INTRODUCTION:Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). METHODS:In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. RESULTS:Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ1-x and Aβ1-40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. CONCLUSIONS:Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Objective: Ponezumab (PF-04360365) is a humanized anti-amyloid beta (A beta) monoclonal antibody designed for treatment of Alzheimer disease (AD). A single 2-hour intravenous infusion of 0.1 to 10 mg/kg was previously shown to be safe and well tolerated in subjects with mild to moderate AD, with measurable effects on plasma and cerebrospinal fluid AA. This phase I, dose-escalation, open-label study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single 10-minute intravenous infusion.Methods: Subjects with mild to moderate AD received ponezumab 1 mg/kg (n = 3), 3 mg/kg (n = 3), 5 mg/kg (n = 4), or 10 mg/kg (n = 5). They were followed up as outpatients for 6 months.Results: All subjects completed the trial. Ponezumab was safe and well tolerated with no deaths, withdrawals, or drug-related moderate, severe, or serious adverse events. Mild drug-related adverse events included headache (3 patients) and lethargy and hypoesthesia (both in 1 patient). No infusion reactions, clinically meaningful laboratory abnormalities, vital sign changes, electrocardiographic changes, or antidrug antibodies were detected. There was no evidence of brain microhemorrhage, vasogenic edema, encephalitis, or other imaging abnormality. Cognitive function showed no treatment-related trends. Ponezumab displayed approximately dose-proportional increases in plasma exposure. Steady-state volume of distribution was 113 to 172 mL/kg, clearance was 2.7 to 3.0 mL/d/kg, and terminal half-life was 35 to 52 days. Plasma maximum observed concentration and the area under the plasma concentration-time profile from time 0 extrapolated to infinite time of A beta(1-x) and A beta(1-40) increased dose-dependently.Conclusions: Administration of ponezumab as a 10-minute infusion was safe and well tolerated and produced effects on plasma AA species comparable with a 2-hour infusion. Shorter infusions may provide more flexibility, comfort, and convenience for patients and caregivers.

This study was designed to investigate the multiple-dose pharmacokinetics, safety, and tolerability of the selective alpha 4 beta 2 nicotinic acetylcholine partial agonist, varenicline, in elderly (65-85 years old) nonsmokers. Fifty male and female subjects with normal renal function for their age were randomized to receive varenicline or placebo once or twice daily for 3 weeks in an investigator- and subject-blinded parallel-group design. Treatment regimens included weekly titration (n = 14; days 1-7, 0.5 mg once daily; days 8-14, 0.5 mg twice daily; days 15-21, 1 mg twice daily); 2-week twice-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 0.5 mg twice daily); 2-week once-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 1 mg once daily); and placebo (n = 10). Approximate dose-proportional increases in systemic exposure of varenicline at steady state, based on maximum concentration and area under the plasma concentration-time curve over the 24-hour period at steady state, were observed across the dose range of 0.5 to 2 mg/d. Median time to maximum concentration was 3 hours. Mean elimination half-life was estimated to be approximately 24 to 32 hours and independent of dose. Varenicline was considered to be safe and well tolerated in this elderly nonsmoking population.

