Neuronal acetylcholine nicotinic receptors (nAChRs) are targets for the development of novel treatments of brain diseases. However, adverse effects (for example, emesis or nausea) associated with high drug maximal exposures or Cmax at nAChRs often hinder the advancement of experimental compounds in clinical trials. Therefore, it is essential to explore the feasibility of maintaining exposures below a predetermined Cmax while sustaining targeted CNS effects. By use of a [123I]5-IA [5-[123I]iodo-3-[2(S)-azetidinylmethoxy]pyridine] displacement SPECT imaging paradigm in nonhuman primates, we compared brain nAChR binding activity elicited by either a bolus injection or by slow infusion of an identical dose of a novel neuronal nicotinic agonist, ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride], where the slow infusion scheme was derived from a two-compartment pharmacokinetic modeling designed to limit the Cmax. We determined [123I]5-IA displacement using doses of ABT-089 (0.04, 0.4, and 1.0 mg/kg i.v.) that encompassed efficacious drug exposures in nonhuman primates and examined the relationship between ABT-089 displacement ratios and plasma exposures. Our results indicated that calculated displacement ratios were quite similar between the two different dosing regimens despite substantial differences in Cmax. In addition, displacement ratios correlated well with drug exposures calculated as the area-under-curve (AUC) of plasma concentration and varied in a dose-dependent manner, suggesting that displacement ratios are driven by the AUC of drug plasma exposure but not Cmax. Our data demonstrate the feasibility of predicting plasma exposures using a two-compartment pharmacokinetic model and its potential for optimizing dosing regimens.
Nicotinic acetylcholine receptors (nAChRs) are excitatory, acetylcholine-gated cation channels that are widely distributed in the central and peripheral nervous systems (Paterson and Nordberg, 2000). nAChRs can be assembled from a range of subunits (α2–α10; β2–β4), in which two of the most abundant nAChR subtypes found in the brain are α7 and α4β2* receptors (Gotti and Clementi, 2004). Investigations of the nicotinic cholinergic system have demonstrated that dysfunction of nAChRs can contribute to a wide spectrum of neurological and psychiatric disorders, including attention deficit hyperactivity disorder, schizophrenia, and Alzheimer's and Parkinson's diseases (Hogg and Bertrand, 2007). As a result, nAChRs have become attractive therapeutic targets for developing novel treatments for these devastating diseases (Decker et al., 2001). However, addiction liability associated with nicotinic compounds and their adverse effect profiles, particularly increased incidence of emesis at higher exposures, have imposed significant hurdles to further clinical development of therapeutic agents acting at nAChRs (Beleslin and Krstić, 1987; Faessel et al., 2006; Hogg and Bertrand, 2007).
Radiotracer imaging techniques, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), have been applied to facilitate CNS drug discovery and development at various stages (Frank and Hargreaves, 2003; Fox et al., 2009; Wong et al., 2009), such as target validation or early proof-of-concept clinical studies. Significant advances in neuroreceptor or transport imaging have offered great insights into brain functions, allowing characterization of receptor density or neurotransmitter systems in normal as well as diseased conditions (Frankle and Laruelle, 2002; Zipursky et al., 2007; Howell, 2008). Specifically, PET/SPECT imaging has been increasingly exploited for dose selection or patient stratification in clinical studies of novel CNS treatments (Wong et al., 2009). To visualize nAChRs binding activity, several radiolabeled analogs of the high-affinity nicotinic ligand A-85380 [3-[2(S)-2-azetidinylmethoxy]pyridine] (Sullivan et al., 1996) have been developed as SPECT tracers (Koren et al., 1998; Musachio et al., 1999; Zoghbi et al., 2001). In particular, 5-[123I]iodo-3-[2(S)-azetidinylmethoxy]pyridine ([123I]5-IA) has been extensively used as a SPECT radioligand for nAChRs. As shown by Fujita et al. (2003a), [123I]5-IA rapidly penetrates the blood-brain barrier with low nonspecific binding and minimal toxicity. In addition, the same authors have also found that [123I]5-IA seems to predominantly label the α4β2* subtype and that radioligand uptake can be displaced by endogenous acetylcholine as well as by nicotine and cytisine (Fujita et al., 2003a).
ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride] is a selective partial agonist at nAChRs that has shown cognitive-enhancing properties in preclinical models of learning and memory (Decker et al., 1997) and, in some studies, in patients with adult attention deficit hyperactivity disorder (Wilens et al., 2006). Similar to other partial agonists, ABT-089 demonstrated a more advantageous safety profile in preclinical species than full agonists (Rueter et al., 2004), consistent with the notion of an increased safety margin of partial agonists relative to full agonists (Hogg and Bertrand, 2007). However, nicotinic compounds may require high doses to achieve clinical efficacy that, unfortunately, elevates the potential for adverse effects. In this study, by use of a [123I]5-IA displacement imaging paradigm (Fujita et al., 2000), we sought to investigate an association for ABT-089 displacement ratios with its pharmacokinetic (PK) parameters (Cmax and AUC) in baboons. We hypothesized that a slow infusion dosing regimen of ABT-089 could produce a lower Cmax but still achieve displacement ratios similar to those of a bolus injection. Toward this goal, we first measured displacement ratios and plasma exposures in baboons injected with a bolus of ABT-089 at a dose of 0.4 mg/kg i.v. PK simulations then were performed to devise a dosing scheme constrained by a predetermined Cmax value, and a corresponding imaging experiment was conducted. Afterward, the studies were repeated at different doses of ABT-089 (0.04 and 1 mg/kg i.v.) to delineate the full dose response. Finally, the relationship between displacements ratios and calculated Cmax or AUC was determined.
Materials and Methods
Animals and Drug Preparation.
All experiments were conducted in accordance with Institutional Animal Care and Use Committee (IACUC) guidelines at the VA Medical Center (West Haven, CT) and were reviewed and approved by the IACUC at Abbott Laboratories. Facilities at the VA Medical Center are further accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC). Ovariectomized female baboons (Papio anubis) (n = 4, age ranged from 6 to 20 years of age) were used as research subjects (10 scans). ABT-089 (Decker et al., 1997) was synthesized at Abbott Laboratories and dissolved in sterile water. The drug was administered intravenously with either a bolus injection or a 24-min slow infusion determined by pharmacokinetic simulations. No-carrier-added sodium [123I]iodide in 0.1 N NaOH (radionuclidic purity = 99.8%) was obtained from MDS Nordion (Vancouver, BC, Canada). Other reagents were of analytical grade and obtained from conventional chemical suppliers. Finally, 5-IA standard and precursor were prepared in-house following the published procedure (Musachio et al., 1999).
Radiochemistry and Metabolite Measurements.
