Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitor [18F]GSK2647544 in Healthy Male Subjects.

PURPOSE: GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), which was in development as a potential treatment for Alzheimer's disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, [18F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study. PROCEDURES: [18F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [18F]trifluoromethylation methodology. Healthy male subjects (n = 4, age range 34-42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of [18F]GSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 µg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (VT). Secondary PK and safety endpoints were also recorded. RESULTS: PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of [18F]GSK2647544 across all the ROIs examined. The mean whole brain VT was 0.56 (95 % CI, 0.41-0.72). Secondary PK parameters, Cmax (geometric mean) and Tmax (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20-40 % of the parent compound [18F]GSK2647544 present after 120 min. CONCLUSIONS: The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA2 activity. TRIAL REGISTRATION: Clintrials.gov: NCT01924858.

Adolescent Clinical Development of Ezogabine/Retigabine as Adjunctive Therapy for Partial-Onset Seizures: Pharmacokinetics and Tolerability.

OBJECTIVES: To explore the pharmacokinetic (PK) profile and safety of ezogabine (EZG)/retigabine (RTG) as adjunctive therapy for uncontrolled partial-onset seizures (POS) in adolescents. METHODS: In this multiple-dose study (NCT01494584), adolescents with POS received EZG/RTG immediate-release tablets three times daily (TID) as adjunctive therapy to 1 to 3 concurrent antiepileptic drugs. The study comprised a screening phase, and a 5- to 8-week treatment phase starting with 100 mg TID up-titrated once weekly by ≤50 mg TID to a maximum dosage of 300 mg TID. There were 8 venous blood samples and 2 finger-prick blood samples collected for PK analysis during 8-hour time periods at the target dosages of 100, 200, and 300 mg TID. RESULTS: This study was terminated prematurely on US Food and Drug Administration advice due to pigmentation/discoloration findings in long-term, open-label extension studies in adults. Five participants (ages 13-16 years) had enrolled in the study. For the EZG/RTG 100-, 200-, and 300-mg doses, the area under the concentration-time curve during the dosage intervals was 1680, 2559, and 3784 ng/hr/mL; maximum plasma concentrations were 370, 536, and 751 ng/mL, and minimum plasma concentrations were 105, 200, and 287 ng/mL, respectively. Venous and finger-prick concentrations of EZG/RTG were similar. No significant adverse events were observed during treatment (133-213 days). CONCLUSIONS: EZG/RTG PK appeared linear across the dosage range of 100 to 300 mg TID in adolescents with POS, and were consistent with adult observations. The small sample size and short study duration preclude conclusions regarding the safety and efficacy of EZG/RTG.

Effect of hemodialysis on pharmacokinetics of ezogabine/retigabine and its N-acetyl metabolite in patients with end stage renal disease.

Ezogabine (EZG)/retigabine (RTG) and its metabolites are mainly eliminated renally. This Phase I study assessed the effect of hemodialysis on the pharmacokinetics of EZG/RTG and its N-acetyl metabolite (NAMR) in patients with end-stage renal disease; tolerability of EZG/RTG was a secondary endpoint. Patients (N=8) received EZG/RTG 100 mg orally 4 hours before (Period 1) or following (Period 2) dialysis. Blood (both periods) and dialysate (Period 1) samples were taken up to 68 hours post dose. Tolerability was assessed throughout both periods. The area under the concentration- time curve (0-68 hours) for EZG/RTG was 33% lower (geometric mean ratio [90% confidence interval]: 0.67 [0.61, 0.73]) on dialysis versus off dialysis and 43% lower for NAMR (0.57 [0.53, 0.62]). Median (range) reductions in plasma concentrations from dialysis start to end were 52% (17-59%) for EZG/RTG and 51% (27-72%) for NAMR. EZG/RTG 100 mg was generally tolerated.

Lack of effect of ezogabine/retigabine on the pharmacokinetics of digoxin in healthy individuals: results from a drug-drug interaction study.