Ponezumab (PF-04360365) is a humanized anti-amyloid mAb under investigation for the treatment of Alzheimer's disease (AD). The pharmacokinetics and pharmacodynamics of ponezumab were evaluated in two phase 1 studies in patients with mild-to-moderate AD, and the results compared. Placebo or ponezumab at 0.1 (n = 6), 0.3 (n = 6), 1 (n = 6), 3 (n = 8), or 10 mg/kg (n = 11) were administered via 2-hour infusion to 37 patients with AD in a randomized, double-blind, placebo-controlled, dose-escalation study (A9951001). A second study (A9951008) was designed as an open-label, parallel-group, dose-escalation trial with ponezumab administered at 1 (n = 3), 3 (n = 3), 5 (n = 4), or 10 (n = 5) mg/kg via 10-minute infusion. Serum analytes for anti-drug antibodies (ADAs), plasma ponezumab and amyloid β (Aβ), and CSF ponezumab, Aβ, and tau/p-tau concentrations were quantified by validated bioanalytical methods. Plasma pharmacokinetics and pharmacodynamics were calculated using non-compartmental analysis. Pharmacokinetics and pharmacodynamics were similar between the two studies. Plasma ponezumab reached maximum concentration (Cmax) shortly after infusion, followed by a biphasic decline. Cmax and area under the concentration-time curve increased in a dose-proportional manner. The pharmacokinetics of ponezumab were linear with a mean terminal half-life of 35-52 days. Ponezumab CSF concentrations at Day 29 post-dose (A9951001) were quantifiable in 2 of 8 patients administered a 10 mg/kg dose (˜0.5% of plasma values). In both studies, plasma Aβ concentrations and time to Cmax (Tmax) increased dose-dependently. The ratios of Cmax/baseline in plasma Aβ concentrations were around 500 in the 10 mg/kg group compared with 1 in the placebo group. At the 10 mg/kg dose (A9951001), mean CSF Aβ percentage change from baseline at Day 29 increased 38% (p < 0.05), 29% (p > 0.05), and 15% (p < 0.05) for Aβ1-x, Aβ1-40, and Aβ1-42, respectively. There were no changes from baseline for CSF tau and p-tau concentrations. ADAs were not detected. The pharmacokinetics of ponezumab were similar between the two studies - linear, with central penetration seen following the highest dose in some patients. Increases in plasma Aβ biomarker response and Tmax were dose dependent. CSF Aβ concentrations increased from baseline at Day 29 for the 10 mg/kg dose. No ADAs were detected.

There are currently several anti-amyloid β (Aβ) monoclonal antibodies (mAbs) in clinical development as potential therapeutics to reduce brain amyloid burden and improve clinical outcome in patients with Alzheimer's disease (AD). Ponezumab (PF-04360365) is a humanized IgG2deltaA mAb that targets amino acids 33-40 of the Aβ1-40 peptide. Moreover, its constant region (Fc) incorporates two site mutations that reduce effector function. The preliminary phase 1 safety and pharmacokinetic data for ponezumab following a single 2-hour intravenous infusion have been previously described. This open-label, single-dose, parallel-group, dose-escalation study with doses of 1 (n = 3), 3 (n = 3), 5 (n = 4) or 10 (n = 5) mg/kg in patients with mild to moderate AD (N = 15) examined the safety and pharmacokinetics of ponezumab following a single 10-minute intravenous administration. Ponezumab was well tolerated with no drug-attributed severe adverse events (SAEs). The most common AEs were upper respiratory tract infections (n = 2 total; n = 1 at 1 mg/kg, n = 1 at 3 mg/kg) and headaches (n = 5 total; n = 2 at 1 mg/kg, n = 1 at 3 mg/kg, n = 2 at 5 mg/kg), all being mild in severity. No clinical or imaging evidence of microhemorrhage, vasogenic edema or encephalitis was noted in any patient. ECGs and routine safety laboratory test results, including CSF cell counts and protein were unremarkable. There was an approximate dose-proportional increase in ponezumab plasma AUCinf and Cmax in the studied dose range of 1 to 10 mg/kg, indicating linear pharmacokinetics. Long mean terminal half-lives for ponezumab (∼6 weeks) across all dose levels were observed. Ponezumab concentrations for all optional CSF samples collected at approximately 6-hours post dose at the 5 (n = 3) and 10 mg/kg (n = 3) dose levels were below the lower limit of quantification (12 ng/mL). The single-dose clinical data obtained indicate ponezumab is well tolerated in humans when administered as a 10-minute infusion over a 1 to 10 mg/kg dose range. The pharmacokinetics of ponezumab appear linear in the studied dose range with plasma exposure increasing in a predictable dose-proportional manner. Safety, tolerability and pharmacokinetics are similar to those previously reported for a 2-hour infusion schedule.

Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α4β2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of varenicline. In vitro, varenicline does not inhibit nor induce the activity of the major CYP enzymes.

