Ahmed A. Othman, PhD, FCP

BACKGROUND: Results from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer's dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25-75 mg) and an open-label extension study (75 mg).

METHODS: The randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10-24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD (n = 77), ABT-126 50 mg QD (n = 108), ABT-126 75 mg QD (n = 73), donepezil 10 mg QD (n = 76), or placebo (n = 104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies.

RESULTS: A total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (-2.29 ± 0.95; one-sided P = 0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, -0.47 ± 0.94 (P = 0.309); ABT-126 50 mg, -0.87 ± 0.85 (P = 0.153); and ABT-126 75 mg, -1.08 ± 0.94 (P = 0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters.

CONCLUSIONS: In the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01527916 , Registered 3 February 2012 (randomized trial). ClinicalTrials.gov NCT01676935 . Registered 29 August 2012 (open-label extension study).

AIM: Daclizumab high yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit of the interleukin-2 receptor and is being developed for treatment of multiple sclerosis (MS). This manuscript characterized the pharmacokinetic-pharmacodynamic (PK-PD) relationships of daclizumab HYP in subjects with MS.

METHODS: Approximately 1400 subjects and 7000 PD measurements for each of three biomarkers [CD25 occupancy, CD56(bright) natural killer (NK) cell count, regulatory T cell (Treg) count] from four clinical trials were analyzed using non-linear mixed effects modelling. Evaluated regimens included 150 or 300 mg subcutaneous (s.c.) every 4 weeks.

RESULTS: CD25 occupancy was characterized using a sigmoidal maximum response (Emax ) model. Upon daclizumab HYP treatment, CD25 saturation was rapid with complete saturation occurring after approximately 7 h and maintained when daclizumab HYP serum concentration was ≥5 mg l(-1) . After the last 150 mg s.c. dose, unoccupied CD25 returned to baseline levels in approximately 24 weeks, with daclizumab HYP serum concentration approximately ≤1 mgl(-1) 1L. CD56(bright) NK cell expansion was characterized using an indirect response model. Following daclizumab HYP 150 mg s.c. every 4 weeks, expansion plateaus approximately at week 36, at which the average maximum expansion ratio is 5.2. After the last dose, CD56(bright) NK cells gradually declined to baseline levels within 24 weeks. Treg reduction was characterized by a sigmoidal Emax model. Average maximum reduction of 60% occurred approximately 4 days post 150 mg s.c. dose. After the last dose, Tregs were projected to return to baseline levels in approximately 20 weeks.

CONCLUSIONS: Robust PK-PD models of CD25 occupancy, CD56(bright) NK cell expansion and Treg reduction by daclizumab HYP were developed to characterize its key pharmacodynamic effects in the target patient population.

A double-blind, placebo-controlled, parallel-group, 24-week, multicenter trial was conducted to evaluate the efficacy and safety of 3 doses of ABT-126, an α7 nicotinic receptor agonist, for the treatment of cognitive impairment in nonsmoking subjects with schizophrenia. Clinically stable subjects were randomized in 2 stages: placebo, ABT-126 25 mg, 50 mg or 75 mg once daily (stage 1) and placebo or ABT-126 50 mg (stage 2). The primary analysis was the change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score for ABT-126 50 mg vs placebo using a mixed-model for repeated-measures. A key secondary measure was the University of California Performance-based Assessment-Extended Range (UPSA-2ER). A total of 432 subjects were randomized and 80% (344/431) completed the study. No statistically significant differences were observed in either the change from baseline for the MCCB neurocognitive composite score (+2.66 [±0.54] for ABT-126 50 mg vs +2.46 [±0.56] for placebo at week 12; P>0.05) or the UPSA-2ER. A trend for improvement was seen at week 24 on the 16-item Negative Symptom Assessment Scale total score for ABT-126 50 mg (change from baseline -4.27±[0.58] vs -3.00±[0.60] for placebo; P=0.059). Other secondary analyses were generally consistent with the primary end point results. Adverse event rates were similar for ABT-126 and placebo. ABT-126 did not demonstrate a consistent effect on cognition in nonsmoking subjects with schizophrenia; however, a trend toward an effect was observed on negative symptoms. ClincalTrials.gov registration: NCT01655680.

