PF-05212377 (SAM760) is a potent and selective 5-HT6 antagonist, previously under development for the treatment of Alzheimer's disease. In vitro, PF-05212377 was determined to be a P-gp/non-BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF-05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (Cbu /Cpu ) of 0.05 in rat and 0.64 in non-human primates (NHP). Based on pre-clinical evidence, brain penetration and target engagement of PF-05212377 was confirmed in NHP using positron emission tomography (PET) measured 5-HT6 receptor occupancy (%RO). The NHP Cpu EC50 of PF-05212377 was 0.31 nM (consistent with the in vitro human 5HT6 Ki : 0.32 nM). P-gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non-human primates and human; brain penetration of PF-05212377 in humans was postulated to be similar to that in non-human primates. In humans, PF-05212377 demonstrated dose and concentration dependent increases in 5-HT6 RO; maximal 5-HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC50 of 0.37 nM (which was similar to the in vitro human 5HT6 binding Ki 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF-05212377, a P-gp/non-BCRP substrate. Clinical trial number: NCT01258751.

SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM-760 was predominantly metabolized by CYP3A (∼85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In the presence of ketoconazole, the mean Cmax and area under the plasma concentration-time curve from time zero extrapolated to infinite time values of SAM-760 showed only a modest increase by 30% and 38%, respectively. In vitro investigation of this unexpectedly low interaction was undertaken using [14C]SAM-760. Radiometric profiling in human hepatocytes confirmed all oxidative metabolites previously observed with unlabeled SAM-760; however, the predominant radiometric peak was an unexpected polar metabolite that was insensitive to the pan-P450 inhibitor 1-aminobenzotriazole. In human hepatocytes, radiometric integration attributed 43% of the total metabolism of SAM-760 to this non-P450 pathway. Using an authentic standard, this predominant metabolite was confirmed as benzenesulfinic acid. Additional investigation revealed that the benzenesulfinic acid metabolite may be a novel, nonenzymatic, thiol-mediated reductive cleavage of an aryl sulfonamide group of SAM-760. We also determined the relative contribution of P450 to the metabolism of SAM-760 in human hepatocytes by following the rate of formation of oxidative metabolites in the presence and absence of P450 isoform-specific inhibitors. The P450-mediated oxidative metabolism of SAM-760 was still primarily attributed to CYP3A (33%), with minor contributions from P450 isoforms CYP2C19 and CYP2D6. Thus, the disposition of [14C]SAM-760 in human hepatocytes via novel sulfonamide metabolism and CYP3A verified the lower than expected clinical DDI when SAM-760 was coadministered with ketoconazole.

Background/Aims: Few studies have modeled individual Neuropsychiatric Inventory (NPI) symptom scores for Alzheimer disease (AD) patients and assessed the value of therapeutic interventions that can potentially impact them. The main objective of this study was to evaluate the impact of new AD symptomatic treatments on relevant health economic outcomes via their potential effects on cognition and neuropsychiatric symptoms such as depression, irritability, anxiety, and sleep disorder. Methods: We enhanced the previously published AHEAD model (Assessment of Health Economics in Alzheimer’s Disease) by including new variables and functional relations to capture the NPI’s individual neuropsychiatric symptoms in addition to the total NPI score. This update allowed us to study the longitudinal effect of improvements in specific NPI subscale scores and the downstream impact on outcomes such as psychiatric medication use, survival, and institutional placement. Results: The model base-case results showed that a hypothetical treatment with symptomatic effects on anxiety, depression, and irritability NPI subscales was not cost-effective; however, the treatment’s cost-effectiveness was improved once a direct link between NPI subscales and mortality was explored or under relatively stronger treatment effects. Conclusion: Treatments that influence specific symptoms within the overall NPI have the potential to improve patient outcomes in a cost-effective way. This model is a useful tool for evaluating target product profiles of drugs with effect on NPI symptoms in early stages of development.

Symptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg.