Objective: To report a case of possible acute tiagabine toxicity secondary to administration of gemfibrozil. Case Summary: A 39-year-old male was taking tiagabine 16 mg orally 3 times per day and carbamazepine 500 mg orally twice per day for complex partial seizures secondary to mesial temporal sclerosis. He was found to have type IV hypertriglyceridemia and was prescribed gemfibrozil. Because he reported severe confusion and altered consciousness shortly after a single 600-mg dose of gemfibrozil, he was admitted for controlled challenge with that drug. A single 300-mg dose of gemfibrozil resulted in lightheadedness and led to a 59% and 75% increase in total tiagabine serum concentrations at 2 and 5 hours, respectively, without significant change in baseline carbamazepine concentrations. Discussion: This is the first report of an interaction between the widely used antihyperlipidemic drug gemfibrozil and tiagabine. Since tiagabine, which was originally developed as an antiepileptic medication, is now being used widely for a variety of other indications such as anxiety and depression, there is an increased risk for clinically significant interactions with gemfibrozil. Conclusions: Increased total and unbound tiagabine concentrations following a single 300-mg dose of gemfibrozil and reproduction of clinical symptoms with gemfibrozil rechallenge suggests the toxicity our patient experienced was due to a pharmacokinetic drug interaction. Use of the Horn Drug interaction Probability Scale showed a probable interaction between gemfibrozil and tiagabine.

The metabolism and disposition of N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide (1), a potent subtype-selective partial agonist at the gamma-aminobutyric acid type A receptor complex, were elucidated in humans following a p.o. dose of N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-[3-(14)C]indole-3-carboxamide monomethane-sulfonate ([(14)C]1). Overall, 1 was well tolerated, with approximately twice as much radioactivity excreted in feces (64.8 +/- 13.3%) as in urine (28.4 +/- 8.8%). Across subjects, the oral clearance of 1 was composed of both renal (10%) and metabolic (< or =90%) components, with the biotransformation of 1 happening predominately via oxidative deamination to either 2-fluoro-4-[(4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)-amino]-phenoxy acetic acid (2) or 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid [3-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-amide (3) and minimally by aliphatic hydroxylation and carbamate formation. Active renal secretion of 1 was observed as its unbound renal clearance was 6-fold greater than the glomerular filtration rate. Experiments using human hepatic in vitro systems were undertaken to better understand the enzyme(s) involved in the clinically observed oxidative biotransformation pathways. N-Dealkylation of 1, the principal metabolic route observed in vivo, was found to be predominately monoamine oxidase-B-mediated with the resulting putative aldehyde intermediate undergoing subsequent oxidation to 2 or reduction to 3.

This study investigated the effect of varenicline on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in 24 adult smokers and compared these findings with data generated using human in vitro systems. Subjects were randomized to receive varenicline 1 mg twice a day or placebo for 13 days and then switched to the alternative treatment after a 1-week washout period. A single dose of warfarin 25 mg was given on day 8 of each treatment period, and serial blood samples were collected over 144 hours postdose. Pharmacokinetic parameters for both (R)- and (S)-warfarin and international normalized ratio (INR) values were determined. Varenicline was assessed as an inhibitor and inducer of human cytochrome P450 activities using liver microsomes and hepatocytes, respectively. Consistent with the in vitro data, no alteration in human pharmacokinetics of warfarin enantiomers was observed with varenicline treatment. The 90% confidence intervals for the ratios of area under the concentration-time curve from zero hours to infinity and peak plasma concentrations were completely contained within 80% to 125%. Warfarin pharmacodynamic parameters, maximum INR, and the area under the prothrombin (INR)-time curve, were also unaffected by steady-state varenicline. Concomitant administration of varenicline and warfarin was well tolerated. Consequently, warfarin can be safely administered with varenicline without the need for dose adjustment.

Both positron emission tomography and single photon emission computed tomography (SPECT) studies suggest that saturation of serotonin transporters (SERT) is present during treatment with therapeutic doses of selective serotonin reuptake inhibitors (SSRIs). Selective serotonin reuptake inhibitors also appear to increase the availability of dopamine transporters (DAT). The current study measured SERT occupancy and modulation of DAT by the serotonin/norepinephrine reuptake inhibitor (SNRI) venlafaxine using [I-123]2 beta-carbomethoxy-3 beta-(4-iodophenyl)-tropane SPECT. Eight healthy subjects were administered open-label venlafaxine extended release capsules (75 mg/d for 4 days followed by 150 mg/d for 5 days). Venlafaxine significantly inhibited [I-123]beta-CIT binding to SERT in the brainstem (55.4%) and the diencephalon (54.1%). In contrast, venlafaxine increased [I-123]beta-CIT binding to DAT in the striatum (10.1%) after 5 days of administration of 150 mg/d. The displacement of [I-123] beta-CIT from brain SERT and the increase in striatal [I-123] beta-CIT binding to DAT appear similar to previous work with the SSRI citalopram (40 mg/d). A literature review of SERT occupancy by marketed SSRIs and the SNRI venlafaxine using SPECT ([I-123] beta-CIT) or positron emission tomography ([C-11])(N-Dimethyl-2-(2-amino4-cyanophenylthio)benzylamine) imaging suggests that therapeutic doses of SNRI are associated with virtual saturation of the serotonin transporter.