AIMS: To characterize the potential effect of daclizumab high-yield process (DAC HYP), a monoclonal antibody that blocks the high-affinity interleukin-2 receptors for treatment of multiple sclerosis, on activity of cytochrome P450 (CYP) enzymes.

METHODS: Twenty patients with multiple sclerosis received an oral cocktail of probe substrates of CYP1A2 (caffeine 200 mg), CYP2C9 (warfarin 10 mg/vitamin K 10 mg), CYP2C19 (omeprazole 40 mg), CYP2D6 (dextromethorphan 30 mg) and CYP3A (midazolam 5 mg) on two sequential occasions: 7 days before and 7 days after subcutaneous administration of DAC HYP 150 mg every 4 weeks for three doses. Serial pharmacokinetic blood samples up to 96 h post dose and 12-h urine samples were collected on both occasions. Area under the curve (AUC) for caffeine, S-warfarin, omeprazole and midazolam, and urine dextromethorphan to dextrorphan ratio were calculated. Statistical analyses were conducted on log-transformed parameters using a linear mixed-effects model.

RESULTS: The 90% confidence intervals (CIs) for the geometric mean ratio (probe substrate with DAC HYP/probe substrate alone) for caffeine AUC from 0-12 h (0.93-1.15), S-warfarin AUC from 0 to infinity (AUC[0-inf]) (0.95-1.06), omeprazole AUC(0-inf) (0.88-1.13) and midazolam AUC(0-inf) (0.89-1.15) were within the no-effect boundary of 0.80-1.25. The geometric mean ratio for urine dextromethorphan to dextrorphan ratio was 1.01, with the 90% CI (0.76-1.34) extending slightly outside the no-effect boundary, likely due to high variability with urine collections and CYP2D6 activity.

CONCLUSIONS: DAC HYP treatment in patients with multiple sclerosis had no effect on CYP 1A2, 2C9, 2C19, 2D6 and 3A activity.

OBJECTIVE: To evaluate the efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).

METHODS: Three hundred RA patients receiving stable doses of MTX were randomly assigned equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12, as determined using the last observation carried forward method.

RESULTS: At week 12, the proportion of ACR20 responses was higher with ABT-494 (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%) (using nonresponder imputation) (P < 0.05 for the 6, 12, and 24 mg doses). There was a significant dose-response relationship among all ABT-494 doses (P < 0.001). The proportions of patients achieving ACR50 and ACR70 responses were significantly higher for all ABT-494 doses (except the 12 mg dose for the ACR70 response) than for placebo, as were changes in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Rapid improvement was demonstrated by significant differences in ACR20 response rates and changes in the DAS28-CRP for all doses compared with placebo at week 2 (the first postbaseline visit). The incidence of adverse events was similar across groups; most were mild, and infections were the most frequent. One serious infection (community-acquired pneumonia) occurred with ABT-494 at 12 mg. There were dose-dependent increases in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, but the LDL cholesterol:HDL cholesterol ratios were unchanged through week 12. Mean hemoglobin levels remained stable at lower doses, but decreases were observed at higher doses.

CONCLUSION: This study evaluated a broad range of doses of ABT-494 in RA patients with an inadequate response to MTX. ABT-494 demonstrated efficacy, with a safety and tolerability profile similar to that of other JAK inhibitors.

BACKGROUND: ABT-494 is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders, with potential for an improved safety profile compared with non-selective JAK inhibitors. This work characterized the pharmacokinetics, safety, and tolerability of ABT-494 following single and multiple dosing of the immediate-release formulation.

METHODS: ABT-494 single (1-48 mg or placebo; n = 56) and multiple (3-24 mg or placebo twice daily for 14 days; n = 44) doses in healthy subjects, as well as multiple doses (3-24 mg or placebo twice daily for 27 days; n = 14) in subjects with rheumatoid arthritis (RA) on a background of methotrexate were evaluated. Pharmacokinetic samples were collected and safety and tolerability were assessed.

