The Importance of Assessing Drug Pharmacokinetics and Pharmacodynamics in the Obese Population During Drug Development.

Obesity remains a US national health crisis and a growing concern worldwide. Concerningly, individuals who are obese are at an increased risk for comorbid diseases that include, but are not limited to, hypertension, diabetes, cardiovascular disease, and cancer. Beyond the risk for developing these conditions, obesity may also impact the pharmacological activity of the therapies being used to treat them and other disease states. The pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of therapies, both currently marketed and under clinical development, may be directly impacted by the physiological alterations that occur secondary to the occurrence of chronic excess body weight. The increased prevalence of this disease should not be ignored. Both private and federal institutions involved in drug research and development should consider, as appropriate, a greater inclusion of individuals who are obese in clinical trials throughout the entirety of drug development, and leverage the available PK, PD, safety, and efficacy data to make more informed dosing recommendations.

First-in-human study to assess the safety, pharmacokinetics, and pharmacodynamics of BMS-986141, a novel, reversible, small-molecule, PAR4 agonist in non-Japanese and Japanese healthy participants.

BMS-986141 is a novel, oral, protease-activated, receptor 4 (PAR4)-antagonist that exhibited robust antithrombotic activity and low bleeding risk in preclinical studies. The pharmacokinetic, pharmacodynamic, and tolerability profiles of BMS-986141 in healthy participants were assessed in a randomized, double-blind, placebo-controlled, single-ascending-dose (SAD; N = 60) study; a multiple-ascending-dose (MAD; N = 32) study; and a Japanese MAD (JMAD; N = 32) study. Exposure was dose-proportional for BMS-986141 2.5 mg and 150 mg; maximum concentrations were 17.6 ng/mL and 958 ng/mL; and areas under the curve (AUC) to infinity were 183 h* × ng/mL and 9207 h* × ng/mL, respectively. Mean half-life ranged from 33.7 to 44.7 hours across dose panels. The accumulation index following once-daily administration for 7 days suggested a 1.3- to 2-fold AUC increase at steady state. In the SAD study, BMS-986141 75 and 150 mg produced ≥80% inhibition of 25-100 µM PAR4 agonist peptide (AP)-induced platelet aggregation, without affecting PAR1-AP-induced platelet aggregation, through ≥24 hours postdose. In the MAD and JMAD studies, BMS-986141 doses ≥10 mg completely inhibited 12.5 µM and 25 µM PAR4-AP-induced platelet aggregation through 24 hours. This study found BMS-986141 was safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. ClinicalTrials.gov ID: NCT02341638.

Why was the study done? Antiplatelet therapies have shortcomings that limit their clinical utility, and there is an unmet need for a new, safe, and effective antiplatelet agent with reduced bleeding risk.PAR4 antagonists are a promising novel class of antiplatelet drugs due to late-stage inhibition of thrombus growth with minimal effects on platelet-driven hemostasis.BMS-986141 is a novel, potent, orally bioavailable, small-molecule antagonist specific for PAR4.What is new? BMS-986141 is safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range.BMS-986141 has robust antithrombotic activity and low bleeding risk.What is the impact? BMS-986141 has the potential to improve the benefit­risk of antiplatelet therapy in patients with atherothrombosis.

New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans.

BMS-986120 is a novel first-in-class oral protease-activated receptor 4 (PAR4) antagonist exhibiting robust antithrombotic activity that has shown low bleeding risk in monkeys. We sought to assess pharmacokinetics, pharmacodynamics, and tolerability of BMS-986120 in healthy participants and platelet responses to BMS-986120 in participants carrying PAR4 A120T variants. Phase I, randomized, double-blind, placebo-controlled single-ascending-dose (SAD; N = 56) and multiple-ascending-dose (MAD; N = 32) studies were conducted. Exposure was approximately dose-proportional: maximum concentrations 27.3 and 1536 ng/mL, areas under the curve (AUC) to infinity of 164 and 15,603 h*ng/mL, and half-lives of 44.7 and 84.1 hours for 3.0 and 180 mg, respectively. The accumulation index suggested an ~2-fold AUC increase at steady state. Single doses of 75 and 180 mg BMS-986120 produced ≥80% inhibition of 12.5 µM PAR4 agonist peptide (AP)-induced platelet aggregation through at least 24 hours postdose, and doses ≥10 mg for ~7 days inhibited aggregation completely through 24 hours. No differences in PAR4-mediated platelet response were seen between AA120 versus TT120 PAR4 variants. In cells expressing A120 or T120 PAR4 proteins, no differences in half-maximal effective concentration in receptor activation by PAR4-AP were observed. BMS-986120 was well tolerated with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range.ClinicalTrials.gov ID: NCT02208882.