INTRODUCTION: The potential for ezogabine/retigabine (EZG/RTG) and its N-acetyl metabolite (NAMR) to inhibit the transporter protein P-glycoprotein-(P-gp)-mediated digoxin transport was tested in vitro. EZG/RTG did not inhibit P-gp. However, NAMR inhibited P-gp in a concentration-dependent manner. Based on these in vitro results, NAMR had the potential to inhibit P-gp at therapeutic doses of EZG/RTG (600-1,200 mg/day). As digoxin has a narrow therapeutic index, inhibition of digoxin clearance may have an impact on its safety. METHODS: An open-label, single-center, two session, fixed-sequence study was conducted to assess the effect of co-administration of therapeutic doses of EZG/RTG on digoxin pharmacokinetics in healthy adults. In session 1, subjects received a single dose of digoxin 0.25 mg. In session 2, EZG/RTG was up-titrated over 6 weeks. Digoxin 0.25 mg was co-administered at EZG/RTG steady-state doses of 600, 900, and, based on tolerability, 1,050/1,200 mg/day. Blood samples were collected over 144 hours for determination of digoxin, EZG/RTG, and NAMR concentrations. Urine samples were collected over 48 hours for determination of digoxin concentrations. RESULTS: Of 30 subjects enrolled, 29 were included in the pharmacokinetic analysis. Compared with digoxin alone, co-administration with EZG/RTG led to small increases in the digoxin plasma area under the concentration-time curve (AUC)0-120 at doses of 600, 900, and 1,050/1,200 mg (geometric mean ratio 1.08, 90% confidence interval [CI] 1.01-1.15; 1.18, 90% CI 1.10-1.27; 1.13, 90% CI 1.05-1.21, respectively). Safety was consistent with previous repeat-dose studies of EZG/RTG in healthy subjects. CONCLUSION: Co-administration of EZG/RTG across the therapeutic range resulted in small, non-dose-dependent and non-clinically relevant increases in digoxin systemic exposure, suggesting that digoxin dose adjustment is not necessary.

The effect of ezogabine on the pharmacokinetics of an oral contraceptive agent.

OBJECTIVES: Ezogabine (EZG) is a potassium-channel opener that has been approved as adjunctive treatment for partial-onset seizures in adults with epilepsy. This Phase I clinical study evaluated the pharmacokinetics (PK), safety, and tolerability of coadministration of EZG and a combined oral contraceptive (OC). METHODS: An open-label drug-interaction study was conducted in healthy, female volunteers aged 18 - 55 years with regular menstrual cycles. The effects of steady-state 750 mg EZG on the PK of a combined OC agent containing 1 mg norethindrone and 0.035 mg ethinyl estradiol were evaluated, along with the effect of the contraceptive hormones on EZG PK. Safety was evaluated by clinical laboratory, vital sign, electrocardiogram, physical examination, and adverse event (AE) assessments. RESULTS: Of 30 enrolled volunteers, 25 completed all treatments. OC did not affect the PK of EZG. EZG increased norethindrone area under the concentration-time curve (AUC) by 28%, with no change in the maximum plasma concentration (Cmax). Ethinyl estradiol Cmax was 21% lower with no change in AUC. The majority of AEs were mild in severity, with the most commonly reported being gastrointestinal disorders and nervous system disorders. No deaths or serious AEs were reported in this study. Five volunteers discontinued treatment due to AEs. CONCLUSIONS: EZG did not have any clinically relevant impact on exposure of OC hormones in this study, and the OC hormones did not alter EZG PK parameters. This study provides PK evidence that doses of EZG and OCs do not need to be altered when co-administered.

Investigation of the impact of urine handling procedures on interpretation of urinalysis findings and product safety in subjects treated with ezogabine.

BACKGROUND: Ezogabine (also known by the international nonproprietary name of retigabine) is an antiepileptic drug codeveloped and comarketed by Valeant Pharmaceuticals North America and GlaxoSmithKline, which reduces neuronal excitability by enhancing the activity of potassium channels and has the potential to have effects on the urinary system through a pharmacologic action on bladder smooth muscle. In a single post-herpetic neuralgia trial, but not in an extensive epilepsy development program, proteinuria was unexpectedly reported in patients receiving ezogabine. Consequently, investigations were conducted to determine whether the reported proteinuria represented a true or false-positive finding. METHODS: Patients receiving ezogabine 900-1200 mg/day in an open-label extension (Study 303) of a Phase III epilepsy trial voluntarily provided urine samples. Fresh samples were analyzed immediately at the study site, and stabilized aliquots were analyzed 1-3 days after collection at two central laboratories. In an open-label study in healthy volunteers receiving ezogabine 600-900 mg/day (Study RTG114137), urine samples were analyzed fresh (<2 hours after collection) and, using two different stabilizers and storage at room temperature, after 24 and 72 hours. Fluid intake was restricted prior to one sample point. Albumin:creatinine ratios were assessed in both studies. RESULTS: In Study 303, there was notable variation in clarity, color, and proteinuria between fresh and stored urine samples, and between samples analyzed at different laboratories. In RTG114137, reporting rates of proteinuria were elevated following storage using one stabilizer, and the frequency of color change from fresh to stored samples differed between the stabilizers and between 24 and 72 hours with one stabilizer. Following fluid restriction, proteinuria rates were elevated with both stabilizers. Poor tolerability of ezogabine 750-900 mg/day resulted in limited titration beyond 750 mg/day and early termination of RTG114137. CONCLUSION: Hydration status, interval between urine collection and analysis, and the type of stabilizer used are all factors that may lead to false-positive proteinuria findings in patients receiving ezogabine and should be borne in mind if abnormalities are reported.

Population pharmacokinetics of onercept in healthy subjects.