RESULTS: ABT-494 followed bi-exponential disposition, with a terminal elimination half-life of 6-16 h and a functional half-life, calculated from maximum observed plasma concentration (C max) to trough plasma concentration (C trough) ratio at steady state, of 3-4 h. ABT-494 exposure was approximately dose proportional over the 3-36 mg dose range, with no significant accumulation with repeated dosing. In subjects with RA, no pharmacokinetic interaction between ABT-494 and methotrexate was observed. The fraction of ABT-494 dose eliminated in urine as unchanged ABT-494 was 14-25 %. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE (15.6 % for ABT-494 vs. 16.7 % for placebo) after multiple twice-daily administration to healthy subjects. No clinically significant changes in laboratory parameters, vital signs, or electrocardiogram findings in healthy or RA subjects were observed.

CONCLUSIONS: The favorable pharmacokinetics, safety, and tolerability results from these studies supported further evaluations of ABT-494 in phase IIb dose-ranging trials in RA and Crohn's disease.

TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifier: NCT01741493.

OBJECTIVE: To compare the efficacy and safety of ABT-494, a novel selective JAK-1 inhibitor, with placebo in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti-tumor necrosis factor (anti-TNF) agent.

METHODS: In this 12-week, double-blind, placebo-controlled, dose-ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti-TNF agent were randomized equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12.

RESULTS: At week 12, significantly more patients receiving ABT-494 (53-71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose-response relationship among all ABT-494 doses (P < 0.001). ACR50 and ACR70 response rates were significantly higher in those receiving ABT-494 (36-42% and 22-26%, respectively) than in those receiving placebo (16% and 4%, respectively). Changes from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) were significantly greater for all doses of ABT-494 than for placebo (P ≤ 0.01). Onset of action of ABT-494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28-CRP (P < 0.001 for 6-18 mg). The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection. Infection rates were higher at higher doses of ABT-494, but no infections were serious. No deaths were reported among those receiving ABT-494.

CONCLUSION: In patients with an inadequate response or intolerance to anti-TNF agents, ABT-494 added to MTX showed rapid, dose-dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class. No new AEs were identified.

OBJECTIVE: The authors sought to evaluate the efficacy and safety of ABT-126, a selective α7 nicotinic receptor partial agonist, in stable patients with schizophrenia.

METHOD: A 12-week, double-blind, placebo-controlled, parallel-group phase 2 study was conducted in 22 centers in the United States. Clinically stable patients with schizophrenia were randomly assigned to receive once-daily dosing with 10 mg of ABT-126, 25 mg of ABT-126, or placebo. The primary efficacy measure was change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) composite score compared with placebo, tested by a one-sided t test. Secondary measures included MCCB domain scores and UCSD Performance-Based Skills Assessment total score, each tested by two-sided t tests.

RESULTS: A total of 207 subjects were randomized, of whom 165 (81%) completed the study. ABT-126 showed an improvement that fell short of significance on the MCCB composite score at week 12 (least squares mean difference from placebo, 1.3 and 1.5 for the 10 mg and 25 mg groups, respectively). A significant treatment-by-smoking status interaction was observed on the mean change from baseline to final MCCB composite score: nonsmokers (N=69) demonstrated a difference from placebo of 2.9 (SE=1.4) in the 10 mg group and 5.2 (SE=1.6) in the 25 mg group, whereas no differences were observed in smokers (N=113). Among the nonsmokers in the ABT-126 25 mg group (N=19), significant improvements compared with placebo occurred at final assessment for verbal learning (least squares mean difference=5.5, SE=1.9), working memory (least squares mean difference=5.4, SE=2.0), and attention/vigilance (least squares mean difference=8.7, SE=2.5). The most frequently reported adverse events for ABT-126 were dizziness, diarrhea, and fatigue (all <8% incidence).

CONCLUSIONS: ABT-126 demonstrated a procognitive effect in nonsmoking subjects, particularly in verbal learning, working memory, and attention.

BACKGROUND AND OBJECTIVES: Daclizumab high-yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit (CD25) of the interleukin-2 receptor. The present work characterized the population pharmacokinetics of daclizumab HYP in healthy volunteers (HVs) and subjects with relapsing-remitting multiple sclerosis (RRMS) and evaluated the effects of covariates on daclizumab HYP exposure.

