Phase 2 trial 1658 INDEX

A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

Probably the most widely adopted and well-known method for estimating the likelihood of a compound (drug) being well absorbed is the rule-of-5 described by Lipinski and co-workers [1]. In analyzing 2245 compounds from the World Drug Index (WDI) database that were either considered for, or entered into, Phase II clinical trials, these authors developed the following rules ... 

The precursor of EpoB, dEpoB, in which the 12,13-oxido linkage is lacking, also acts on microtubule assembly with a better therapeutic index than EpoB. dEpoB is currently in Phase II clinical trials. Bioassays were performed on E)-9,... 

As mentioned earlier, the clinical trials with TCAs in children and adolescents with MDD have generally been disappointing ( 120, 122,123). In addition, these medications have a less favorable adverse effect profile and thus higher patient attrition rates during the acute treatment phase compared with newer antidepressants. They also have a lower therapeutic index (i.e., difference between therapeutic and toxic dose see Chapter 7). 

Before a product can be produced at a plant technically capable of doing so, a scale-up phase is required. Constraint (3.37) sets the scale-up variable to 1 if a product is produced at a plant while constraint (3.38) ensures the continuity of product-plant allocations. Equation (3.39) initializes the status at the beginning of the planning horizon and equations (3.40) and (3.41) create the secondary demand for production trials associated with a scale-up decision. The plant index is included to allow for a relaxation of restriction (3.27) which states that only one plant type per plant class can be established at a site. 

Based upon these observations and following Phase I safety studies, a Phase II randomized, double-blind, controlled clinical trial was undertaken to treat active ulcerative colitis with escalating doses of ISIS 2302. Based on an intent-to-treat analysis, 59% (13/22) of patients treated daily with 240 mg ISIS 2302 enema over six weeks achieved a positive response, as measured by Disease Activity Index (DAI)... 

The failure of drugs at later stages of development, particularly in clinical trials, is very expensive for drug developers and, more importantly, patients. To better understand the key reasons for these failures, Lipinski et al,14 undertook an analysis of the properties of compounds that entered Phase II human clinical trials. They selected a subset of 2245 compounds from the World Drug Index (WDI) database of over 50000 compounds after eliminating the majority of compounds for various well-reasoned criteria. This subset of compounds had assigned trade names and, as a result, were assumed to have entered Phase II oral efficacy studies and be expected to have superior physico-chemical properties since they would have passed most of the other earlier clinical trial hurdles. 

The Lipinski Rule-of-Five almost certainly represents the first real attempt to identify a drug-like filter for molecular databases. Lipinski analysed the compounds within the World Drag Index that had progressed to Phase II clinical trials or better and discovered a simple set of rales that have been used extensively since their publication in 1997. The LRoF states that a compound may have lower membrane permeability or poorer absorption if two or more of the rules are violated. These rules are a compound should have no more than 5 hydrogen-bond donors, no more than... 

Exatecan is a novel synthetic camptothecin derivative with a unique hexacyclic structure. It does not require metabolic activation, whereas irinotecan does. In vitro experiments in various cell lines have suggested that exatecan may be 6 and 28 times more active than SN-38 (7-ethyl-lO-hydroxycamptothecin, the active metabolite of irinotecan) and topotecan respectively. Furthermore, it has a 2-10 times higher therapeutic index than irinotecan and topotecan. In addition, exatecan may even be active in P-glycoprotein-mediated multidrug-resistant tumor cells. Its dose-limiting adverse effects are neutropenia and liver dysfunction. The recommended dosages of exatecan for phase II trials are 0.5 mg/m /day or 0.3 mg/ m /day as a 30-minute infusion on 5 consecutive days for minimally pretreated and heavily pretreated patients respectively (14,15). 

In the third stage, i.e., the various phases of clinical trials, pharmacokinetics is studied in detail in order to obtain the therapeutic index, to study drag-drag interactions, and to design dosage regimes. 

The Rule-of-Five (Ro5) is one of the best known and widely accepted drug-likeness filters. The Ro5 was derived from an analysis of 2,245 drug candidates from World Drug Index (WDI) with assigned United States Adopted Name (USAN) or International Proprietary Name (INN) that are believed to have reached Phase II trials. It states that a compound violating any two of the following rules is likely to be poorly absorbed ... 

Alberts DS, Green S, Hannigan EV, et al. Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide Final report by the Southwest Oncology Group of a phase 111 randomized trial in stages III and IV ovarian cancer [published erratum appears in J Clin Oncol 1992 10 1505]. J Clin Oncol 1992 10 706-717. 

DITPA treatment improved left ventricular performance in rat and rabbit post-M I models of heart failure. In a double-blind, placebo controlled, pilot phase II clinical study in 19 patients with NYHA class II or III CHF in 2003, DITPA demonstrated a significant increase in cardiac index, as well as improvements in diastolic function, systemic vascular resistance, and cholesterol and triglyceride levels. In this study, DITPA was well tolerated, with no significant increase in heart rate or significant adverse events. Subsequently, a larger trial was initiated which, however, was discontinued in October 2006, based on a business decision by Titan. 

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