Varenicline is a novel selective alpha4beta2 nicotinic acetylcholine partial agonist developed for smoking cessation. This study investigated the single- and multiple-dose pharmacokinetics, safety, and tolerability of varenicline in elderly (> or = 65 years) smokers. Twenty-four elderly smokers with normal renal function for their age (estimated creatinine clearance > or = 70 mL/min) received varenicline 1 mg once daily (n = 8) or placebo (n = 4) for 7 days, or 1 mg twice daily (n = 8) or placebo (n = 4) for 6 days with a single dose on day 7 in a double-blind, parallel group and placebo-controlled design. There was no evidence of concentration- or time-dependent changes in varenicline pharmacokinetics upon repeat dosing. Once- and twice-daily dosing was associated with an approximate 2-fold and 3-fold increase, respectively, in systemic exposure to varenicline. Varenicline was well tolerated; all adverse events reported were mild to moderate in intensity. Thus, no dose adjustment is necessary based on age alone.

Varenicline is a novel and selective alpha4beta2 nicotinic acetylcholine receptor partial agonist developed for smoking cessation. The primary objectives of this double-blind, placebo-controlled, dose-escalation study were to determine the pharmacokinetics, safety, and tolerability of multiple oral doses of varenicline given as tablets once (1 mg, 2 mg, and 3 mg) or twice (1 mg) daily to healthy adult smokers. Within each dose level, 8 subjects were randomized to varenicline and 4 subjects to placebo. Varenicline was well tolerated at doses up to and including 2 mg daily. Dose-proportional increases in maximum observed plasma concentrations and area under the plasma concentration-time curve from time zero to the end of the dosing interval values were observed between the 1-mg and 2-mg daily doses of varenicline. Once- and twice-daily dosing resulted, on average, in an approximate 2- and 3-fold increase in varenicline systemic exposure, respectively, compared with single dose. There was no evidence of concentration- or time-dependent changes in the pharmacokinetics of varenicline upon repeat dosing.

The pharmacokinetics of 2,000 mg of sulfadiazine administered twice daily (BID) versus those of 1,000 mg administered four times a day were compared in eight human immunodeficiency virus-infected patients. No differences in pharmacokinetic parameters were detected between the regimens. These data provide a pharmacokinetic rationale for BID dosing of sulfadiazine for the treatment and suppression of toxoplasmosis.

ObjectiveTo evaluate the relationship between the acute inflammatory response after surgical trauma and changes in hepatic cytochrome P450 3A4 activity, compare changes in cytochrome P450 3A4 activity after procedures with varying degrees of surgical stress, and to explore the time course of any potential drug-cytokine interaction after surgery. DesignProspective, open-label study with each patient serving as his or her own control. SettingUniversity-affiliated, acute care, general hospital. PatientsA total of 16 patients scheduled for elective repair of an abdominal aortic aneurysm (n = 5), complete or partial colectomy (n = 6), or peripheral vascular surgery with graft (n = 5). InterventionsCytochrome P450 3A4 activity was estimated using the carbon-14 [14C]erythromycin breath test (ERMBT) before surgery and 24, 48, and 72 hrs after surgery. Abdominal aortic aneurysm and colectomy patients also had an ERMBT performed at discharge. Blood samples were obtained before surgery, immediately after surgery, and 6, 24, 32, 48, and 72 hrs after surgery for determination of plasma concentrations of interleukin-6, interleukin-1&bgr;, and tumor necrosis factor-&agr;. Clinical markers of surgical stress that were collected included duration of surgery, estimated blood loss, and volume of fluids administered in the operating room. Measurements and Main ResultsERMBT results significantly declined in all three surgical groups, with the lowest value at the time of the 72-hr study in all three groups. There was a trend toward differences in ERMBT results among groups that did not reach statistical significance (p = .06). The nadir ERMBT result was significantly and negatively correlated with both peak interleukin-6 concentration (rs = −.541, p = .03) and log interleukin-6 area under the curve from 0 to 72 hrs (rs = −.597, p = .014). Subjects with a peak interleukin-6 of >100 pg/mL had a significantly lower nadir ERMBT compared with subjects with a peak interleukin-6 of <100 pg/mL (35.5% ± 5.2% vs. 74.7% ± 5.1%, p < .001). ConclusionsAcute inflammation after elective surgery was associated with a significant decline in cytochrome P450 3A4 activity, which is predictive of clinically important changes in the metabolism of commonly used drugs that are substrates for this enzyme.

