Active comparator drugs

The goal of equivalence trials is to demonstrate that the test drug and an active comparator drug are equivalent. Like several words that we have already encountered in this book (e.g., significance), the word equivalent is used in both everyday language and in Statistics, but its use in Statistics is specific. In this context, equivalence means that, in the best case scenario, the test treatment is... 

Active comparators Obtaining active comparator drug Blinding, reformulations and bioequivalence Disclosure of trade secrets to competitors Placebo-control justifications Use of appropriate dose ranges Risks demonstrating superiority of competitor... 

Fominoben [18053-31 -1] (66) is another nonnarcotic drug which has shown antitussive activity comparable to codeiae when adrninistered both orally or parenteraHy ia a variety of animal species (95). 

A different task was pursued by the CM of CsA with various maleates 339 [ 148]. The CM demanded in this case the highly active Hoveyda catalyst D, that exhibits potency not reached by the phosphine-containing catalysts C and E. Under the conditions given in Scheme 65, metathesis with maleates 339 led (E)-selectively to the a,/J-unsaturated ester derivatives 340 in high yield. Compounds 340 still demonstrated activity comparable to that of CsA and are thus potential soft drugs via esterase-mediated biotransformation to the corresponding inactive carboxylic acids 341. 

Over 10000 quinolone antibacterial agents have now been synthesized. Nalidixic acid is regarded as the progenitor of the new quinolones. It has been used for several years as a clinically important drug in the treatment of urinary tract infections. Since its clinical introduction, other 4-quinolone antibacterials have been synthesized, some of which show considerably greater antibacterial potency. Furthermore, this means that many types of bacteria not susceptible to nahdixic acid therapy m be sensihve to the newer derivahves. The most important development was the introduction of a fluorine substituent at C-6, which led to a considerable increase in potency and spectrum of activity compared with nalidixic add. These second-generation quinolones are known as fluoroquinolones, examples of which are ciprofloxacin and norfloxacin (Fig. 5.19). 

A series of DAT selective 3-phenyltropanes have been reported to have potential for treatment of cocaine abuse [33,36,37]. RTI-336,15 (reuptake IC50 — 4.1 nM) was the most potent among these tropane derivatives in locomotor activity and drug discrimination it was less stimulatory than cocaine, and had the slowest onset and longest duration of action. It also reduced self-administration of cocaine in rats and rhesus monkeys. Interestingly, in rhesus monkeys trained to self-administer cocaine, when coadministrated with either citalopram or sertraline, 15 produced significantly more robust reductions in cocaine self-administration compared with 15 alone [38]. 

The direct transport of absorbed drugs into systemic circulation, effectively by-passing the first-pass effect of the liver and gastrointestinal tract Lower enzymatic activity compared to the gastrointestinal tract or liver Amenability to self-medication, which increases patient compliance Possibility of pulsatile delivery of some drugs to simulate the biorhythmic release of these drugs Lower risk of overdosage Achievement of controlled release... 

Compared to the nasal and rectal routes, the buccal mucosa has low enzymatic activity, and drug inactivation due to biochemical degradation is not as rapid and extensive [8]. 

The use of prodrugs with higher lipophrlicity compared to the parent molecule is realized in the classical example of heroin and morphine. Heroin, the di-acetyl derivative of morphine, penetrates the BBB by one log order better than morphine and is cleaved by tissue esterases to release the active parent drug. As follows from fhe pharmacokinetic principles shown in Section 2.3.2.1 (Eq. 2.3), brain concentration is a function of bofh BBB permeability, reflected by and plasma area under the curve ... 

Active comparators are included to act as a benchmark or gold standard against which the new drug is to be compared. The selection of comparator depends on the specific objectives of the trial. The main considerations are as follows. 

Will one active comparator serve for all corm-tries in which the drug will be marketed ... 

In clinical trials intended to provide sufficient evidence for marketing approval of drugs, what is most important is to collect rmequivocal evidence of a positive risk-benefit profQe relative to an active comparator or placebo. For diseases that are life-threatening or those associated with severe morbidity, it is preferable that the primary endpoint is of clinical relevance, examples being mortality, a measurement of the patient s quality of life, such as rehef of disease-related s)unp-toms, improvement in ability to carry out normal activities or reduced hospitalization time. Unfortunately such trials may need to be very large consequently they tend to have a long duration, and can be extremely costly. 

It is widely accepted that two placebo-controlled pivotal studies are necessary, although it is not clear whether this is a mandatory regulation in the FDA or EMEA regulations. There is, however, a certain insurance in this approach as studies, even of drugs that are effective, can occasionally fail to show a statistically positive result if the treated population somehow deviates from the norm or if the placebo response is unexpectedly increased. In Europe the use of an active comparator in a pivotal study is more common. 

A double-blind randomised study is recommended for the confirmation study unless there are substantial scientific reasons not to do so. In many cases, an active comparator is preferred to an inactive placebo, as evidence of similar efficacy to the premium priced product will be an advantage for obtaining favourable reimbursement price. Nevertheless, choice of the placebo increasing to demonstrates absolute efficacy of the drug and has been accepted by many study sites. 

Efficacy. To date, more than 15 clinical trials have been conducted comparing fluvoxamine with other active agents and placebo. Imipramine was the most common comparator drug used, and studies have indicated that fluvoxamine was effective as the reference drug, although significantly supe-... 

Venlafaxine is dependent on CYP 2D6 and 3A3/4 enzymes for its biotransformation and eventual clearance ( 138, 139 and 140). CYP 2D6 converts venlafaxine into 0-desmethylvenlafaxine (ODV), which is believed to have pharmacological activity comparable with the parent drug based on in vitro studies (141). Thus, this metabolite is to venlafaxine as norfluoxetine is to fluoxetine in that the half-life of ODV is longer than that of the parent drug, although it is only 12 hours versus 14 days for norfluoxetine. 

Pauli KD, Shoemaker RH, Hodes L et al. Display and analysis of patterns of differential activity of drugs against human tumor cell lines development of mean graph and COMPARE algorithm. J Aar/ Cancer Inst 1989 81 1088-1092. 

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