[123I]5-IA was prepared using a modification of a previously published procedure (Horti et al., 1999). In brief, the following components were added to a vial with dry Na[123I]I/NaOH: 125 μl of 75% acetic acid and 25% water, 100 μg of N-tert-butoxycarbonyl-protected trimethylstannyl precursor (Koren et al., 1998) in 50 μl of methanol, and 125 μl of a 5 mg/ml solution of chloramine-T in methanol. The reaction mixture was heated at 100°C for 14 to 16 min, cooled for 4 to 6 min in ice-cold water, and quenched by the addition of 100 μl of a 100 mg/ml aqueous solution of Na2S2O5. The vial headspace was flushed with 10 ml of air into a charcoal filter, and then the quenched reaction mixture was injected onto a reverse-phase HPLC column, and the vial was rinsed with 0.2 to 0.3 ml of 50% aqueous acetonitrile and also injected into reverse-phase HPLC column. The column (Nova-Pak C18, 4 μm, 4.6 × 250 mm; Waters, Milford, MA) was eluted with a mixture of acetonitrile and water [67:33 (v/v)] at a flow rate of 1.0 ml/min. The fraction containing the radiolabeled N-tert-butoxycarbonyl-protected intermediate was collected into a 50-ml flask preloaded with 1 ml of trifluoroacetic acid, and the solvents were removed on a rotary evaporator at 40-45°C under reduced pressure and argon gas flow. The dry residue in the flask was treated with a mixture of 1 ml of trifluoroacetic acid and 4 ml of dichloromethane for 5 to 7 min at room temperature. Afterward, the content of the flask was evaporated to dryness (rotary evaporator, 40-45°C, reduced pressure, argon gas flow), reconstituted in 2 × 0.5 ml of 10% aqueous acetonitrile, and injected onto a reverse-phase HPLC column for final purification. The column (Gemini C18, 5 μm,, 4.6 × 250 mm; Phenomenex, Torrance, CA) was eluted with a mixture of acetonitrile, water, and trifluoroacetic acid [10:90:0.2 (v/v/v)] at a flow rate of 1.0 ml/min. The final product fraction was collected into a 50-ml flask, and the solvents were removed on a rotary evaporator at 40-45°C under reduced pressure and argon gas flow. The dry residue in the flask was dissolved in 0.4 ml of ethanol followed by 6 to 6.5 ml of sterile 0.9% sodium chloride for injection. The resulting solution was filtered through a 0.2-μm sterilizing filter into a sterile empty vial. Quality control testing included visual inspection, determination of radioactivity concentration, identity, and radiochemical purity by HPLC as well as pH, pyrogen content, and sterility. Decay-corrected production yield was in the range of 12 to 50%. Each synthesis produced tracers with high specific activity (>5000 Ci/mmol) and radiochemical purity (>95%). Finally, concentrations of parent [123I]5-IA and its metabolite in the plasma as well as free faction were measured using venous blood samples as described previously by Zoghbi et al. (2001).
Pharmacokinetic Calculations and Simulations.
Calculations and simulations were run on a Dell OptiPlex GX620 with 2.0 Gb of RAM and a 2.8-GHz Intel processor running on Microsoft Windows XP Professional and WinNonlin Professional, version 5.2.1 (Pharsight Corporation, St. Louis, MO). Pharmacokinetic parameters (Cmax and AUC0-∞) were determined by fitting a two-compartment model (Gabrielsson and Weiner, 1999) using plasma exposure data obtained from each subject. The selection of two-compartment model, instead of a one-compartment model, was based on the Akaike Information Criterion, a measure of goodness of fit (Ludden et al., 1994), as well as visual inspection of the measured versus predicted concentration-time profiles. A schematic diagram of the two-compartment model is shown below where the model was parameterized in terms of total clearance (CL) and distribution clearance (CLd) and central (Vc) and tissue (Vt) volume of distribution. As a basis for initial dosing regimen prediction, ABT-089 pharmacokinetics previously determined in cynomolgus monkeys (Vc = 2 l/kg, Vt = 3 l/kg, CL = 1.9 l · h−1 · kg−1, CLd = 3.5 l · h−1 · kg−1) were assumed to be predictive of those in baboon (Scheme 1).
Using this model, simulated intravenous infusions to baboon of various doses and infusion durations were performed to determine the dosing regimen that would best approximate the optimally efficacious ABT-089 plasma concentration-time profile in rhesus monkeys (Decker et al., 1997). In addition to Cmax and AUC0-∞, area under the plasma concentration-time curve was determined from the time of the start of the dose infusion to 100 min (1.67 h, AUC0-1.67 h) because maximal displacement (receptor occupancy) was observed at or near the 100-min time point.
[123I]5-IA SPECT Imaging.