METHODS: Measurable serum concentrations (n = 17,139) from 1670 subjects in seven clinical studies (three phase I, one immunogenicity, one phase II with extension, and one phase III) were included in this pharmacokinetic analysis using non-linear mixed-effects modeling. The three phase I studies evaluated single or multiple doses that ranged from 50 to 400 mg with either intravenous or subcutaneous (SC) administration in HVs (n = 71). The phase II with extension studies evaluated doses of 150 or 300 mg SC every 4 weeks (n = 567), and the immunogenicity (n = 113) and the phase III (n = 919) studies evaluated 150 mg SC every 4 weeks, all in RRMS patients.

RESULTS: A two-compartment model with first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Clearance (CL) was 0.212 L/day and the central volume of distribution was 3.92 L, scaled by [body weight (kg)/68] with exponents of 0.87 and 1.12, respectively. The peripheral volume of distribution was 2.42 L. Absorption lag time, mean absorption time, and absolute bioavailability (100-300 mg SC) were 1.61 h, 7.2 days, and 88 %, respectively. The daclizumab HYP terminal half-life was 21 days. Baseline CD25, age, and sex did not influence daclizumab HYP pharmacokinetics. Body weight explained 37 and 27 % of the inter-individual variability for CL and central volume of distribution, respectively. Neutralizing antibody (NAb)-positive status (included as a time-varying covariate) increased daclizumab HYP CL by 19 %.

CONCLUSIONS: Consistent with previous findings in HVs, this analysis including extensive data from RRMS patients demonstrates that daclizumab HYP is characterized by slow CL, linear pharmacokinetics at doses above 100 mg, and high SC bioavailability. The pharmacokinetics of daclizumab HYP were not influenced by age (range 18-66 years), the sex of adult subjects, or the baseline CD4+CD25+ T cells (target level). The impact of covariates (body weight, NAb) on daclizumab HYP pharmacokinetics is unlikely to be clinically relevant.

BACKGROUND: ABT-126 is a potent, selective α7 nicotinic acetylcholine receptor agonist with putative procognitive effects as a monotherapy in treating Alzheimer's disease (AD).

OBJECTIVE: This randomized, double-blind, placebo-controlled multicenter study (NCT01549834) investigated the efficacy and safety of ABT-126 in subjects with mild-to-moderate AD who were taking stable doses of acetylcholinesterase inhibitors (AChEIs).

METHODS: Subjects received 25 mg ABT-126 (n = 143), 75 mg ABT-126 (n = 145), or placebo (n = 146) once daily for 24 weeks. Subjects who completed the 24-week double-blind study were eligible to enroll in a 28-week open-label extension study (NCT01690195) and received 75 mg ABT-126 daily. The primary efficacy endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog).

RESULTS: Neither dose of ABT-126 demonstrated significant improvement compared with placebo in the primary efficacy endpoint. However, 25 mg ABT-126 demonstrated significant improvement compared with placebo in ADAS-Cog scores at week 4 (least squares mean difference, -1.21; standard error, 0.51; p <  0.010, one-sided); 75 mg ABT-126 did not demonstrate significant improvements in ADAS-Cog scores compared with placebo at any time point. A treatment effect was not observed for any secondary efficacy measures of cognition, function, or global improvement. ABT-126 was generally well tolerated; the most common adverse events were agitation, constipation, diarrhea, fall, and headache.

CONCLUSIONS: Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD.

BACKGROUND: Daclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the α subunit (CD25) of the high-affinity interleukin-2 receptor, has demonstrated efficacy for treatment of relapsing forms of multiple sclerosis in Phase II and III clinical trials.

OBJECTIVE: To characterize the pharmacokinetics (PK) of DAC HYP following repeated administration of the 150 mg subcutaneous (SC) dose every 4 weeks (q4wk), the proposed clinical regimen in patients with relapsing-remitting multiple sclerosis (RRMS).

METHODS: Twenty-six patients with RRMS received DAC HYP 150 mg SC q4wk for a total of six doses. Serial PK blood samples were collected over the first and last dosing intervals and trough PK samples were collected between these doses. Blood samples for immunogenicity assessment were collected throughout the study. Serum DAC HYP levels and anti-DAC HYP antibodies were characterized using validated immunoassays. PK parameters were estimated using noncompartmental analysis.

