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Parsaclisib, a selective, potent phosphatidylinositol 3-kinase delta inhibitor being developed for the treatment of cancer and autoimmune diseases, is primarily metabolized by cytochrome P450 (CYP) 3A4. This study assessed the pharmacokinetics (PK) and safety of parsaclisib alone or combined with itraconazole (potent CYP3A inhibitor) or rifampin (potent CYP3A4 inducer) in healthy participants. In this open-label, fixed-sequence study, cohort 1 received oral parsaclisib 10 mg once daily on days 1 and 8 and oral itraconazole 200 mg once daily on days 4-11; cohort 2 received oral parsaclisib 20 mg once daily on days 1 and 11 and oral rifampin 600 mg once daily on days 4-12. Parsaclisib plasma concentration was tested and PK parameters calculated by noncompartmental analysis. Geometric mean ratios (GMRs) and 2-sided 90% confidence intervals (CIs) were estimated by 2-factor analysis of variance. Thirty-six healthy participants were enrolled (18 per cohort). Parsaclisib maximum plasma drug concentration (C max ) and area under the concentration-time curve extrapolated to infinity (AUC 0-∞ ) were increased by 21% and 107% with concomitant itraconazole versus parsaclisib alone (GMR, 1.21; 90%CI, 1.14-1.29; and 2.07; 90%CI, 1.97-2.17, respectively). Parsaclisib C max and AUC were reduced by 43% and 77%, respectively, with concomitant rifampin versus parsaclisib alone (GMR, 0.57; 90%CI, 0.53-0.60; and 0.23; 90%CI, 0.21-0.24, respectively). Headache was the most common adverse event, reported by 13.9% of participants (all in cohort 2). Single-dose parsaclisib alone or combined with itraconazole or rifampin appeared safe and well tolerated in healthy participants. Parsaclisib dose adjustment may be necessary with concomitant administration of strong CYP3A4 inhibitors or inducers., (© 2020 Incyte Corporation. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

The effects of itraconazole on the pharmacokinetics of rovatirelin were investigated in an open-label, single-sequence drug-drug interaction study in 16 healthy subjects. Subjects were administered a single oral dose of rovatirelin (1.6 mg) on day 1 and day 15. From day 8 through 16, subjects received daily oral doses of itraconazole (200 mg/day). Concentrations of rovatirelin and (thiazolylalanyl)methylpyrrolidine (TAMP), the major metabolite of rovatirelin formed by cytochrome P450 (CYP) 3A4/5, were determined in plasma and urine. Pharmacokinetic parameters were used to evaluate the drug-drug interaction potential of rovatirelin as a victim. With coadministration, maximum concentration (C max ) and area under the concentration-time curve extrapolated to infinity (AUC inf ) of rovatirelin increased 3.05-fold and 2.82-fold, respectively, and the 90% confidence intervals of the ratios for C max (2.64-3.52) and AUC inf (2.47-3.23) did not fall within the 0.8-1.25 boundaries. Urinary excretion of rovatirelin increased at almost the same ratio as the AUC inf ratio with coadministration; however, renal clearance did not change. C max , AUC inf , and urinary excretion of TAMP were decreased by coadministration. Itraconazole has the potential to inhibit drug transport via intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); therefore, substrate assessments of rovatirelin for the 2 transporters were evaluated using Caco-2 cell monolayers. In vitro studies showed that rovatirelin is a substrate for P-gp but not for BCRP. The current study shows that itraconazole's effect on rovatirelin pharmacokinetics is mediated through inhibition of CYP3A4/5 and intestinal P-gp., (© 2020, The American College of Clinical Pharmacology.)

Accumulating evidence indicates that selective antagonism of kappa opioid receptors may provide therapeutic benefit in the treatment of major depressive disorder, anxiety disorders, and substance use disorders. LY2456302 is a high-affinity, selective kappa opioid antagonist that demonstrates >30-fold functional selectivity over mu and delta opioid receptors. The safety, tolerability, and pharmacokinetics (PK) of LY2456302 were investigated following single oral doses (2-60 mg), multiple oral doses (2, 10, and 35 mg), and when co-administered with ethanol. Plasma concentrations of LY2456302 were measured by liquid chromatography-tandem mass spectrometry method. Safety analyses were conducted on all enrolled subjects. LY2456302 doses were well-tolerated with no clinically significant findings. No safety concerns were seen on co-administration with ethanol. No evidence for an interaction between LY2456302 and ethanol on cognitive-motor performance was detected. LY2456302 displayed rapid oral absorption and a terminal half-life of approximately 30-40 hours. Plasma exposure of LY2456302 increased proportionally with increasing doses and reached steady state after 6-8 days of once-daily dosing. Steady-state PK of LY2456302 were not affected by coadministration of a single dose of ethanol. No clinically important changes in maximum concentration (Cmax ) or AUC of ethanol (in the presence of LY2456302) were observed., (© 2014, The American College of Clinical Pharmacology.)