All scans were acquired at Molecular NeuroImaging L.L.C. (New Haven, CT) on the NeuroFocus SPECT camera (NeuroLogica, Danvers, MA), a research-dedicated brain-imaging camera with an isotropic spatial resolution of approximately 2.5 to 3.5 mm. Four ovariectomized female baboons (16–17 kg) were used for the study. Animals were fasted for 18 to 24 h before imaging. On the day of imaging, the baboon was first anesthetized with intramuscular ketamine (10 mg/kg) and glycopyrrolate (0.01 mg/kg), transferred to the SPECT camera, and immediately intubated with an endotracheal tube for continued anesthesia with 2.5% isoflurane administered through a rebreathing circuit. An intravenous perfusion line was established in a leg vein for injection of fluids for hydration and collection of blood samples for metabolite analysis. Furthermore, a second line was established in the other leg for injection of the radiotracer. It is noteworthy that the interval between ketamine administration and the injection of [123I]5-IA was at a minimum of 2 h to allow the physiology of the animal to stabilize under anesthesia. The subject's head was immobilized within the gantry with a “bean bag” that hardens upon evacuation of air (Olympic Medical, Seattle, WA). Body temperature was kept between 36.1 and 38.5°C using a heated water blanket, and vital signs, including heart rate, respiration rate, oxygen saturation, and body temperature, were monitored every 15 min during the study. The acquisition time for each data point was approximately 22 min, and the total imaging time was approximately 6 h.
Pharmacokinetic Analysis of ABT-089 Exposures.
Plasma samples were collected and immediately stored in a freezer for later analysis. Samples were shipped from Molecular NeuroImaging L.L.C. to Abbott Laboratories and analyzed for concentrations of ABT-089. In brief, ABT-089 was selectively removed from plasma using protein precipitation with a mixture of acetonitrile and methanol [4:1 (v/v)]. Samples then were vortexed vigorously followed by centrifugation. The supernatant was transferred and evaporated to dryness with a gentle stream of nitrogen under gentle heat (approximately 35°C). Afterward, samples were reconstituted by vortexing with mobile phase. ABT-089 and its internal standard were separated from coextracted contaminants on a 50 × 3-mm Thermo Betasil CN column with an acetonitrile/ammonium acetate (10 mM) [16:84 (v/v)] mobile phase at a flow rate of 0.4 ml/min with a 10-μl injection. Finally, ABT-089 was quantified using multiple reaction monitor detection with a turbo ionspray source on a mass spectrometer (Applied Biosystems, Foster City, CA).
Raw data were reconstructed using an iterative three-dimensional algorithm provided by the manufacturer in which spatial filtering, noise reduction, and uniform attenuation correction (μeff = 0.012 mm−1) were applied. Once reconstructed, image data were coregistered to a standard imaging template using statistical parametric mapping (Welcome Department of Cognitive Neurology, London, UK). Afterward, a radioligand-specific volume of interest (VOI) template was applied using multimodality radiological image processing (MEDx; Sensor System, Sterling, VA), in which each image volume (thalamus, frontal and parietal cortices, and cerebellum) was identified in the dynamic SPECT dataset. Total counts within the VOI, total volume of VOI, and count density (counts/voxel) were determined for each region from individual subjects. Accordingly, time-activity curves (TACs) were generated from VOIs, depicting the regional brain count density, reflecting total uptake. These TACs then were corrected for radioactive decay, and a calibration factor obtained from phantom studies was applied. Finally, the volume of distribution (VT) of each VOI was derived and normalized by the concentration of the free [123I]5-IA parent compound in plasma (fP) at each time point. In the past, we have used and validated VT/fP as a suitable measure for nAChR binding activity because of the absence of a receptor-poor reference region (Fujita et al., 2000). Thus, calculations of the displacement were determined by taking the mean of the three images before either ABT-089 injection as a baseline, (VT/fP)baseline, and subtracting the postdisplacing dose nadir, (VT/fP)nadir, and then expressing this delta as percentage of baseline as follows: percentage displacement [%] = ([(VT/fP)baseline − (VT/fP)nadir] × 100)/(VT/fP)baseline.