Background: Limited data exist on the presence of pregabalin in human breast milk of nursing mothers. Objectives: This study aimed to determine pregabalin concentrations in breast milk, estimate the infant daily pregabalin dose from nursing mothers, and evaluate pregabalin pharmacokinetic data in lactating women (≥ 12 weeks postpartum). Methods: In this multiple-dose, open-label, pharmacokinetic study, 4 doses of pregabalin 150 mg were administered orally at 12-hour intervals. Urine, blood, and breast milk samples were collected up to 12, 24, and 48 hours, respectively, following the fourth dose. Pharmacokinetic parameters were estimated using noncompartmental methods. Adverse events were monitored throughout. Results: Ten healthy lactating women (age 24-37 years) received pregabalin. Geometric mean pregabalin Cmaxss and AUCτ values in breast milk were approximately 53% and 76%, respectively, of those for plasma. The mean amount of pregabalin in breast milk recovered in a 24-hour period after the last dose was 574 μg (range, 270-1720 μg), which is approximately 0.2% of the administered daily maternal dose of 300 mg. The estimated average daily infant dose of pregabalin from breast milk was 0.31 mg/kg/day, which would be approximately 7% (23% coefficient of variation) of the body weight normalized maternal dose. Approximately 89% of the dose administered was recovered in urine. Renal clearance averaged 68.2 mL/min. Adverse events were of mild or moderate severity. Conclusion: Lactation appears to have had little influence on pregabalin pharmacokinetics. Overall, the estimated dose of pregabalin in breastfed children of women receiving pregabalin is low. Pregabalin was well tolerated in lactating women. Declaration of Conflicting Interests The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Peter A. Lockwood, Lynne Pauer, Joseph M. Scavone, Maud Allard, Laure Mendes da Costa, Tanja Alebic-Kolbah, Anna Plotka, Christine W. Alvey, and Marci L. Chew were all full-time employees of Pfizer at the time the study was completed and hold stock and/or stock options in Pfizer. Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Pfizer, which was involved in the study design, the collection, analysis, and interpretation of the data, the writing of the report, and the decision to submit the paper for publication. Medical writing support was provided by Penny Gorringe, MSc, of Engage Scientific Solutions and funded by Pfizer.

Kidney plays a critical role in the elimination of xenobiotics. Drug-drug interactions (DDIs) via inhibition of renal organic anion (OAT) and organic cation (OCT) transporters have been observed in the clinic. This study examined the quantitative predictability of renal transporter-mediated clinical DDIs based on basic and mechanistic models. In vitro transport and clinical pharmacokinetics parameters were used to quantitatively predict DDIs of victim drugs when coadministrated with OAT or OCT inhibitors, probenecid and cimetidine, respectively. The predicted changes in renal clearance (CLr) and area under the plasma concentration-time curve (AUC) were comparable to that observed in clinical studies. With probenecid, basic modeling predicted 61% cases within 25% and 94% cases within 50% of the observed CLr changes in clinic. With cimetidine, basic modeling predicted 61% cases within 25% and 92% cases within 50% of the observed CLr changes in clinic. Additionally, the mechanistic model predicted 54% cases within 25% and 92% cases within 50% of the observed AUC changes with probenecid. Notably, the magnitude of AUC changes attributable to the renal DDIs is generally less than 2-fold, unlike the DDIs associated with inhibition of CYPs and/or hepatic uptake transporters. The models were further used to evaluate the renal DDIs of Pfizer clinical candidates/drugs, and the overall predictability demonstrates their utility in the drug discovery and development settings.

