A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience
Issue link: http://innovationscns.epubxp.com/i/499434
Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] 22S falls. 21 Reduction in delta waves are thought to be an indicator of a lack of deep sleep and through PK/PD modeling of almorexant it was determined that during sleep subjects showed greater delta activity and deeper sleep (i.e., a property that zolpidem does not have). Inferred from these results that this first in-man study with almorexant could provide an indication of the pharmacology and PK/PD modeling needed to determined what the clinically effective dose would be, seemingly below 400mg and in the region of 100 to 200mg, which would be at the low therapeutic range (i.e., similar to that of an effect with zolpidem 5mg). In the end, this was deemed to be a successful program, as a 50mg dose of almorexant was not an effective sleep aid and 100 to 200mg exhibited dose- dependent effects in patients with insomnia. The 200mg dose did exhibit significant safety concerns and the compound was later withdrawn for side-effects that were not associated with the drug effect on sleep parameters and not being deemed to be a class problem. Merck Corporation has recently received approval for Suvorexan (another orexin antagonist) using a similar approach (Figure 3). Example 2—Cannabinoid CB1 antagonist rimonabant and surinabant. Unlike the abovementioned case with almorexant, this is more of a postmortem case as to try to understand what went wrong. Specifically, the reports of four suicides in the rimonabant group versus one in the placebo group initially led to drug termination. There were many other side effects in the psychiatric group leading to halting of this drug during clinical development, which contributed to the entire drug class being taken with it. Rimonabant is a drug registered by Sanofi-Aventis and had not undergone pharmacodynamic evaluation in healthy volunteers as had the drug in the previous example. However, the drug was capable of reducing the effects of THC and represented a starting point for devising studies in the evaluation of surinabant. It was decided to first isolate THC from cannabis and then devise an inhalation method to determine peripheral/central pharmacologic activity using PK/PD analysis with relevance of these measures to be used later in clinical trials. 22 As it was not known how much suppression in THC effects was needed according to these models, essentially investigators had to wait for clinical trial results with rimonabant to be able to reverse model back. Interestingly, plasma concentrations of rimonabant disappears rapidly but CNS effects r emained prolonged. Heart rate effects did not accumulate to additional dosages of drug, and this in fact was deemed to be a peripheral CB 1 receptor effect versus impact on central pharmacologic activity. 23 Given the ability to parse peripheral and central effects out with this agent, this rational approach was then undertaken with the follow-up agent surinabant. Fittingly, there is a dose-related reduction in heart rate with surinabant, and if a PK/PD model is created, it was hoped that what would be the highest dose that one could achieve a 10-percent reduction in heart rate would be the effective dose. This level of inquiry would still, however, not lead to anything related to what would be the dose needed for weight reduction (a primary endpoint of the study drug). A dose-related reduction of feeling high from THC was only appreciated with ribonabant 60mg, and caused only a 60-percent reduction in this subjective effect. The types of side effects encountered with surinabant also occurred within the same dose range as that for ribonabant. There was indeed a dose- related weight reduction in people who quit smoking, and 20mg of ribonabant appeared similar to the 10mg of surinabant when tested, which showed levels of THC suppression at 40 percent peripheral and 60 percent centrally. So the question was "Which measure is needed to see the desired weight reduction effect?" Many thought that after these studies, lower doses of drug related to the peripheral effect is what was needed, and then came along drinabant. Drinabant is a cannabinoid analog more peripherally restrictive, and 7TM is also restricted in central penetration and considered to be clinically effective in weight reduction. But these latter drugs never underwent clinical trials. In short, it was felt that much lower levels of central penetration will be associated with reduced psychiatric side effects while still maintaining the efficacy of FIGURE 3. Pharmacology-guided dose selection—case 1: almorexant first dual ORX1/2- antagonist (DORA). (Figure reproduced with permission. Hoever P, De Haas S, Winkler J, et al. Orexin receptor antagonism, a new sleep-promoting paradigm: first-in-humans study with almorexant. CPT 2010;87:593-600).