Figure 1 illustrates the TACs obtained from a baboon administered with ABT-089 at 0.4 mg/kg via a bolus injection (Fig. 1A) or slow infusion (Fig. 1B). These data indicate that, regardless of the dosing regimen used, the highest uptake of [123I]5-IA was found in thalamus with moderate binding in frontal and parietal cortices, whereas minimal activity was shown in cerebellum. These distributions are consistent with results reported from previous in vivo studies (Chefer et al., 1998; Fujita et al., 2000). Furthermore, considering regional differences in the rate of changes in activities before and after the ABT-089 injection (Fig. 1), the displacement by ABT-089 showed greater effect in thalamus (high nAChR density) than cerebellum (low nAChR density), suggesting that displacement resulted from specific nAChR binding and not from nonspecific binding. [123I]5-IA has been validated and commonly used for imaging nAChRs in vivo across species in which the highest uptake of [123I]5-IA in brain was consistently found in thalamus and with moderate cortical binding in rodents (Fox et al., 2009), primates (Baldwin et al., 2006), and human (Fujita et al., 2003b).
Corresponding measured and simulated PK data are shown in Fig. 2 where the kinetics of plasma exposures seem to be well described using a two-component model. A lower Cmax was achieved when ABT-089 was given by slow infusion. Furthermore, our data show that ABT-089 displaced [123I]5-IA binding more rapidly when the drug was given by a bolus injection, which can be associated with kinetics of drug exposures. Images of [123I]5-IA uptake acquired at baseline and after ABT-089 infusion at various doses (0.01, 0.4, and 1 mg/kg i.v., slow infusion) are shown in Fig. 3, whereas the measured and simulated kinetics of ABT-089 exposures from each dosing group are shown in Fig. 4. It is evident that the binding activity in the thalamus was significantly diminished at the higher doses of ABT-089 and varied in a dose-related fashion. Table 1 lists plasma PK parameters (Cmax, AUC0-∞, and AUC0-1.67 h) calculated from each subject as well as corresponding displacement ratios in which ABT-089 pharmacokinetics in baboon (Vc = 1.7 l/kg, Vt = 2.6 l/kg, CL = 1.6 l · h−1 · kg−1, CLd = 4.0 l · h−1 · kg−1) were similar to those previously observed in cynomolgus monkeys. Consistent with imaging data, a dose response was observed from the calculated displacement ratios. It is remarkable that there is a good agreement in displacement ratios (mean ± S.E.M.) when 0.4 mg/kg ABT-089 was given via a bolus injection (42 ± 5.7%) or by slow infusion (38 ± 5.6%), even though the observed Cmax values are substantially different (see Table 1 and Fig. 4). These findings demonstrate the feasibility of reducing Cmax and maintaining targeted displacement ratios. Finally, plots of displacement ratios as a function of Cmax, AUC0-∞, or AUC0-1.67 h of the drug exposure are shown in Fig. 5, A to C, respectively. AUC0-1.67 h was specifically calculated because the TACs that delineated the [123I]5-IA displacements mainly occurred within the first 100 min or 1.67 h after ABT-089 infusion (Fig. 1). The results indicate that, compared with Cmax, displacement ratios can be better characterized by AUC0-∞ or AUC0-1.67 h when a one-phase exponential association model is used. Thus, our data indicate that the displacement ratio is probably driven by the AUC of drug exposure, regardless of the dosing regimens used. Finally, a strong correlation (R2 = 0.97, p < 0.001) was found between AUC0-∞ and AUC0-1.67 h (Fig. 5D), suggesting that AUC0-1.67 h can well represent AUC0-∞ and that AUC of plasma exposure beyond 1.67 h is essentially negligible.