OBJECTIVE: To develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of onercept (recombinant human tumour necrosis factor [TNF] receptor-1) in healthy subjects. SUBJECTS AND METHODS: Onercept pharmacokinetics data were obtained from 48 healthy male and female subjects (four phase I studies). In study A, 12 subjects received increasing single intravenous doses of onercept either 5 and 50mg or 15 and 150mg. In study B, 12 subjects received single intravenous, subcutaneous and intramuscular doses of onercept 50mg. Study C investigated the pharmacokinetics of onercept following repeat subcutaneous administration of six doses of 50mg every 48 hours in 12 subjects. Study D investigated the pharmacokinetics of onercept following repeat subcutaneous administration of six doses of 100mg and 150mg over 2 weeks in 12 subjects. Nonlinear mixed-effects modelling software NONMEM was used to build a base model, while the final model was determined after selection of the covariates. RESULTS: The disposition of onercept was described using a two-compartment model with two absorption processes (a first-order followed by a zero-order) and included a constant baseline, accounting for the endogenous TNF receptor-1 levels. Slow absorption of onercept following subcutaneous and intramuscular administration was observed and suggested that absorption was the rate-limiting process. The population mean (coefficient of variation %) values for clearance, absorption rate constant, volume of distribution of the central compartment, bioavailability of onercept and baseline TNF receptor-1 levels were 4.03 L/h (13.3%), 0.04 h-1 (29.1%), 4.42L (6.2%), 0.90 (23.8%) and 1.68 microg/L (20.4%), respectively. The only significant covariates were found to be dose (which affected clearance), and day (which affected absorption rate constant); however, the effects were small (10-15%) and are unlikely to be of any clinical relevance. CONCLUSION: The proposed population pharmacokinetic model characterises well the overall pharmacokinetic profile of onercept after intramuscular, subcutaneous and intravenous administration in healthy subjects. The pharmacokinetics of onercept showed modest intersubject variability.

A phase I study of the pharmacokinetics, pharmacodynamics, and safety of single- and multiple-dose anastrozole in healthy, premenopausal female volunteers.

OBJECTIVE: To evaluate the pharmacokinetic, pharmacodynamic, and safety profiles of the aromatase inhibitor anastrozole in healthy, premenopausal women. DESIGN: Phase I, single-center study. SETTING: Infertility clinic. PATIENT(S): Twenty-six women with regular ovulatory cycles: 20 received either a single dose of 5 mg, 10 mg, 15 mg, or 20 mg anastrozole, or remained untreated; 6 received five daily doses of 10 mg or 15 mg anastrozole. INTERVENTION(S): Anastrozole was administered on cycle day 2 for the single-dose groups and on days 2-6 for the multiple-dose groups. Ultrasound follicular development and endometrial biopsies were performed. Safety was determined from adverse event reports and laboratory parameters. MAIN OUTCOME MEASURE(S): Pharmacokinetics, pharmacodynamics, and safety. RESULT(S): The pharmacokinetics of anastrozole were linear, predictable, and consistent with previously published data in healthy volunteers. In the single-dose groups, E2 levels reached their nadir 3-6 hours after administration, decreasing by an average of 39% from baseline. Follicle-stimulating hormone levels rose by 13%, 52%, 49%, and 75% in the 5-mg, 10-mg, 15-mg, and 20-mg groups, respectively, at approximately 24 hours after dosing. Most subjects recruited just one mature follicle, with no apparent effect on endometrial maturation. No safety concerns were noted. CONCLUSION(S): Anastrozole was well tolerated and suppressed E2 levels, with a resultant increase in FSH.

No effect of the novel antidiabetic agent nateglinide on the pharmacokinetics and anticoagulant properties of warfarin in healthy volunteers.

The novel hypoglycemic agent nateglinide is pharmacologically distinct from oral hypoglycemic agents such as sulfonylureas and repaglinide. The present study investigated the effects in healthy volunteers of multiple doses of nateglinide on the pharmacokinetics and pharmacodynamics of warfarin. The study comprised a randomized two-group, two-way crossover, open-label design in 12 healthy male subjects. One group of 6 subjects initially received a single oral dose of warfarin 30 mg and then, after a 7- to 14-day washout, received both warfarin and nateglinide (120 mgnateglinide, 10 min before meals for 4 days and a single dose of 30 mg warfarin on the second day). The alternate group of 6 subjects received treatments in the opposite order. Pharmacokinetic profiles were derived from plasma warfarin and nateglinide concentrations. Prothrombin measurements were evaluated in both periods as a measure of warfarin activity. When administered alone or in combination, there were no statistically significant differences in mean warfarin (R- and S-enantiomers) or nateglinide pharmacokinetic parameters. The concurrent administration of nateglinide and warfarin did not affect the maximal change in prothrombin time that follows warfarin administration. In this study, there was no evidence of an effect of coadministration of nateglinide on the pharmacodynamic action of warfarin or any pharmacokinetic interaction between warfarin and nateglinide.