As part of a phase 2b study protocol (NCT00895895) for the 5HT 6 antagonist SAM-531, a 24-week interim analysis was conducted to assess futility and, in the event of non-futility, to select dose(s) for subsequent development. The pre-specified interim analyses included a model-based dose-response analysis of the longitudinal effects of SAM-531 on ADAS-cog and a comparison with the longitudinal profile for the donepezil 10 mg QD active control arm, leveraging prior data where appropriate. A disease progression model (DPM) describing the change in ADAS-cog over time under a variety of covariate settings had recently been developed on behalf of the Coalition Against Major Disease (CAMD) initiative, and was used in the analysis and interpretation of the SAM-531 interim data. The DPM was updated with terms to characterize the dose-response and time course of effect of SAM-531, and applied to a data set containing both historical and SAM-531 interim data. Longitudinal means for the placebo arm diverged from historical trends, but were contained, or in the case of the 18-week visit nearly contained, within 90% prediction intervals based on the model. Longitudinal means for the donepezil arm were fully consistent with model predictions based on historical data. Based on simulation from the fitted model, a 5 mg QD regimen of SAM-531 was estimated to be associated with a 1.26 point (90% CI: 0.23-2.29) reduction in ADAS-cog relative to placebo at 24 weeks. The model-based estimate of the placebo time course, based on both current trial data and historical data, provided a relevant comparator against which to estimate the effects of SAM-531. Despite an unusual mean trend in the placebo arm, the location of the trial placebo data relative to the predictive distribution based on historical placebo data supported the determination that the current trial was not a “failed” trial. Use of this model-based comparator suggests a positive dose-response for SAM-531, albeit not one with a magnitude of effect sufficient to support further development of the compound at this time.

Many of the cognitive deficits seen in Alzheimer's disease (AD), result from progressive loss of cholinergic neurons, and may be mimicked in healthy volunteers by administration of the muscarinic receptor antagonist, scopolamine, which produces a transient cholinergic blockade. The clinical relevance and the predictive value of the scopolamine model are supported by the fact that donepezil can reverse scopolamine-induced deficits in healthy subjects. Selective 5-HT6 receptor antagonists, which indirectly modulate cholinergic and glutaminergic tone in relevant brain regions, may be able to similarly reverse scopolamine-induced deficits and thereby provide a mechanistic signal. Randomized, double-blind, placebo-controlled 5-way crossover study to evaluate the effect of a single dose of SAM-760 (5, 20 or 60 mg), donepezil (10 mg; positive control) or placebo on scopolamine (0.5mg) induced psychomotor and cognitive deficits in 30 young healthy adults. A computerized battery of neuropsychological tests (CogState) was administered during each crossover period; the key outcome measure was the Groton Maze Learning Task (GMLT). In addition to safety, exploratory phamacodynamic (PD) and pharmacokinetic (PK) measures were also assessed. The cognitive test battery was well tolerated and subject performance met standards of data integrity. Within-subject variability in performance on the battery was consistent with previous studies. There was a significant learning effect, but the carryover effect was not significant. Peak effect of scopolamine occurred 1–3 hours -postdose. Donepezil partially reversed cognitive deficits on most but not all measures of the battery. None of the SAM-760 doses were able to significantly ameliorate the effects of scopolamine. All study drug treatments received in the trial were well-tolerated with the exception of one SAE of mood disorders with suicidal ideation occurring in the donepezil cohort. A dose of 0.5mg scopolamine induced comprehensive cognitive impairment in healthy young subjects as anticipated. A single 10mg dose of donepezil ameliorated the majority of these effects, whereas SAM-760, at the evaluated doses, did not demonstrate an effect. 5-HT6 antagonism by itself may be insufficient to ameliorate a profound cholinergic deficit. Alternatively, chronic dosing with a 5-HT6 antagonist may be required to effect a change in such an experimental scopolamine model.

PD0332334 (PD334) is a novel beta amino acid analog of pregabalin (Pgb). Pregabalin has been previously studied in six clinical studies of general anxiety disorder (GAD). Because these compounds have similar pharmacology, certain features of their dose response relationships could be similar. Thus, data from the pregabalin GAD program was used to provide information about the safety (incidence of somnolence) and efficacy (reduction in Hamilton Anxiety Rating score) dose response relationships for PD334 in GAD. This chapter illustrates the use of prior pregabalin data from other large-scale clinical studies to select the PD334 dose range to study in Phase 3, and the implementation of models based on assumptions of common PD334/pregabalin dose-response features that resulted from consideration of the comparative pharmacology. External validation of the PD334 dose-response model with Phase 3 data is demonstrated.