In this study, we examined the association between ABT-089 displacement ratios and plasma exposures in baboons using [123I]5-IA SPECT imaging in which the dosing regimen was determined using two-compartment modeling with predetermined PK profiles. Our key finding is that similar displacement ratios were obtained for a given dose of ABT-089, regardless of whether the drug was given as a bolus injection or by slow infusion (Table 1). In particular, we showed that ABT-089 plasma exposures can be predicted by PK simulations, whereas the Cmax can be established within a predetermined value (Fig. 2). Because the CNS-related adverse effects of nicotinic compounds are mainly driven by the Cmax (Mansner and Mattila, 1977; Freeman et al., 1987), our data provide evidence that adverse effects can be potentially circumvented without compromising targeted binding activities.
In the past, PET imaging has been applied to determine the relationship between receptor binding and drug plasma exposure to drive dose selection for clinical studies (Farde et al., 1989; Movin-Osswald et al., 1994). For example, to study the PK profile of raclopride and its relationship with pharmacodynamic responses, Movin-Osswald et al. (1994) have previously examined the effect of administration rate on acathisia and prolactin. From their study, it was concluded that the frequency and duration of acathisia produced by raclopride seemed to mostly relate to plasma exposures, whereas the infusion rate was probably more correlated with the severity of symptoms. In fact, the high incidence of acathisia was associated with increased AUC of raclopride (Movin-Osswald et al., 1994). In light of the findings that acathisia is driven by high D2-receptor occupancy (>80%) (Nyberg et al., 1995), our nAChR occupancy data are consistent with the previous findings that dopamine D2-receptor binding activity is most probably determined by AUC instead of Cmax. Nonetheless, in contrast to administering ascending doses infused over the same duration or the same dose administered over different rates, we determined the dosing regimen based on a two-compartment PK model that allows the adjustment of the dose and infusion times simultaneously. More importantly, the current approach can potentially be extended to predict the optimal oral-dosing regimens for human studies and thus facilitates the clinical development of novel therapeutics.
Previous radioligand binding studies have shown that ABT-089 interacts with high affinity at the α4β2* subtype of both rodent and human nAChRs in which affinities were measured by displacement of specific [3H](−)-cytisine binding from rat brain membranes (Ki = 17 nM) and from human α4β2* nAChRs stably expressed in a human embryonic kidney cell line (Rueter et al., 2004). Results from our in vivo imaging study show that ABT-089 displaces [123I]5-IA uptake at brain regions with a high density of α4β2* nAChRs, which is consistent with these in vitro data. In contrast to in vitro studies, however, changes in the affinity state of receptors (Quick and Lester, 2002) or internalization may influence observed [123I]5-IA binding patterns (Fujita et al., 2003a). ABT-089 has been shown to improve behavioral performance across a range of cognitive domains in animals (Decker et al., 1997) but has demonstrated a mixed picture of efficacy in humans (Wilens et al., 2006; Bain et al., 2009; Gault et al., 2009). One challenge to the development of compounds as ionotropic receptor agonists is the propensity for such compounds to demonstrate complex dose-response relationships. In the case of ABT-089, optimal efficacy on tasks such as delayed match to sample in primates is seen at peak exposures of 2 to 50 ng/ml and tends to diminish at higher exposures (Decker et al., 1997). Therefore, the standard approach of phase 2 dose selection of maximizing the dose based on phase 1 tolerability limits may not be optimal for a compound with this type of profile. For this reason, a translational receptor-occupancy study, with corresponding preclinical efficacy data, may assist in the evaluation of doses selected for clinical trials. For example, the lowest dose used in this study (0.04 mg/kg) was chosen to produce plasma exposures known to be efficacious in the delayed match-to-sample task in nonhuman primates (Fig. 6). Based on the exposure-receptor occupancy curve shown in Fig. 4, these exposures are expected to produce receptor occupancy of approximately 10 to 30%, which is substantially lower than those of needed to see efficacy with G protein-coupled receptor antagonists (e.g., >60-70% for D2 antagonists). However, these findings are consistent with values obtained with other agonists [e.g., ziprasidone at the 5HT1A receptor (Grimwood and Hartig, 2009)]. This finding of behavioral efficacy with low receptor occupancy can be also reconciled with the steep dose-response curve observed for ABT-089 in primates (Prendergast et al., 1998), suggesting that receptor occupancies substantially beyond 20 to 30% do not provide additional cognitive efficacy and may diminish efficacy.