Herb-drug interactions are being recognized for their potential to reduce the efficacy of, or cause additive side effects with, conventional medications. Herb use, particularly when undisclosed to investigators, may be a potential unforeseen confounding variable in clinical trials. The use of herbal products by patients enrolled in clinical trials should be determined and considered as a confounding variable.

In humans, somatosensory stimulation results in increased corticomotoneuronal excitability to the stimulated body parts. The purpose of this study was to investigate the underlying mechanisms. We recorded motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) from abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles. MEP amplitudes, recruitment curves (RC), intracortical inhibition (ICI), intracortical facilitation (ICF), resting (rMT) and active motor thresholds (aMT) were recorded before and after a 2‐h period of ulnar nerve electrical stimulation at the wrist. Somatosensory input was monitored by recording somatosensory evoked potentials. To differentiate excitability changes at cortical vs. subcortical sites, we recorded supramaximal peripheral M‐responses and MEPs to brainstem electrical stimulation (BES). In order to investigate the involvement of GABAergic mechanisms, we studied the influence of lorazepam (LZ) (a GABAA receptor agonist) relative to that of dextromethorphan (DM) (an NMDA receptor antagonist) and placebo in a double‐blind design. We found that somatosensory stimulation increased MEP amplitudes to TMS only in the ADM, confirming a previous report. This effect was blocked by LZ but not by either DM or placebo and lasted between 8 and 20 min in the absence of (i) changes in MEPs elicited by BES, (ii) amplitudes of early somatosensory‐evoked potentials or (iii) M‐responses. We conclude that somatosensory stimulation elicited a focal increase in corticomotoneuronal excitability that outlasts the stimulation period and probably occurs at cortical sites. The antagonistic effect of LZ supports the hypothesis of GABAergic involvement as an operating mechanism.

Study Objective. To compare the pharmacokinetics of subcutaneous and intravenous fludarabine in patients with lupus nephritis. Design. Open‐label, randomized, crossover trial conducted with a phase I‐II trial. Setting. Government research hospital. Patients. Five patients with lupus nephritis. Intervention. Fludarabine 30 mg/m 2 /day was administered either subcutaneously or as a 0.5‐hour intravenous infusion for 3 consecutive days. All patients received oral cyclophosphamide 0.5 g/m 2 on the first day of each cycle. Measurements and Main Results. Plasma samples were collected before and 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the first dose. Urine was collected at 6‐hour intervals for 24 hours. Plasma and urine were analyzed for fluoro‐arabinofuranosyladenine (F‐ara‐A), fludarabine's main metabolite, using high‐performance liquid chromatography. Compartmental techniques were used to determine the pharmacokinetics of F‐ara‐A; a linear two‐compartment model best described them. Comparison of the pharmacokinetics between subcutaneous and intravenous administration was done by using a Wilcoxon signed rank test. No significant differences were found between subcutaneous and intravenous administration in median (interquartile range) maximum concentrations of 0.51 (0.38‐0.56) and 0.75 (0.52‐0.91) mg/L, respectively, or in fitted area under the concentration‐time curves from 0–24 hours of 4.65 (4.17‐4.98) and 4.55 (3.5‐4.94) mg•hour/L, respectively. Bioavailability of F‐ara‐A after subcutaneous dosing was approximately 105% of the bioavailability after intravenous administration. Differences in renal clearance and percentage of dose excreted in urine for subcutaneous and intravenous administration were nonsignificant. No injection site reactions were seen with subcutaneous dosing. Conclusion. Subcutaneous and intravenous administration of fludarabine appear to have similar pharmacokinetics in patients with lupus nephritis. Subcutaneous injection may offer a convenient alternative to intravenous administration.

Study Objective. To determine the population pharmacokinetics of phenylacetate using iterative two‐stage analysis implemented with ADAPT II software.