|
|
|
|
|
|
|
transit time from 4 hours to 2 hours [4]. Collaborative studies between drug metabolism and clinical pharmacology groups on the mechanism of ranitidine absorption using cultured human Caco-2 cells showed absorption to be paracellular and not transcellular [5]. The collaboration of pharmaceutics and clinical pharmacology led to a new effervescent tablet that is bioequivalent to the marketed tablet and is now on the market. |
|
|
|
|
|
|
|
|
This experience helped create several systematic changes in the way we develop drugs. Determining the characteristics of gastrointestinal absorption site using intubation techniques now is performed commonly when either the drug is not well absorbed or is likely to be considered for alternative formulations (e.g., controlled release, suppository). This simple study helps predict the feasibility of developing other formulations and shows physiologic restrictions in absorption processes. By routinely knowing the drug's solubility, permeability (e.g., Caco-2 [6]), and human hepatic intrinsic clearance (e.g., human hepatocyte [7]), it is possible to select drugs from research that are likely to be well absorbed. Low oral bioavailability accounts for a large proportion of drugs that fail in Phase I. By integrating this information into a physiologic absorption model, both time and money can be saved. |
|
|
|
|
|
|
|
|
Problem 2: Can the maximally tolerated dose by predicted from lower doses for a cancer drug in the first Phase I dose-escalation clinical trial? |
|
|
|
|
|
|
|
|
During the first single-dose escalation studies in humans it is useful to predict the dose associated with the maximal effect or the maximally tolerated effect from lower doses. When a surrogate or direct measure of pharmacodynamic effect is available, this prediction can be done by fitting the dose or drug concentration-response data to a model (e.g., sigmoid Emax, linear regression). Benefits include sparing patients excessive toxicity and increasing study efficiency by decreasing dosage increments. |
|
|
|
|
|
|
|
|
The synthetic topoisomerase I inhibitor GG211 is being developed for various solid-tumor cancers. The initial single-dose escalation study to determine the maximally tolerated dose was conducted at two sites in the United States and Europe using the same protocol. Following intravenous administration the active lactone form is converted to an inactive acid by a pH-dependent process. During dose escalation, key safety information (e.g., platelets, neutrophils) was accumulated from both sites by clinical research scientists and blood samples were analyzed at the company within days of collection from patients. The pharmacokineticist graphed and computer fit the data that was then interpreted by the development team led by a company oncologist. Information collected and analyzed by the company was routinely shared with the clinical sites. An objective was to predict the dose that would produce a drop in the blood platelet count not exceeding 75,000/mm3 and neutrophil count not exceeding 750/mm3. |
|
|
|
|
|