A double-blind, placebo- and active comparator-controlled, randomized, single-ascending-dose study was conducted to investigate the safety, pharmacokinetics, and pharmacodynamics of ACT-462206, a novel dual orexin receptor antagonist. Healthy male subjects received single oral doses of 5, 25, 100, 200, 400, 1,000, and 1,500 mg ACT-462206 (n = 6 per group) or placebo (n = 2 per group). In addition, subjects in the 400-mg group received a single oral dose of 400 mg almorexant (two-way crossover). ACT-462206 was generally well tolerated. Sleepiness, headache, and fatigue were the most frequently reported adverse events. The incidence of sleepiness appeared dose-dependent. ACT-462206 was absorbed with a median tmax of 1.5-4.0 hours. The elimination half-life varied from 4.8 to 11.2 hours. A clinically relevant reduction in vigilance and attention, alertness, and motor coordination was recorded at ACT-462206 doses ≥200 mg. The onset was between 20 and 45 minutes after drug intake, the maximum effect between 1 and 2 hours after drug administration, and these impairing effects largely disappeared within 8 hours post-dose. Doses of 400-1,000 mg ACT-462206 were similarly efficacious to 400 mg almorexant, with a trend for an earlier onset of action with ACT-462206. The present results confirm the activity of ACT-462206 as an orexin antagonist., (© 2014, The American College of Clinical Pharmacology.)

Fedratinib (SAR302503/TG101348) is a Janus kinase 2 (JAK2)-selective inhibitor in clinical development for the treatment of myelofibrosis. In this randomized, placebo-controlled, Phase 1 study, the pharmacokinetics, pharmacodynamics and tolerability of ascending single doses of fedratinib (10-680 mg) were assessed in healthy male subjects. Fedratinib was rapidly absorbed, with peak plasma concentration observed approximately 3 hours after dosing. The mean terminal half-life of fedratinib was approximately 67 hours, which was unaffected by dose. Fedratinib exposure increased in a greater than dose-proportional manner. Suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation, indicative of JAK2 inhibition, was observed at 3 hours post-dose for subjects in the 300, 500, and 680 mg groups, with the level of suppression increasing with dose. The relationship between fedratinib exposure and suppression of STAT3 phosphorylation was described using an inhibitory effect sigmoid Emax model, with an EC50 of 1,210 ng/mL in healthy subjects. The most common adverse events were mild gastrointestinal toxicities., (© 2013, The American College of Clinical Pharmacology.)

Dipeptidyl peptidase-4 (DPP-4) inhibition is a well- characterized treatment for type 2 diabetes mellitus (T2DM). The objective of this model-based meta-analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). Publicly available data involving late-stage or marketed DPP-4 inhibitors were leveraged for the analysis. Nonlinear mixed-effects modeling was performed to describe the relationship between DPP-4 inhibition and mean response over time. Plots of the relationship between metrics of DPP-4 inhibition (ie, weighted average inhibition [WAI], time above 80% inhibition, and trough inhibition) and response after 12 weeks of daily dosing were evaluated. The WAI was most closely related to outcome, although other metrics performed well. A model was constructed that included fixed effects for placebo and drug and random effects for intertrial variability and residual error. The relationship between WAI and outcome was nonlinear, with an increasing response up to 98% WAI. Response to DPP-4 inhibitors could be described with a single drug effect. The WAI appears to be a useful index of DPP-4 inhibition related to HbA1c. Biomarker to response relationships informed by model-based meta-analysis can be leveraged to support study designs including optimization of dose, duration of therapy, and patient population.

Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant.

This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti-factor Xa activity) and plasma concentrations of R1663 were dose-dependent and showed low to moderate (<40%) intersubject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time to maximum concentration of R1663): clotting times were prolonged up to 2.5-fold, whereas endogenous thrombin potential (ETP) and peak height were decreased by 48% and 85% from their baseline values, respectively. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations, with IC50 values of 182 and 2680 ng/mL for peak height and ETP, respectively. Oral doses of R1663 up to 480 mg were well tolerated, with predictable pharmacodynamics and pharmacokinetics. R1663 prolonged clotting times (PT, aPTT) and inhibited thrombin generation without increasing bleeding time.

Three phase 1 studies of eliglustat tartrate (Genz-112638), an oral inhibitor of glucosylceramide synthase under development for treating Gaucher disease type 1 (GD1), evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after escalating single doses (n = 99), escalating multiple doses (n = 36), and food (n = 24). Eliglustat tartrate was well tolerated at single doses ≤ 20 mg/kg and multiple doses ≤ 200 mg bid, with 50 mg bid producing plasma concentrations in the predicted therapeutic range. No serious adverse events occurred. Mild to moderate events of nausea, dizziness, and vomiting increased in frequency with escalating single and multiple doses. Single doses ≥ 10 mg/kg caused mild increases in electrocardiogram PR, QRS, and QT/QTc intervals. Single-dose pharmacokinetics showed dose linearity but not proportionality. Maximum plasma concentrations occurred at ~2 hours, followed by a monophasic decline with a ~6-hour terminal half-life. Unchanged drug in 8-hour urine collections was <1.5% of administered doses. Food did not significantly affect the rate or extent of absorption. Multiple-dose pharmacokinetics was nonlinear, showing higher than expected plasma drug concentrations. Steady state was reached ~60 hours after bid dosing. Higher drug exposure occurred in slower CYP2D6 metabolizers. Based on favorable results in healthy participants, a phase 2 trial of eliglustat tartrate was initiated in GD1 patients.

Vernakalant hydrochloride injection (RSD1235) is a relatively atrial-selective antiarrhythmic agent that converts atrial fibrillation rapidly to sinus rhythm. The pharmacokinetics of vernakalant were explored in healthy volunteers and in patients with atrial fibrillation or atrial flutter in 4 clinical studies. Key pharmacokinetic parameters analyzed were the maximum plasma concentration and the area under the plasma concentration-time curve. Vernakalant exhibited linear pharmacokinetics over the dose range of 0.1 mg/kg to 5.0 mg/kg in healthy subjects, and generally showed dose proportionality in patients with atrial fibrillation or atrial flutter who received 1 or 2 vernakalant infusions. Vernakalant was metabolized rapidly via 4-O-demethylation by cytochrome P450 (CYP)2D6 to its major metabolite RSD1385, which then circulated predominantly as an inactive glucuronide conjugate. In most patients, the maximum plasma concentration of RSD1385 glucuronide exceeded that of vernakalant. Unconjugated RSD1385 was found at low levels in all patients demonstrating either a cytochrome P450 CYP2D6 "extensive metabolizer" or "poor metabolizer" phenotype or genotype; however, CYP2D6 poor metabolizers had even lower levels of unconjugated RSD1385. The impact of CYP2D6 metabolizer status on vernakalant exposure was explored in patients with atrial fibrillation or atrial flutter who received a therapeutic regimen (3 mg/kg initially via 10-minute intravenous infusion followed by a second 2 mg/kg 10-minute infusion if atrial fibrillation persisted after a 15-minute observation period). In the subset that received 2 vernakalant infusions, there was little difference in vernakalant maximum plasma concentration or area under the plasma concentration-time curve from the start of the first infusion to 90 minutes between CYP2D6 poor metabolizers and extensive metabolizers or between those who did or did not receive concomitant CYP2D6-inhibitor medications. Gender, age, and renal function did not have a clinically significant influence on the pharmacokinetics of vernakalant. These results suggest that an assessment of CYP2D6 expression may not be needed when vernakalant is administered acutely and intravenously to patients with atrial fibrillation.

Vildagliptin is an orally effective, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled, time-lagged, parallel-group study in a total of 60 healthy Chinese participants. Single- and multiple-dose pharmacokinetics and pharmacodynamics, and safety and tolerability of vildagliptin were assessed following administration of 25, 50, 100, or 200 mg qd, or 50 mg bid. Vildagliptin was rapidly absorbed (tmax 1.5-2.0 hours) across the dose range of 25 to 200 mg and was quickly eliminated with a terminal elimination half-life (t1/2) of approximately 2 hours. Consistent with the short t1/2, no accumulation of vildagliptin was observed following the administration of multiple doses (accumulation factors were 1.00-1.05 across the 25- to 200-mg dose range). Vildagliptin AUC and Cmax values increased in an approximately dose-proportional fashion (dose proportionality constant beta 1.00-1.16). Administration of vildagliptin 25 to 200 mg led to rapid and near-complete (>95%) inhibition of DPP-4 activity for at least 4 hours after dosing, which was associated with increases in plasma active glucagon-like peptide-1 of up to 2- to 3-fold compared with placebo. The duration of DPP-4 inhibition increased with dose. Glucose and insulin levels were not affected by vildagliptin in healthy participants, consistent with the fact that the glucose-lowering effects of vildagliptin occur in a glucose-dependent fashion. Vildagliptin was well tolerated at the highest tested dose of 200 mg qd. Vildagliptin 25 to 200 mg qd exhibits approximately dose-proportional pharmacokinetics with no evidence of accumulation after multiple dosing in healthy Chinese participants. Vildagliptin demonstrates potent inhibition of DPP-4 activity with excellent tolerability at doses of up to and including 200 mg qd.

We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.

Vildagliptin is a potent and selective dipeptidyl peptidase IV inhibitor in development for the treatment of type 2 diabetes that improves glycemic control by enhancing alpha- and beta-cell responsiveness to glucose. Two open-label, single-dose, randomized, crossover studies in healthy subjects (ages 18-45 years) investigated the dose proportionality of vildagliptin pharmacokinetics (n = 20) and the effect of food (n = 24) on vildagliptin pharmacokinetics. There was a linear relationship (r(2) = 0.999) between vildagliptin doses of 25, 50, 100, and 200 mg and area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)). Dose proportionality was assessed using a statistical power model [X = alpha x (dose)(beta)]. The 90% confidence intervals of the proportionality coefficient, beta, for AUC(0-infinity) (1.15-1.19) and C(max) (1.04-1.14) indicated that deviations from dose proportionality were small (<7.7%). Doubling of dose led to 2.1- to 2.3-fold increases in AUC(0-infinity) and C(max) but no dose-dependent changes in time to reach C(max) or terminal elimination half-life. Administration of vildagliptin 100 mg following a high-fat meal decreased C(max) by 19% and AUC(0-infinity) by 10%. Vildagliptin displays approximately dose-proportional pharmacokinetics over the 25- to 200-mg dose range, and administration with food has no clinically relevant effect on vildagliptin pharmacokinetics.

Vildagliptin is a novel antidiabetic agent that is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV, the enzyme responsible for degradation of the incretin hormones. This open-label, randomized, 3-period crossover study investigated the potential for pharmacokinetic interactions in 18 healthy subjects during coadministration of vildagliptin and digoxin. Subjects were randomized to receive each of 3 treatments: vildagliptin 100 mg qd, digoxin (0.5 mg, then 0.25 mg qd on days 2-7), and the combination vildagliptin/digoxin for 7 days. Coadministration of digoxin with vildagliptin had no effect on exposure to vildagliptin (geometric mean ratios [90% confidence interval]: AUC(0-24h), 0.99 [0.95-1.03]; C(max), 0.95 [0.85-1.06]) or to digoxin (AUC(0-24h), 1.02 [0.94-1.12]; C(max), 1.08 [0.97-1.20]). In addition, no changes in t(max), t((1/2)), and CL/F were observed for either drug. These results indicate that no dose adjustment is necessary when vildagliptin and digoxin are coadministered.

This randomized, open-label, placebo-controlled, 7-period crossover study assessed dose-response relationships following single oral doses (10-400 mg) of vildagliptin in 16 patients with type 2 diabetes mellitus. Plasma levels of parent drug, dipeptidyl peptidase-4 activity, glucose, insulin, and glucagon were measured during 75-g oral glucose tolerance tests performed after an overnight fast, 30 minutes after drug administration. The t(max) for parent drug was observed between 0.5 and 1.5 hours postdose. Both C(max) and AUC(0-8 h) increased dose proportionately. Both onset and duration of dipeptidyl peptidase-4 inhibition were dose dependent, but >90% inhibition occurred within 45 minutes and was maintained for >/=4 hours after each dose. Glucose excursions and glucagon levels during oral glucose tolerance tests were significantly and similarly decreased after each dose of vildagliptin, and insulin levels were significantly and similarly increased after each dose level. Unlike findings during mixed-meal challenges, vildagliptin increases plasma insulin levels during oral glucose tolerance tests in patients with type 2 diabetes mellitus.

The effect of rifampin, a cytochrome P450 3A4 inducer, on the pharmacokinetics of atrasentan was assessed in 12 healthy male subjects in an open-label study. Single doses of atrasentan 10 mg were administered orally on days 1 and 12. Rifampin 600 mg was given once daily from days 4 through 14. On day 12, atrasentan and rifampin were administered simultaneously. Blood samples were collected before and during 72 hours after each atrasentan dose. On average, rifampin increased atrasentan peak plasma concentrations by 150% and reduced its terminal half-life by 77% (P<.05), without affecting the AUC or peak time of atrasentan. Rifampin may affect atrasentan pharmacokinetics by acting as both an inhibitor of organic anion transporting polypeptide-mediated hepatic uptake of atrasentan and an inducer of atrasentan metabolism. The effect of rifampin on atrasentan pharmacokinetics may depend on the time of rifampin administration relative to that of atrasentan.

Lasofoxifene, a selective estrogen receptor modulator for osteoporosis management, is metabolized primarily by hepatic oxidation and conjugation. This study compared the pharmacokinetics of 0.25 mg lasofoxifene in subjects with mild (Child-Pugh grade A, n = 6) or moderate (Child-Pugh grade B, n = 6) hepatic impairment and healthy volunteers (n = 6). Analysis of variance was used to calculate 90% confidence intervals for the ratios (impaired/healthy) of least squares mean log maximum plasma concentration (C(max)) and area under the curve (AUC) values. Lasofoxifene pharmacokinetics was similar between healthy and mild hepatic impairment subjects: ratios of C(max) and AUC from 0 to infinity (AUC([0-infinity])) were 101% (75.0-138) and 95.5% (77.9-117), respectively. In subjects with moderate hepatic impairment, ratios of C(max) and AUC([0-infinity]) were 121% (89.6-165) and 138% (112-169), respectively; mean terminal half-life was 252 hr compared to 193 hr in healthy subjects. Dose adjustment should not be required for subjects with mild to moderate hepatic impairment.

Lasofoxifene, a next-generation selective estrogen receptor modulator, is undergoing phase 3 clinical development for osteoporosis. This study evaluated daily lasofoxifene for 14 days in healthy postmenopausal women. A loading dose of 5 times the daily dose was followed by daily doses of 0.01 mg (n = 8), 0.03 mg (n =8), 0.1 mg(n = 16), 0.3 mg (n =9), 1 mg (n = 8), or placebo (n = 16). Samples were collected for pharmacokinetic and pharmacodynamic assessments. Lasofoxifene was well tolerated; study drug-associated adverse events were mild and unrelated to dose. There was a predictable increase in plasma concentrations of lasofoxifene with dose. Pharmacokinetic parameters included mean half-life of 165 hours, mean area under the plasma concentration-time curve from time 0 to 24 hours ranging from 1.67 ng x h/mL to 137 ng x h/mL, and mean maximum observed plasma concentration ranging from 0.09 ng/mL to 6.43 ng/mL. Lasofoxifene partially suppressed luteinizing hormone, follicle-stimulating hormone, low-density lipoprotein, and N-telopeptide.

Lasofoxifene is in late-stage development for the prevention and treatment of osteoporosis. Digoxin is commonly prescribed for arrhythmias and congestive heart failure, has a narrow therapeutic index, and may be coadministered with lasofoxifene. This study was conducted to determine the effect of lasofoxifene (4-mg loading dose on day 11 followed by 0.5 mg/d on days 12-20) on the steady-state pharmacokinetics of digoxin (0.25 mg/d on days 1-20) in 12 healthy postmenopausal women. On days 10 and 20, blood and urine samples were collected for 24 hours to determine digoxin concentrations. The 90% confidence interval (CI) of least squares mean ratio for maximum concentration (C(max)) and area under the plasma concentration-time curve (AUC) was calculated. Lasofoxifene had no effect on digoxin plasma pharmacokinetics with a ratio (90% CI) of 95.4% (84.6%-107%) and 103% (97.7%-108%) for C(max) and AUC(0-24), respectively. The ratio of the percentage of dose eliminated unchanged in urine in 24 hours was 127% (116% to 142%). Coadministration of lasofoxifene had no effect on the steady state pharmacokinetics of digoxin.

Prolongation of QT interval on an electrocardiogram is a valuable predictor of a drug's ability to cause potentially fatal ventricular tachyarrhythmia (torsades de pointes). Darifenacin is a muscarinic M3 selective receptor antagonist developed for the treatment of overactive bladder, a debilitating condition that is particularly prevalent in the older population. This 7-day, randomized, parallel-group study (n=188) measured QT/QTc interval in healthy volunteers receiving once-daily darifenacin at steady-state therapeutic (15 mg) and supratherapeutic (75 mg) doses, alongside controls receiving placebo or moxifloxacin (positive control, 400 mg) once daily. There was no significant increase in QTcF interval with darifenacin treatment compared with placebo. Mean changes from baseline at pharmacokinetic Tmax versus placebo were -0.4 and -2.2 milliseconds in the darifenacin 15 mg and 75 mg groups, respectively, compared with +11.6 milliseconds in the moxifloxacin group (P<.01). This study demonstrates that darifenacin does not prolong QT/QTc interval.

Four separate studies were conducted to examine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of eletriptan, a 5-HT(1B/1D) receptor agonist being developed for the treatment of migraines, after oral and intravenous administration. Fifty-five males received oral (1.5-30 mg or 30-120 mg) or intravenous (1.67-50 microg/kg or 50-102 microg/kg) eletriptan in four double- and single-blind, placebo-controlled, ascending-dose crossover studies. The maximum plasma concentration (Cmax) and area under the concentration curve (AUC) appeared linear over all dose ranges, with an apparent terminal half-life of 4 to 5 hours. Clearance and volume of distribution remained constant with dose. The time to first occurrence of Cmax (tmax) for oral eletriptan was approximately 1 hour and was unaffected by dose. Comparison of AUC values suggested an absolute bioavailability of approximately 50%. A linear PK/PD model, fitted to the data, predicted small, transient elevations in diastolic blood pressure following eletriptan doses > or = 60 mg. These effects were considered unlikely to be clinically significant. Eletriptan was well tolerated, and treatment-related adverse events were mild to moderate and transient. These PK properties should result in eletriptan having a rapid onset and sustained duration of action in terms of migraine efficacy.

The pharmacokinetics, safety, and tolerability of the 5-HT(1B/1D) agonist eletriptan were characterized in a randomized, double-blind, placebo-controlled, dose escalation study. Healthy males received single oral doses of 10 to 120 mg. Following screening and baseline measurements, plasma and saliva eletriptan concentrations were measured at intervals over 48 hours and 24 hours, respectively. Samples were analyzed using high-performance liquid chromatography with ultraviolet detection. Both the maximum plasma concentration and the area under the plasma eletriptan concentration-time curve showed an essentially linear relationship to the administered dose. Eletriptan exhibited a median time to maximum plasma concentration of 1 to 1.25 hours and a mean elimination half-life of 3.6 to 7.0 hours. Mean salivary-plasma ratios for pharmacokinetic parameters generally remained constant across the 30 to 90 mg dose range. Eletriptan was well tolerated, with mostly mild and transient adverse events. In conclusion, oral doses of eletriptan in the therapeutic range were rapidly absorbed and exhibited essentially linear plasma and saliva pharmacokinetics.

The purpose of this study was to determine the pharmacokinetics and safety of eletriptan in different phases of the menstrual cycle. Female volunteers (n = 16) with a regular menstrual cycle (28 +/- 4 days) received a single oral dose of 80 mg eletriptan during each of the four cycle phases: phase 1 (menses), days 1 to 4; phase 2 (follicular), days 6 to 10; phase 3 (ovulatory), days 11 to 13; and phase 4 (luteal), days 21 to 24. Eletriptan plasma concentrations were determined from serial plasma samples taken during a 24-hourperiod after dosing. Blood pressure, pulse rate, and ECG measurements were performed at baseline, 1 and 24 hours after dosing. No significant differences between phases were observed for maximum plasma concentration (cmax, range of means = 188-234 ng/ml), time to maximum concentration (tmax, range of means = 1.8-2.5 h), or systemic exposure (area under the curve [AUC], range of means = 1194-1514 ng x h/ml). Although there was a statistically significant difference in the terminal phase elimination rate constant (kel) between phases 1 and2 (0.175/h vs. 0.158/h, p = 0.044), the corresponding difference in terminal phase half-life (t 1/2) (4.0 h vs. 4.4 h) was not considered to be clinicallyrelevant. No clinically relevant differences in blood pressure, pulse rate, or ECG were observed, and the incidence, nature, and severity of adverse events were similar in all phases. The different phases of the menstrual cycle had no clinically significant effect on the pharmacokinetics, safety, or tolerability of oral 80 mg eletriptan in healthy females.

This study investigates the pharmacokinetics and safety profile of Z-321, (4R)-3-(indan-2-ylacetyl)-4-(1-pyrrolidinyl-carbonyl)-1,3-thiazoli dine, a novel specific orally active prolyl endopeptidase (PEP) inhibitor. Following a preliminary safety evaluation wherein 2 subjects received 3.75 and 15 mg doses and 2 other subjects received 7.5 and 30 mg doses, 16 subjects were assigned to two groups of 8 subjects each. In each group, 6 subjects were to receive active treatment, and 1 or 2 subjects were to receive placebo treatment. One group received 60 mg under fasted and fed conditions. A separate group of 8 subjects received 60 mg of Z-321 or a placebo in a bid regimen for 6 days and the morning dose on day 7. The concentrations of Z-321 and its main metabolites--R- and S-sulfoxide; RR-, SS-, and RS-indanol; and indanolsulfoxides in plasma and urine--were determined by the HPLC method. In the multiple-dose study, the cholinesterase activity was gradually increased and reached above the normal range on day 8 in 3 of 6 subjects given Z-321 and gradually returned to the normal range after completion of dosing. The elevation of plasma cholinesterase activity was considered to be an action of Z-321, but this remains to be verified. In a single-dose study at a dose of 30 mg, headache and vomiting were observed in 1 of 6 subjects. In the multiple-dose study, slight skin itching and eczema in 3 and 2 of 6 subjects, respectively, and headache in 2 of 6 subjects were observed, but all symptoms were not severe. There were no other abnormal findings in objective signs and laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, and urinalysis. The Cmax of Z-321 at 30, 60, and 120 mg in the fasting state were 63.7 +/- 23.9, 102.0 +/- 43.1, and 543.3 +/- 437.0 ng/ml (mean +/- SD), respectively, at 0.9 hours after administration, and the t1/2 was about 1.8 hours. There were no dramatic changes in the pharmacokinetics of Z-321 in the presence of food. In the multiple-dose study, there was no drug accumulation trend in plasma. These results indicate that Z-321 has acceptable pharmacodynamic and pharmacokinetics profiles for clinical use without any serious adverse events, as verified in healthy young male volunteers.

The diuretic effects, pharmacokinetics, and safety of CI-977, a new centrally acting selective kappa-opioid agonist, were determined in 16 healthy subjects. Subjects received single intramuscular doses of CI-977 (5, 15, or 25 micrograms) or placebo 1 week apart according to a randomized, double-blind, placebo-controlled, four-period, crossover design. Serial blood and urine specimens were collected after each dose. Significant dose-related decreases in negative free water clearance and urine osmolality and increases in urine volume were observed after administration of 15- and 25-micrograms doses of CI-977. CI-977 had no effect on urine electrolyte excretion or serum antidiuretic hormone. Absorption of CI-977 was rapid with individual tmax values ranging from 0.17 to 1.5 hours. Cmax and AUC(0-infinity) increased proportionally with dose. Individual elimination half-life values ranged from 0.6 to 3.3 hours and were independent of dose. Changes in free water clearance were related to CI-977 Cmax (r2 = 0.29, P = 0.0001) and AUC(0-4 hr) (r2 = 0.32, P = 0.0001) values. The most frequently reported adverse events after CI-977 administration were dizziness, fatigue, paresthesia, headache, vasodilatation (facial flushing), emotional lability, high feeling, and abnormal thinking. The frequency and intensity of adverse events increased with increasing CI-977 dose. In conclusion, CI-977 Cmax and AUC(0-infinity) increased in proportion to dose over the range of 5 to 25 micrograms; decreases in negative free water clearance were related to CI-977 dose and Cmax and AUC(0-4 hr) values; and the frequency and intensity of adverse events increased with increasing CI-977 dose.