RESULTS: DAC HYP showed slow SC absorption with a median time to reach maximum observed concentration (Cmax) value of ~1 week. Steady state was reached by the fourth injection. At steady state, DAC HYP mean serum Cmax, minimum observed concentration (Cmin), and area under the concentration-time curve within a dosing interval (AUCtau) values were 29.1 µg/mL, 14.9 µg/mL, and 638 µg · day/mL, respectively, with intersubject variability of 35%-40%. The AUC accumulation ratio was ~2.5 at steady state. DAC HYP had a long elimination half-life of ~22 days and low apparent clearance (0.274 L/day). Nine patients tested positive for anti-DAC HYP antibodies, with no impact on DAC HYP clearance in this limited data set.

CONCLUSION: The PK of DAC HYP in patients with RRMS are consistent with those previously reported in healthy volunteers. The half-life of ~3 weeks and the low fluctuations in peak and trough concentrations of serum DAC HYP support the once-monthly SC dosing regimen.

Daclizumab high-yield process (DAC HYP) is a humanized monoclonal antibody that selectively blocks the $\alpha$-subunit (CD25) of the high-affinity interleukin-2 receptors, and has shown robust efficacy as a treatment for multiple sclerosis (MS). This work quantitatively characterized the relationship between DAC HYP serum concentrations and saturation of CD25 expressed on antigen-rich target T cells in blood.

IntroductionThe safety and efficacy of the novel α7 nicotinic acetylcholine receptor agonist ABT-126 were investigated in subjects with mild-to-moderate Alzheimer's dementia (AD).IntroductionThe safety and efficacy of the novel α7 nicotinic acetylcholine receptor agonist ABT-126 were investigated in subjects with mild-to-moderate Alzheimer's dementia (AD).

Oral levodopa-carbidopa (LC-oral) treatment in advanced Parkinson's disease (PD) is associated with motor complications due to large fluctuations in levodopa plasma concentrations. Levodopa–carbidopa intestinal gel (LCIG) provides individualized continuous levodopa–carbidopa delivery through intrajejunal infusion. This study evaluated the pharmacokinetics, safety, and efficacy of LCIG relative to LC-oral in Japanese subjects with advanced PD.

BACKGROUND AND OBJECTIVE: Daclizumab is a humanized monoclonal antibody that blocks the α-subunit of the interleukin-2 receptor with demonstrated benefits in the treatment of multiple sclerosis. The present work aimed to characterize the pharmacokinetics of daclizumab high-yield process (HYP) in healthy volunteers.

METHODS: Three double-blind, randomized, placebo-controlled, phase I studies evaluated the pharmacokinetics of daclizumab HYP in healthy volunteers following single subcutaneous administration (50, 150, or 300 mg), multiple subcutaneous administrations (100 or 200 mg biweekly with a 200 mg loading dose), or single intravenous administration (200 or 400 mg). Measurable serum concentrations (n = 925) from 70 subjects treated with daclizumab HYP in the three studies were analyzed using non-linear mixed-effects modeling.

RESULTS: A two-compartment model with a first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Daclizumab HYP clearance, inter-compartmental clearance, and central and peripheral volumes of distribution were 10 mL/h, 44 mL/h, 3.89 L, and 2.52 L, respectively, scaled by [bodyweight (kg)/70] with 0.54 and 0.64 exponents for clearance and volume parameters, respectively. Lag-time, mean absorption time, and absolute bioavailability (100-300 mg) for subcutaneous administration were 2 h, 4.6 days, and 84 %, respectively. Bodyweight explained only ~20 % of daclizumab HYP pharmacokinetic variability. With this limited dataset, sex, age, race, or presence of antibodies did not correlate with daclizumab HYP clearance. The estimated effective half-life was 21-25 days. The developed model was robust in bootstrap evaluation and predicted the data adequately in stochastic simulations.

CONCLUSIONS: Daclizumab HYP is characterized by slow clearance, linear pharmacokinetics (at doses ≥100 mg), high subcutaneous bioavailability, and a half-life suitable for monthly administration.

AIMS: ABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia.

METHODS: This was a randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic. In each dose group, five to seven and two to three participants were assigned to ABT-288 and placebo, respectively.