We examined uptake of the model therapeutic agent, minoxidil, into appendages, stratum corneum (SC), and through human skin, under the influence of different vehicles. Quantitative estimation of therapeutic drug deposition into all three areas has not previously been reported. Finite doses of minoxidil (2%, w/v) in formulations containing varying amounts of ethanol, propylene glycol (PG), and water (60:20:20, 80:20:0, and 0:80:20 by volume, respectively) were used. Minoxidil in SC (by tape stripping), appendages (by cyanoacrylate casting), and receptor fluid was determined by liquid scintillation counting. At early times (30 min, 2 h), ethanol-containing formulations (60:20:20 and 80:20:0) caused significantly greater minoxidil retention in SC and appendages, compared to the formulation lacking ethanol (0:80:20). A significant increase in minoxidil receptor penetration occurred with the PG-rich 0:80:20 formulation after 12 h. We showed that deposition of minoxidil into appendages, SC, and skin penetration into receptor fluid were similar in magnitude. Transport by the appendageal route is likely to be a key determinant of hair growth promotion by minoxidil.

Analyses using different techniques and data types have reported conflicting results on the progression of Alzheimer's disease (AD), and whether the annual decline in cognition has changed over the past two decades. In an Alzheimer's Association press release in July 2008, it was suggested that a slower rate of cognitive decline in placebo-treated patients may reduce the ability to show effectiveness of new therapies. Model-based analyses of literature data and of individual studies were undertaken to assess factors influencing disease progression, including temporal trends. Summary study-level data from 52 studies representing 19,972 patients and 84,441 individual observations were used to develop a longitudinal meta-analysis model describing the time course of change in ADAS-cog in patients receiving placebo or acetylcholinesterase inhibitors. Patient-level data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and legacy studies available at Pfizer were also used to develop a similar patient-level model that described ADAS-cog changes for individual patients, as well as a combined summary/patient-level model. Disease severity (at baseline, year of study conduct or publication), APOe4 status (where available) and demographic factors were assessed as potential covariates. Results were compared with meta-analyses and individual study analyses reported at ICAD 2008. Across all analyses, the most important factor determining the annual change in ADAS-cog in mild-to-moderate AD was baseline severity. Baseline severity on ADAS-cog was well predicted by baseline MMSE. Evidence that disease progression has changed remarkably as a function of time is minimal and mixed, with annual progression rates ranging from 4.91 to 6.4 within individual analyses. Acetylcholinesterase inhibitor effects were adequately described as a symptomatic offset. A similar model structure can adequately describe data from the literature and within individual studies for mild-to-moderate AD. The model allows for ongoing inclusion of new patient-level and summary-study level data, hypothesis testing for new covariates as they arise, and appropriate clinical trial simulation and testing of trial performance characteristics for various trial designs used in patients with mild-to-moderate AD. The results suggest that 6 months may be an inadequate duration to assess whether average disease progression has changed over the past two decades.

Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200–400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials.

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products" made this scientific approach to the drug approval process possible.

PURPOSE:Pregabalin is being evaluated for the treatment of neuropathic pain. Two phase 2 studies were simulated to determine how precisely the dose that caused a one-point reduction in the pain score could be estimated. The likelihood of demonstrating at least a one-point change for each available dose strength was also calculated.METHODS:A pharmacokinetic-pharmacodynamic (PK/PD) model relating pain relief to gabapentin plasma concentrations was derived from a phase 3 study. The PK component of the model was modified to reflect pregabalin PK. The PD component was modified by scaling the gabapentin concentration-effect relationship to reflect pregabalin potency, which was based on preclincal data. Uncertainty about the potency difference and the steepness of the concentration-response slope necessitated simulating a distribution of outcomes for a series of PK/PD models.RESULTS:Analysis of the simulated data suggested that after accounting for the uncertainty, there was an 80% chance that the dose defining the clinical feature was within 45% of the true value. The likelihood of estimating a dose that was within an acceptable predefined precision range relative to a known value approximated 60%. The minimum dose that should be studied to have a reasonable chance of estimating the dose that caused a one-point change was 300 mg.CONCLUSIONS:Doses that identify predefined response may be imprecisely estimated, suggesting that replication of a similar outcome may be elusive in a confirmatory study. Quantification of this precision provides a rationale for phase 2 trial design and dose selection for confirmatory studies.