Apixaban Single-Dose Pharmacokinetics, Bioavailability, Renal Clearance, and Pharmacodynamics Following Intravenous and Oral Administration.

This randomized, double-blind, placebo-controlled, ascending single intravenous (IV) bolus-dose study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of apixaban, a direct factor Xa (FXa) inhibitor approved for multiple indications. Eight healthy subjects were randomized 3:1 (apixaban:placebo) within each IV dose cohort (0.5, 1.25, 2.5, 3.75, and 5 mg). The 2.5-mg IV panel also received 5 mg of oral apixaban or placebo. Blood samples were collected for PK and PD, including international normalized ratio, modified prothrombin time (mPT), and anti-FXa activity. Apixaban had 66.2% oral bioavailability, dose-proportional exposure, 17 to 26 L steady-state volume of distribution, and 3.2 to 3.5 L/h total plasma clearance. Renal clearance was ≈27%. Anti-FXa activity and mPT changes followed the apixaban plasma concentration-time profile; both were highly correlated with concentration (R2 = 0.99 and R2 = 0.93 for anti-FXa activity and mPT, respectively). International normalized ratio remained within reference range (0.9-1.3). There were no serious or bleeding-related adverse events. Overall, an apixaban single IV bolus was safe and well tolerated over a 10-fold dose range by these subjects. Apixaban had good oral bioavailability, dose-proportional exposure, and constant plasma clearance over a broad dose range, with modest renal clearance. Apixaban PD were consistent with reversible FXa inhibition.

Apixaban Pharmacokinetics and Pharmacodynamics in Subjects with Mild or Moderate Hepatic Impairment.

BACKGROUND: Hepatic impairment can impact apixaban pharmacokinetics and pharmacodynamics by decreasing cytochrome P450-mediated metabolism and factor X production. OBJECTIVE: This study evaluated the effect of mild or moderate (Child-Pugh A and B) hepatic impairment on apixaban pharmacokinetics, pharmacodynamics, and safety. METHODS: This open-label, parallel-group, single-dose study included eight mildly and eight moderately hepatically impaired subjects, and 16 healthy subjects. Subjects received a single oral apixaban 5-mg dose (day 1). Pharmacokinetic, pharmacodynamic, and safety assessments were completed at prespecified time points. Apixaban maximum plasma concentration and area under the concentration-time curve to infinity were compared between subjects with hepatic impairment and healthy subjects. RESULTS: Apixaban area under the concentration-time curve to infinity point estimates and 90% confidence intervals were 1.03 (0.80-1.32) and 1.09 (0.85-1.41) for subjects with mild and moderate hepatic impairment vs healthy subjects. Maximum plasma concentration results were similar. Mean (standard deviation) apixaban unbound fraction was 6.8% (1.4), 7.9% (1.8), and 7.1% (1.3) in subjects with mild or moderate hepatic impairment and in healthy subjects. Mean change from baseline in international normalized ratio (3 h post-dose) was 14.7%, 12.7%, and 10.7% for subjects with mild or moderate hepatic impairment and healthy subjects, respectively. A direct relationship was observed between apixaban anti-factor Xa activity and plasma concentration across groups. No serious adverse events or discontinuations due to adverse events occurred. CONCLUSIONS: Mild or moderate hepatic impairment had no clinically relevant impact on apixaban pharmacokinetic or pharmacodynamic measures, suggesting that dose adjustment may not be required.

Warming Arctic summers unlikely to increase productivity of shorebirds through renesting.