RESULTS: Of the 67 participants enrolled, nine participants (on ABT-288) were prematurely discontinued, in seven of these due to adverse events. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. The most common adverse events, in decreasing frequency (from 31 to 5%), were abnormal dreams, headache, insomnia, dizziness, somnolence, dysgeusia, dry mouth, psychotic disorder, parosmia and tachycardia. Adverse events causing early termination were psychotic events (four) and increased creatine phosphokinase, pyrexia and insomnia (one each). The half-life of ABT-288 ranged from 28 to 51 h, and steady state was achieved by day 12 of dosing. At comparable multiple doses, ABT-288 exposure in subjects with schizophrenia was 45% lower than that previously observed in healthy subjects. At trough, ABT-288 cerebrospinal fluid concentrations were 40% of the total plasma concentrations.

CONCLUSIONS: ABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. The greater ABT-288 tolerability was not due to limited brain uptake.

AIMS: Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa-carbidopa delivery through intrajejunal infusion. This study characterized the population pharmacokinetics of levodopa following a 16 h jejunal infusion of LCIG or frequent oral administration of levodopa-carbidopa tablets (LC-oral) in subjects with advanced Parkinson's disease (PD).

METHODS: A non-linear mixed-effects model of levodopa pharmacokinetics was developed using serial plasma concentrations from an LCIG phase 1 study and a phase 3 double-blind, double-dummy study of the efficacy and safety of LCIG compared with LC-oral in advanced PD patients (n = 68 for model development; 45 on LCIG and 23 on LC-oral). The final model was internally evaluated using stochastic simulations and bootstrap and externally evaluated using sparse pharmacokinetic data from 311 subjects treated in a long term safety study of LCIG.

RESULTS: The final model was a two compartment model with a transit compartment for absorption, first order elimination, bioavailability for LCIG (97%; confidence interval = 95% to 98%) relative to LC-oral, different first order transit absorption rate constants (LCIG = 9.2 h(-1) vs. LC-oral = 2.4 h(-1) ; corresponding mean absorption time of 7 min for LCIG vs. 25 min for LC-oral) and different residual (intra-subject) variability for LCIG (15% proportional error, 0.3 μg ml(-1) additive error) vs. LC-oral (29% proportional error, 0.59 μg ml(-1) additive error). Estimated oral clearance and steady-state volume of distribution for levodopa were 24.8 l h(-1) and 131 l, respectively.

CONCLUSIONS: LCIG administration results in faster absorption, comparable levodopa bioavailability and significantly reduced intra-subject variability in levodopa concentrations relative to LC-oral administration.

BACKGROUND: ABT-288, a highly selective histamine-3 receptor antagonist, demonstrated efficacy across several preclinical cognitive domains, and safety in healthy subjects and elderly volunteers.

OBJECTIVE: Evaluate the efficacy and safety of ABT-288 in subjects with mild-to-moderate Alzheimer's dementia.

METHODS: The study used a randomized, double-blind, placebo- and active-controlled, parallel group design with pre-defined futility criteria to permit early study termination. A total of 242 subjects were randomized in an equal ratio to ABT-288 1 mg or 3 mg, donepezil 10 mg, or placebo once daily for 12 weeks. The primary efficacy endpoint was the change from baseline to final evaluation on the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score.

RESULTS: The study was prematurely terminated because futility criteria were met. Point estimates on the ADAS-Cog scores for both ABT-288 dose groups were numerically inferior to placebo but no statistical differences were detected. Donepezil demonstrated statistically significant improvement. Adverse events were generally mild and self-limiting.

CONCLUSION: ABT-288 did not demonstrate efficacy in the symptomatic treatment of Alzheimer's dementia.

BACKGROUND: Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube.

METHODS: In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥ 30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994.

FINDINGS: From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4.04 h (SE 0.65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2.14 h (0.66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference -1.91 h [95% CI -3.05 to -0.76]; p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11 h (SE 0.75) in the intestinal gel group and 2.24 h (0.76) in the immediate-release oral group (difference 1.86 [95% CI 0.56 to 3.17]; p=0.0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube.

INTERPRETATION: Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study.

FUNDING: AbbVie.