The relatively low occupancy required for the partial agonist ABT-089 in animal models contrasts with the much higher level of occupancy required for the D2-partial agonist aripiprazole. Aripiprazole has been recently approved for treating psychiatric disorders and requires 90% receptor occupancy to achieve efficacy in preclinical animal models (Natesan et al., 2006) as well as in patients with schizophrenia (Gründer et al., 2008). Unlike other D2-partial agonists that failed in clinical development, aripiprazole has high affinity for D2/D3 receptors and a long plasma half-life, which leads to high-receptor occupancy over a long period time (Gründer et al., 2008). The difference in receptor occupancy required for these two partial agonists is probably related to differences in the role of dopaminergic transmission in psychosis and nicotinic cholinergic transmission in cognitive function. Given the efficacy of D2 antagonists in psychosis, the therapeutic action of aripiprazole in psychosis probably involves a partial agonist-induced reduction in dopaminergic transmission. In contrast, the cognitive effects of nAChR agonists are generally prevented by nAChR antagonists, suggesting that nAChR receptor activation is important for this action, although receptor desensitization may play a role in some therapeutic effects of nAChR agonists [e.g., antidepressant effects reported by Shytle et al. (2002)]. Indeed, an understanding of the dose/receptor-occupancy relationship is important in the interpretation of clinical trial data of drugs that act as receptor agonists, because the result can be dictated by intrinsic characteristics of the specific compound (e.g., affinity or plasma half-life).
In summary, PET and SPECT imaging can allow confirmation of brain penetration and target engagement and subsequently drive the dose selection for later clinical development; both imaging techniques have been increasingly exploited as a valuable tool for CNS drug discovery (Wong et al., 2009). In this work, by comparison of bolus and slow infusion dosing regimens, we demonstrated that displacement of [123I]-5IA by ABT-089 is predominantly driven by the AUC0-∞ instead of the Cmax. In conjunction with PK simulations, we showed that desired ABT-089 plasma exposure profiles can be established without diminishing targeted receptor occupancy levels. Because adverse effects of nicotinic agonists are mainly driven by the Cmax, this observation indicates that a larger therapeutic window can be achieved through careful selection of dosing regimens, assuming that clinical efficacy is imparted by receptor binding in vivo.
Participated in research design: Chin, Carr, Llano, Tamagnan, Decker, and Fox.
Conducted experiments: Barret and Xu.
Contributed new reagents or analytic tools: Xu, Koren, and Marsh.
Performed data analysis: Chin, Carr, Xu, Batis, Seibyl, and Tamagnan.
Wrote or contributed to the writing of the manuscript: Chin, Carr, Llano, Barret, Xu, Koren, Tamagnan, Decker, Day, and Fox.
We thank Drs. Chih-Hung Lee, Timothy Esbenshade, R. Scott Bitner, Robert Lenz, and Mario Saltarelli for insightful discussion.
This work was supported in part by Abbott Laboratories.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
- neuronal acetylcholine nicotinic receptor
- area under the curve
- central nervous system
- 2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride
- positron emission tomography
- single photon emission computed tomography
- maximal plasma exposure; CL systemic clearance
- volume of distribution of plasma
- volume of distribution of tissue
- intercompartmental clearance
- volume of interest
- free plasma concentration
- volume of distribution
- high-performance liquid chromatography
- time-activity curve
- Received August 16, 2010.
- Accepted December 14, 2010.
- U.S. Government work not protected by U.S. copyright