Climate change in the Arctic is leading to earlier summers, creating a phenological mismatch between the hatching of insectivorous birds and the availability of their invertebrate prey. While phenological mismatch would presumably lower the survival of chicks, climate change is also leading to longer, warmer summers that may increase the annual productivity of birds by allowing adults to lay nests over a longer period of time, replace more nests that fail, and provide physiological relief to chicks (i.e., warmer temperatures that reduce thermoregulatory costs). However, there is little information on how these competing ecological processes will ultimately impact the demography of bird populations. In 2008 and 2009, we investigated the survival of chicks from initial and experimentally-induced replacement nests of arcticola Dunlin (Calidris alpina) breeding near Utqiagvik, Alaska. We monitored survival of 66 broods from 41 initial and 25 replacement nests. Based on the average hatch date of each group, chick survival (up to age 15 days) from replacement nests (Si = 0.10; 95% CI = 0.02-0.22) was substantially lower than initial nests (Si = 0.67; 95% CI = 0.48-0.81). Daily survival rates were greater for older chicks, chicks from earlier-laid clutches, and during periods of greater invertebrate availability. As temperature was less important to daily survival rates of shorebird chicks than invertebrate availability, our results indicate that any physiological relief experienced by chicks will likely be overshadowed by the need for adequate food. Furthermore, the processes creating a phenological mismatch between hatching of shorebird young and invertebrate emergence ensures that warmer, longer breeding seasons will not translate into abundant food throughout the longer summers. Thus, despite having a greater opportunity to nest later (and potentially replace nests), young from these late-hatching broods will likely not have sufficient food to survive. Collectively, these results indicate that warmer, longer summers in the Arctic are unlikely to increase annual recruitment rates, and thus unable to compensate for low adult survival, which is typically limited by factors away from the Arctic-breeding grounds.

Assessing recovery of spectacled eiders using a Bayesian decision analysis.

Assessing species status and making classification decisions under the Endangered Species Act is a critical step towards effective species conservation. However, classification decisions are liable to two errors: i) failing to classify a species as threatened or endangered that should be classified (underprotection), or ii) classifying a species as threatened or endangered when it is not warranted (overprotection). Recent surveys indicate threatened spectacled eider populations are increasing in western Alaska, prompting the U.S. Fish and Wildlife Service to reconsider the federal listing status. There are multiple criteria set for assessing spectacled eider status, and here we focus on the abundance and decision analysis criteria. We estimated population metrics using state-space models for Alaskan breeding populations of spectacled eiders. We projected abundance over 50 years using posterior estimates of abundance and process variation to estimate the probability of quasi-extinction. The decision analysis maps the risk of quasi-extinction to the loss associated with making a misclassification error (i.e., underprotection) through a loss function. Our results indicate that the Yukon Kuskokwim Delta breeding population in western Alaska has met the recovery criteria but the Arctic Coastal Plain population in northern Alaska has not. The methods employed here provide an example of accounting for uncertainty and incorporating value judgements in such a way that the decision-makers may understand the risk of committing a misclassification error. Incorporating the abundance threshold and decision analysis in the reclassification criteria greatly increases the transparency and defensibility of the classification decision, a critical aspect for making effective decisions about species management and conservation.

Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review.

Apixaban is an oral, direct factor Xa inhibitor that inhibits both free and clot-bound factor Xa, and has been approved for clinical use in several thromboembolic disorders, including reduction of stroke risk in non-valvular atrial fibrillation, thromboprophylaxis following hip or knee replacement surgery, the treatment of deep vein thrombosis or pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism. The absolute oral bioavailability of apixaban is ~ 50%. Food does not have a clinically meaningful impact on the bioavailability. Apixaban exposure increases dose proportionally for oral doses up to 10 mg. Apixaban is rapidly absorbed, with maximum concentration occurring 3-4 h after oral administration, and has a half-life of approximately 12 h. Elimination occurs via multiple pathways including metabolism, biliary excretion, and direct intestinal excretion, with approximately 27% of total apixaban clearance occurring via renal excretion. The pharmacokinetics of apixaban are consistent across a broad range of patients, and apixaban has limited clinically relevant interactions with most commonly prescribed medications, allowing for fixed dosages without the need for therapeutic drug monitoring. The pharmacodynamic effect of apixaban is closely correlated with apixaban plasma concentration. This review provides a summary of the pharmacokinetic, pharmacodynamic, biopharmaceutical, and drug-drug interaction profiles of apixaban. Additionally, the population-pharmacokinetic analyses of apixaban in both healthy subjects and in the target patient populations are discussed.

Evaluation of the single-dose pharmacokinetics and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.

PURPOSE: This double-blind, placebo-controlled, intra-subject, dose-escalation study assessed single-dose safety, pharmacokinetics, and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects. SUBJECTS AND METHODS: Sixteen healthy male Japanese and sixteen healthy male Caucasian subjects, matched for age, weight, and smoking status were randomized to receive four sequential single oral doses of either apixaban (2.5, 10, 25, and 50 mg) or matched placebo. Doses were separated by a ≥5-day washout. Blood samples were collected for the determination of apixaban plasma concentration, clotting times (international normalized ratio [INR], activated partial thromboplastin time, and modified prothrombin time [mPT]), and ex vivo thrombin generation (TG). Urine samples were collected for the analysis of apixaban concentration. RESULTS: Ascending single doses of apixaban 2.5-50 mg were safe and well tolerated by all subjects. Apixaban exposure increased the dose proportionally up to 10 mg. Apixaban reached maximum concentrations (C max) 3-4 h postdose, with mean C max ranging from 52.5-485.0 to 44.8-494.3 ng/mL in Japanese and Caucasian subjects. The mean half-life was ~8 and ~13 h and the renal clearance was 1.1 and 0.8 L/h in Japanese and Caucasian subjects, respectively. Pharmacodynamic assessments were similar between ethnic groups, with comparable dose-related prolongation of INR and mPT and inhibition of TG. CONCLUSION: Ascending single doses of apixaban over a 20-fold dose range were safe and well tolerated in Japanese and Caucasian subjects in this study. The consistency between pharmacokinetic and pharmacodynamic measures in Japanese and Caucasian subjects indicates that apixaban may be administered as a fixed dose with no need for adjustment in Japanese patients.

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation.

This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I-III studies. Apixaban exposure was characterized by a two-compartment PPK model with first-order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P-glycoprotein (P-gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non-Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P-gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose-reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5-mg and 5-mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant.

Regional Gastrointestinal Absorption of Apixaban in Healthy Subjects.

This study was conducted to investigate the extent of absorption in different regions of the gastrointestinal (GI) tract. The relative bioavailability of an apixaban crushed tablet was also assessed to investigate the effect of dissolution on absorption. This was an open-label, randomized, 4-period, 4-treatment crossover study with a 7-day washout period balanced for first-order residual effects in 12 healthy subjects. Subjects received a single dose of a 2.5-mg apixaban solution administered orally, released in the distal small intestine and in the ascending colon. In addition, subjects received a single dose of a 2.5-mg apixaban crushed tablet released in the ascending colon. The solution and crushed tablet were delivered via Enterion capsules. The location of Enterion capsules was monitored using scintigraphic imaging. Apixaban maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration (AUC0-t ) decreased by approximately 60% when it was delivered to the distal small bowel compared with the oral administration. A greater decrease was observed when it was delivered to the ascending colon, with reductions of 90% and 84% in Cmax and AUC0-t , respectively. A crushed tablet delivered to the ascending colon resulted in exposure that was approximately 40% of that observed for solution released in the same region. These findings indicate that apixaban exhibits region-dependent absorption and that dissolution/solubility of the solid-dose form is limited in the ascending colon. Apixaban absorption decreased progressively along the GI tract, indicating that absorption occurs primarily in the upper GI tract.

First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects.

AIMS: The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. METHODS: This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study of 2-h (part A) and 5-day (part B) intravenous (IV) infusions of BMS-962212. Part A used four doses (1.5, 4, 10 and 25 mg h-1 ) of BMS-962212 or placebo in a 6:2 ratio per dose. Part B used four doses (1, 3, 9 and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese (n = 4 active, n = 1 placebo) subjects per dose. The PK, PD, safety and tolerability were assessed throughout the study. RESULTS: BMS-962212 was well tolerated; there were no signs of bleeding, and adverse events were mild. In parts A and B, BMS-962212 demonstrated dose proportionality. The mean half-life in parts A and B ranged from 2.04 to 4.94 h and 6.22 to 8.65 h, respectively. Exposure-dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C). The maximum mean aPTT and FXI:C change from baseline at 20 mg h-1 in part B was 92% and 90%, respectively. No difference was observed in weight-corrected steady-state concentrations, aPTT or FXI:C between Japanese and non-Japanese subjects (P > 0.05). CONCLUSION: BMS-962212 has tolerability, PK and PD properties suitable for investigational use as an acute antithrombotic agent in Japanese or non-Japanese subjects.

Apixaban pharmacodynamic activity in umbilical cord, paediatric, and adult plasma.

The objective was to characterise apixaban pharmacodynamic (PD) activity in umbilical cord (UC), paediatric, and adult plasma. Plasma was obtained from blood samples from six UC donors, 70 paediatric (neonates [birth-≤1 month], infants [>1-≤6 months], toddlers [>6 months-≤2 years], young children [>2-≤6 years], children [>6-≤12 years], adolescents [>12-≤18 years]), and six adult (19-45 years) subjects. Plasma spiked with apixaban 0 (baseline), 30, or 110 ng/ml was analysed for anti-factor Xa activity, factor X levels, prothrombin time (PT), and modified PT (mPT). Apixaban had similar concentration-related effects on anti-factor Xa activity across groups (30 ng/ml: 0.223-0.295 IU/ml; 110 ng/ml: 1.212-1.474 IU/ml). Endogenous baseline factor X levels were 43 %-68 % lower in plasma from UC and subjects ≤6 months versus adults. Factor Xa inhibition (percentage change from baseline in apparent factor X levels) was similar for both apixaban concentrations across groups, except UC, neonate, and infant groups, which showed greater inhibition vs adults for apixaban 110 ng/ml. Baseline PT and mPT were similar across groups. Apixaban had no effect on PT at the concentrations tested. Apixaban 110 ng/ml prolonged mPT similarly across groups (44.4-53.2 s to 64.5-70.0 s); no prolongation was found with apixaban 30 ng/ml. Apixaban demonstrated consistent concentration-related effects on other PD endpoints in plasma samples from all age groups, except factor Xa inhibition.

The effect of apixaban on the pharmacokinetics of digoxin and atenolol in healthy subjects.

PURPOSE: Apixaban is often coadministered with treatments for cardiovascular comorbidities, which may lead to unintended drug-drug interactions (DDIs). The effects of apixaban on pharmacokinetics (PK) of multidose Lanoxin® (digoxin) and single-dose Tenormin® (atenolol) and the effects of single-dose atenolol on apixaban PK in healthy subjects were investigated in two Phase 1 studies. PATIENTS AND METHODS: The digoxin DDI study was an open-label, multidose, two-treatment, single-sequence study in which subjects received digoxin 0.25 mg q6h on day 1, then once daily on days 2-10, followed by apixaban 20 mg and digoxin 0.25 mg once daily on days 11-20. The atenolol DDI study was an open-label, single-dose, randomized, three-period, three-treatment, crossover study in which subjects received a single oral dose of apixaban 10 mg, atenolol 100 mg, or apixaban 10 mg plus atenolol 100 mg. The 90% confidence intervals (CIs) for the ratios of geometric means of peak plasma concentration (Cmax) and area under the concentration-time curve (AUCtau), with and without apixaban were calculated. Absence of effect was concluded if the point estimates and 90% CI were within the equivalence interval of 80%-125% (digoxin) or 70%-143% (atenolol). A similar analysis was performed to assess the effect of atenolol on apixaban. RESULTS: Apixaban had no clinically relevant effect on the PK of either atenolol or digoxin: point estimates and 90% CI for both digoxin and atenolol Cmax and AUC were entirely within their respective no-effect intervals. Apixaban Cmax and AUCinf were slightly decreased (ie, 18% and 15% lower, respectively) following atenolol coadministration. No serious or major bleeding-related adverse events were reported during either study. CONCLUSION: Apixaban had no effect on the PK of digoxin and there was no clinically relevant interaction between apixaban and atenolol. Coadministration of digoxin or atenolol with apixaban in healthy subjects was generally well tolerated.

Apixaban Versus Warfarin for Mechanical Heart Valve Thromboprophylaxis in a Swine Aortic Heterotopic Valve Model.

OBJECTIVE: Warfarin is the current standard for oral anticoagulation therapy in patients with mechanical heart valves, yet optimal therapy to maximize anticoagulation and minimize bleeding complications requires routine coagulation monitoring, possible dietary restrictions, and drug interaction monitoring. As alternatives to warfarin, oral direct acting factor Xa inhibitors are currently approved for the prophylaxis and treatment of venous thromboembolism and reduction of stroke and systemic embolization. However, no in vivo preclinical or clinical studies have been performed directly comparing oral factor Xa inhibitors such as apixaban to warfarin, the current standard of therapy. APPROACH AND RESULTS: A well-documented heterotopic aortic valve porcine model was used to test the hypothesis that apixaban has comparable efficacy to warfarin for thromboprophylaxis of mechanical heart valves. Sixteen swine were implanted with a bileaflet mechanical aortic valve that bypassed the ligated descending thoracic aorta. Animals were randomized to 4 groups: control (no anticoagulation; n=4), apixaban oral 1 mg/kg twice a day (n=5), warfarin oral 0.04 to 0.08 mg/kg daily (international normalized ratio 2-3; n=3), and apixaban infusion (n=4). Postmortem valve thrombus was measured 30 days post-surgery for control-oral groups and 14 days post-surgery for the apixaban infusion group. Control thrombus weight (mean) was significantly different (1422.9 mg) compared with apixaban oral (357.5 mg), warfarin (247.1 mg), and apixiban 14-day infusion (61.1 mg; P<0.05). CONCLUSIONS: Apixaban is a promising candidate and may be a useful alternative to warfarin for thromboprophylaxis of mechanical heart valves. Unlike warfarin, no adverse bleeding events were observed in any apixaban groups.

Evaluation of Crushed Tablet for Oral Administration and the Effect of Food on Apixaban Pharmacokinetics in Healthy Adults.

PURPOSE: These studies evaluate the relative bioavailability of crushed apixaban tablets and the effect of food on apixaban pharmacokinetic properties. METHODS: An open-label, randomized, crossover study in 33 healthy adults compared the bioavailability of 2 × 5-mg apixaban tablets administered whole (reference), crushed and suspended in 30 mL of water, and crushed and mixed with 30 g of applesauce. A second open-label, randomized, crossover study in 22 healthy adults compared apixaban 1 × 5-mg tablet administered when fasted (reference) or immediately after consumption of a high-fat, high-calorie meal. Point estimates and 90% CIs for geometric mean ratios were generated for Cmax, AUC0-∞, and AUC0-t. FINDINGS: Cmax and AUC met bioequivalence criteria for crushed tablets in water. Cmax and AUC decreased by 21.1% and 16.4%, respectively, with the lower bound of the CIs falling below the bioequivalence criteria for crushed tablets with applesauce. Similarly, administration of whole tablets with a high-fat, high-calorie meal reduced apixaban Cmax and AUC by 14.9% and 20.1%, respectively. The exposure reductions in both studies were considered not clinically significant. IMPLICATIONS: Apixaban tablets can be administered crushed or whole, with or without food. The results of these alternative methods of administration support their use in patients who have difficulty swallowing tablets. ClinicalTrials.gov identifiers: NCT02101112 and NCT01437839.

Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa.

OBJECTIVE: Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous apixaban were evaluated in an open-label, randomized, sequential crossover study. METHODS: Twenty healthy participants received single doses of apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15. Finally, participants received single doses of apixaban 5 mg intravenously and 10 mg orally separately on days 12 and 14 in one of two randomized sequences. RESULTS: Apixaban, given intravenously and orally, was safe and well tolerated when administered in the presence and absence of rifampin. Apixaban absolute oral bioavailability was 49 % when administered alone and 39 % following induction by rifampin. Rifampin reduced apixaban area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 39 % after intravenous administration and by 54 % after oral administration. Rifampin induction increased mean clearance by 1.6-fold for intravenous apixaban and mean apparent clearance by 2.1-fold for oral apixaban, indicating rifampin affected both pre-systemic and systemic apixaban elimination pathways. CONCLUSION: Co-administration of apixaban with rifampin reduced apixaban exposure via both decreased bioavailability and increased systemic clearance.

Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban.

This open-label study evaluated apixaban pharmacokinetics, pharmacodynamics, and safety in subjects with mild, moderate, or severe renal impairment and in healthy subjects following a single 10-mg oral dose. The primary analysis determined the relationship between apixaban AUC∞ and 24-hour creatinine clearance (CLcr ) as a measure of renal function. The relationships between 24-hour CLcr and iohexol clearance, estimated CLcr (Cockcroft-Gault equation), and estimated glomerular filtration rate (modification of diet in renal disease [MDRD] equation) were also assessed. Secondary objectives included assessment of safety and tolerability as well as international normalized ratio (INR) and anti-factor Xa activity as pharmacodynamic endpoints. The regression analysis showed that decreasing renal function resulted in modestly increased apixaban exposure (AUC∞ increased by 44% in severe impairment with a 24-hour CLcr of 15 mL/min, compared with subjects with normal renal function), but it did not affect Cmax or the direct relationship between apixaban plasma concentration and anti-factor Xa activity or INR. The assessment of renal function measured by iohexol clearance, Cockcroft-Gault, and MDRD was consistent with that determined by 24-hour CLcr . Apixaban was well tolerated in this study. These results suggest that dose adjustment of apixaban is not required on the basis of renal function alone.

Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.

An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in apixaban concentration. A single 5-mg oral dose of apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on apixaban clearance.