{Introduction: ABT-288 is a highly potent histamine-3 receptor antagonist that has demonstrated pro-cognitive effects in preclinical models relevant to schizophrenia. This study evaluated the efficacy and safety of two doses of ABT-288 in the treatment of cognitive impairment associated with schizophrenia. Methods: A randomized, double-blind, placebo-controlled, parallel-group 12-week study was conducted at 23 centers in the United States. Clinically stable subjects with schizophrenia were randomized in an equal ratio to ABT-288 10mg, ABT-288 25mg, or placebo once daily while continuing their antipsychotic regimen. The primary efficacy measure was the change from baseline to day 84 evaluation on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) composite score vs placebo. Secondary measures included cognitive functioning and psychiatric scales. Safety assessments and sparse pharmacokinetic sampling were also conducted. Results: A total of 214 subjects were randomized. The mean baseline MCCB composite score was 28.4. Approximately 80% of subjects completed the study. The MCCB composite score mean change from baseline to day 84 was numerically worse for both the 10mg (1.90

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.

Aim To characterize quantitatively the relationship between ABT-102, a potent and selective TRPV1 antagonist, exposure and its effects on body temperature in humans using a population pharmacokinetic/pharmacodynamic modelling approach. Methods Serial pharmacokinetic and body temperature (oral or core) measurements from three double-blind, randomized, placebo-controlled studies [single dose (2, 6, 18, 30 and 40 mg, solution formulation), multiple dose (2, 4 and 8 mg twice daily for 7 days, solution formulation) and multiple-dose (1, 2 and 4 mg twice daily for 7 days, solid dispersion formulation)] were analyzed. nonmem was used for model development and the model building steps were guided by pre-specified diagnostic and statistical criteria. The final model was qualified using non-parametric bootstrap and visual predictive check. Results The developed body temperature model included additive components of baseline, circadian rhythm (cosine function of time) and ABT-102 effect (Emax function of plasma concentration) with tolerance development (decrease in ABT-102 Emax over time). Type of body temperature measurement (oral vs. core) was included as a fixed effect on baseline, amplitude of circadian rhythm and residual error. The model estimates (95% bootstrap confidence interval) were: baseline oral body temperature, 36.3 (36.3, 36.4)°C; baseline core body temperature, 37.0 (37.0, 37.1)°C; oral circadian amplitude, 0.25 (0.22, 0.28)°C; core circadian amplitude, 0.31 (0.28, 0.34)°C; circadian phase shift, 7.6 (7.3, 7.9) h; ABT-102 Emax, 2.2 (1.9, 2.7)°C; ABT-102 EC50, 20 (15, 28) ng ml−1; tolerance T50, 28 (20, 43) h. Conclusions At exposures predicted to exert analgesic activity in humans, the effect of ABT-102 on body temperature is estimated to be 0.6 to 0.8°C. This effect attenuates within 2 to 3 days of dosing.

Aims Laser (radiant-heat) evoked potentials (LEPs) from vertex-EEG peak-to-peak (PtP) amplitude were used to determine acute antinociceptive/antihyperalgesic efficacy of ABT-102, a novel TRPV1 antagonist efficacious in preclinical pain models, compared with active controls and placebo in normal and UVB-inflamed skin. Methods This was a randomized, placebo- and active-controlled, double-blind, intra-individual, crossover trial. Twenty-four healthy subjects received six sequences of single doses of ABT-102 (0.5, 2, 6 mg), etoricoxib 90 mg, tramadol 100 mg and placebo. Painful stimuli were induced by CO2-laser on normal and UVB-inflamed skin. LEPs and visual analogue scale (VAS-pain) ratings were taken at baseline and hourly up to 8 h post-dose from both skin types. Results Compared with placebo, significant mean decreases in the primary variable of LEP PtP-amplitude from UVB-inflamed skin were observed with ABT-102 6 mg (P < 0.001), ABT-102 2 mg (P = 0.002), tramadol 100 mg (P < 0.001), and etoricoxib 90 mg (P = 0.001) over the 8 h period; ABT-102 0.5 mg was similar to placebo. ABT-102 6 mg was superior to active controls over the 8 h period (P < 0.05) whereas ABT-102 2 mg was comparable. Improvements in VAS scores compared with placebo were observed with ABT-102 6 mg (P < 0.001) and ABT-102 2 mg (P = 0.002). ABT-102 average plasma concentrations were 1.3, 4.4 and 9.4 ng ml−1 for the 0.5, 2 and 6 mg doses, respectively. There were no clinically significant safety findings. Conclusions TRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation.

Aim The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Methods Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. Results ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Conclusions Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients.