report. The syndrome had an initial phase lasting one to two months, with effects mainly on the respiratory system and the accumulation of fluid in the lungs. There were many deaths at this early stage from respiratory failure. In the next phase (two to four months) there was muscle pain and liver damage. In the final phase there was muscle wasting and weight loss and the skin was affected (see box). 

Phase III Definitive safety and efficacy in patients to define benefit-to-risk relationship and to confirm the dose-response relationship (therapeutic confirmation). 

Emilien, G. van Meurs, W. Maloeaux, J.M. The dose-response relationship in Phase I clinical trials and beyond use, meaning, and assessment. Pharmacol. Ther. 2000, 88 (1), 33-58. 

It is impossible to adjust for noncompliance at the analysis phase without making assumptions about the dose-response relationship, which is often not well understood and might vary greatly from one subject to another. It is always important to assess the level of compliance at the end of the trial so that one might gain some appreciation, qualitative and incomplete as it may be, of what one should expect when the drug is taken as prescribed. 

Nonparametric approaches have been developed mainly because of the lack of knowledge about the dose-response relationship at the beginning of the Phase 1 trial and because of the small sample size in these trials. Most of them use the up-and-down scheme. Several authors proposed a design based on the random walk rules (RWR) (14,15), which provides an accurate estimate of MTD as a quantile, or the use of isotonic regressions. 

These models often incorporate intermediate biomarker responses. Consequently, trial simulations driven by PK models, rather than more traditional dose-response relationships, will enable more detailed simulations. For example, exposure differences due to interactions, inclusion of special populations, or from dosing regimen or formulation changes may be explored with the PK models driving PD responses. This will place additional emphasis on the modeler to develop reliable PK models using Phase 1 and 2 data that translate into the patient population. Appropriate consideration of covariates, as discussed later, will be an important part of this development. 

A variety of continuous TV infusion fluorouracil regimens have been developed to increase the duration of drug exposure during the S phase of the cell cycle and increase DNA-dependent cytotoxicity. Some of these schedules involve short (24- to 48-hour) weekly or biweekly or protracted continuous fluorouracil infusions for up to 12 weeks. Doses of fluorouracil employed in 24 to 48 hour infusions generally range from 1000 to 2000 mg/m per day. A regimen utilizing 300 mg/m per day for 10 weeks is considered the maximally tolerated dose for protracted continuous infusion. Based on the assumption that a dose-response relationship exists for colorectal cancer, this approach is one of the most efficacious methods of dose intensification for fluorouracil. The maximum cumulative fluorouracil dose that can be administered via continuous IV infusion in... 

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