The use of PET imaging, with highly selective radiotracers, is increasing in the area of pharmaceutical research to determine the in vivo
human pharmacokinetics and/or pharmacodynamics of new chemical entities, and even approved drugs, that act directly in the brain (Fowler et al, 1999
; Nutt et al, 2007
; Kegeles et al, 2008
; Volkow et al, 2009
). PET imaging is a safe and relatively noninvasive method to determine CNS penetration and distribution, and for targeting pharmacodynamic activity at molecular brain sites. Carbon-11, because of its short half-life (20.4
min), permits serial studies in the same individual (baseline PET scan and up to three more PET scans in a day), allowing an individual to serve as his/her own control and reducing the effect of inter- and intrasubject variability. In addition, plasma drug concentrations obtained at the time of PET imaging can serve as a means of showing whether there is a relationship between plasma drug levels and pharmacodynamic effects in the brain. When these two measures are positively correlated, plasma drug levels can serve as a biomarker for pharmacodynamic effects of a drug in the brain and assist in the selection of dosing regimens for future efficacy trials, thereby reducing the length and cost of drug development.
PET studies have been carried out with different MAO subtype-selective [11
C]radiotracers to measure the degree, duration and specificity of brain MAO inhibition by various drugs in humans and to determine dosing intervals. These studies have been conducted with both reversibly binding radiotracers, such as the MAO-A radiotracer [11
C]harmine (Bergström et al, 1997
; Ginovart et al, 2006
), and irreversibly binding radiotracers such as the MAO-A and MAO-B radiotracers [11
C]clorgyline and [11
C]L-deprenyl-D2, respectively (Fowler et al, 1993
; Bench et al, 1991
). Irreversibly binding radiotracers such as [11
C]N-methylspiperone have also been used to measure dopamine D2/D3 receptor occupancy by neuroleptic drugs (Wong et al, 1986
). When quantifying data with irreversibly binding radiotracers such as [11
C]clorgyline, the potential of flow limitation in brain regions with high enzyme activity and low blood flow must be considered. However, the dynamic range of values for DV and for λk3
for the thalamus–cerebellum for [11
C]harmine and for [11
C]clorgyline are 2.1 and 2.5, respectively (data from Ginovart et al, 2006
and Fowler et al, 1996
). This data comparison suggests that the effect of blood flow is minimal for [11
C]clorgyline using the modeling strategy described in this study.
C]clorgyline as the radiotracer, we have shown that CX157 enters the brain rapidly after oral dosing, producing a dose- and time-related inhibition of brain MAO-A in human subjects. The effect of CX157 was greatest at 2
h and recovered to baseline within 24
h after a single dose. This indicates the reversible nature of the inhibition of brain MAO-A by CX157 and supports its classification as a RIMA. After repeated b.i.d. dosing with CX157, a more sustained inhibition of MAO-A over the 12-h period was observed. These latter data suggest that continuous therapeutic levels of MAO-A inhibition could be achieved with multiple dosing regimens of CX157.
Intersubject variability in the percent MAO-A inhibition was observed in some of the subjects receiving the same dose of CX157 measured at the same specific time point. This variability appeared related to observed individual differences in CX157 pharmacokinetics, as supported by the high correlation between the plasma concentration of CX157 and the percent inhibition of [11C]clorgyline binding for all subjects, at all doses and at each time point examined (). This strong correlation also suggests that a rapid equilibrium exists in the distribution of CX157 between plasma and CNS compartments, and that the activity of CX157 at the effector site (brain MAO-A) is proportional to its concentration in plasma at any given time.
When the data were fit to a sigmoid Emax
model using nonlinear regression, it showed that plasma concentration of CX157 could serve as a biomarker of the pharmacodynamic inhibition of brain MAO-A, supporting the use of this relationship for modeling therapeutic dosing regimens of CX157, on the basis of the existing pharmacokinetic database. In future efficacy trials, it may also be possible to determine more accurately the therapeutic level of brain MAO-A inhibition through a comparison of individual clinical outcome measures and corresponding steady-state plasma concentrations of CX157. In this regard, traditional MAO inhibitor drugs (eg, tranylcypromine and phenelzine) have been prescribed for decades, but the degree of MAO-A inhibition required to produce an antidepressant effect has never been directly determined by comparing brain MAO-A inhibition and clinical response in patients. Peripheral measures of monoamine metabolites (eg, 3,4-dihydroxyphenylglycol (DHPG) or 3-methoxy-4-hydroxyphenylglycol (MHPG)) in individuals taking MAOIs have provided a broad range of estimates (ie, 20–80% of inhibition of MAO-A) for therapeutic efficacy with these drugs (McDaniel, 1986
; Berlin et al, 1990
; Holford et al, 1994
; Radat et al, 1996
; Zimmer, 1990
), leaving investigators unsure of a therapeutic dose range for clinical trials.
The most widely studied RIMAs are moclobemide, toloxatone, befloxatone and brofaromine. These RIMAs appear to be comparable with other antidepressant drugs in terms of efficacy and tolerability (Lotufo-Neto et al, 1999
). However, none of the RIMAs are approved in the United States and are therefore without an effect on the treatment of MDD. For most of the RIMAs studied, therapeutic dose ranges were established by traditional methods. Initially, moclobemide and esuprone were evaluated in vivo
using PET imaging with [11
C]harmine, although a kinetic modeling analysis was not applied (Bergström et al, 1997
). Similar to CX157, both of these drugs showed their peak effect on MAO-A at early times after the administration of the last dose. But unlike CX157, moclobemide and esuprone showed only a slight tendency for reversal of MAO-A inhibition by 11 and 23
h, respectively, after treatment cessation. In addition, there was no correlation observed between plasma drug levels and brain MAO-A inhibition for esuprone, and plasma pharmacokinetic values were not reported for moclobemide. More recently, Ginovart et al (2006)
developed a kinetic modeling approach to quantify [11
C]harmine binding after treatment with moclobemide. In that study, they were able to analyze that a therapeutic dose of moclobemide (300
mg b.i.d.) inhibited between 64 and 79% of [11
C]harmine binding, but no moclobemide plasma pharmacokinetics were reported. Therefore, it would appear that CX157 is the first agent in the RIMA class with documented reversible inhibition of brain MAO-A, which is correlated to its plasma concentration. Given the observed correlation between inhibition of brain MAO-A binding and plasma pharmacokinetics of CX157, it is likely that these data will assist in optimizing the therapeutic dose and obtaining regulatory approval for the clinical use of CX157 in this therapeutic area. In this regard, the pharmacodynamic/pharmacokinetic relationship observed using CX157 may provide a means of establishing a therapeutic dose in MDD that would minimize side effects for this agent and further reduce the risk of dietary interactions.
Because serotonin, norepinephrine and dopamine are metabolized by MAO-A, drugs that inhibit MAO-A cause an elevation in these three monoamine neurotransmitters in the brain (Da Prada et al, 1989
). These neurotransmitters are involved in mood, arousal and the sense of well-being, and thus their elevation in the CNS is believed to be the main mechanism underlying the efficacy of MAO-A inhibitor drugs in the treatment of MDD (Chen et al, 2008
). The neurobiological rationale for the efficacy of MAO-A inhibitors and other drugs that increase these neurotransmitters received strong support by the recent discovery that individuals with MDD have elevated levels of brain MAO-A (Meyer et al, 2006
). This finding is consistent with a low monoamine synaptic activity in depressed patients and with the efficacy of MAO-A inhibitors and other drugs that increase these neurotransmitters.