Janice Pursley

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.

Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects

AIM Apixaban is an oral, direct, factor-Xa inhibitor approved for thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This open label, parallel group study investigated effects of extremes of body weight on apixaban pharmacokinetics, pharmacodynamics, safety and tolerability. METHOD Fifty-four healthy subjects were enrolled [18 each into low (≤50 kg), reference (65-85 kg) and high (≥120 kg) body weight groups]. Following administration of a single oral dose of 10 mg apixaban, plasma and urine samples were collected for determination of apixaban pharmacokinetics and anti-factor Xa activity. Adverse events, vital signs and laboratory assessments were monitored. RESULTS Compared with the reference body weight group, low body weight had approximately 27% [90% confidence interval (CI): 8-51%] and 20% (90% CI: 11-42%) higher apixaban maximum observed plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC(0,∞)), respectively, and high body weight had approximately 31% (90% CI: 18-41%) and 23% (90% CI: 9-35%) lower apixaban Cmax and AUC(0,∞) , respectively. Apixaban renal clearance was similar across the weight groups. Plasma anti-factor Xa activity showed a direct, linear relationship with apixaban plasma concentration, regardless of body weight group. Apixaban was well tolerated in this study. CONCLUSION The modest change in apixaban exposure is unlikely to require dose adjustment for apixaban based on body weight alone. However, caution is warranted in the presence of additional factors (such as severe renal impairment) that could increase apixaban exposure.

Quantitative determination of pioglitazone in human serum by direct-injection high-performance liquid chromatography mass spectrometry and its application to a bioequivalence study

A simple, high throughput, direct-injection high-performance liquid chromatography tandem mass spectrometry method (LC/MS/MS) has been developed and validated for the quantitation of pioglitazone in human serum. After mixing the internal standard with a sample, a 10 microl portion of the mixture was directly injected into a high-flow LC/MS/MS system, which included an extraction column, an analytical column and a six-port switching valve. The on-line extraction was achieved on an Oasis HLB column (1 mm x 50 mm, 30 microm) with a 100% aqueous loading mobile phase containing 5 mM ammonium acetate (pH 4.0) at a flow rate of 4 ml/min. The extracted analyte was eluted by a mobile phase which contained 5 mM ammonium acetate and acetonitrile. The analytical column was a Luna C18 column (4.6 mm x 50 mm, 5 microm). Detection was achieved by positive ion electrospray tandem mass spectrometry. The lower limit of quantitation of the method was 9 ng/ml. The standard curve, which ranged from 9 to 1350 ng/ml, was fitted by a weighted (1/x2) quadratic regression model. The validation results demonstrated that this method had satisfactory precision and accuracy across the calibration range. There was no evidence of instability of the analyte in human serum following three freeze-thaw cycles, and samples could be stored for at least 2 weeks at -30 degrees C. This method was used to analyze pioglitazone concentrations in human serum samples from a bioequivalence study of a blinded Actos formulation (encapsulated 15 mg tablet) and an Actos 15 mg tablet. The blinded formulation was shown to be bioequivalent to an Actos 15 mg tablet.

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.

Multiplexed LC-MS/MS method for the simultaneous quantitation of three novel hepatitis C antivirals, daclatasvir, asunaprevir, and beclabuvir in human plasma

Dual or triple combination regimens of novel hepatitis C direct-acting antivirals (DAA, daclatasvir, asunaprevir, or beclabuvir) provide high sustained virological response rates and reduced frequency of resistance compared to clinical monotherapy. To support pharmacokinetic (PK) assessments in clinical studies, a multiplexed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantitation of daclatasvir, asunaprevir, beclabuvir (BMS-791325) and its active metabolite (BMS-794712) in human plasma was developed and validated. Human plasma samples were extracted with methyl-t-butyl ether followed by an LC-MS/MS analysis, which was conducted in a multiple reaction monitoring (MRM) mode. The lower limits of quantitation (LLOQ) were 1 ng/mL for daclatasvir, asunaprevir, and BMS-794712, and 2 ng/mL for beclabuvir. Intra-run precision (≤4.5% CV), inter-run precision (≤2.9% CV), and accuracy (±5.3% deviation) based on different concentration levels (low, geometric mean, mid and high) of the quality control samples (QCs) provided evidence of the methods accuracy and precision. Selectivity and matrix effect on LC-MS/MS detection, stability in plasma, and potential interference of coadministered drugs (ribavirin and interferon) were all evaluated and the results were acceptable. Method reproducibility was demonstrated by the reanalysis of a portion of study samples. The cross-validation results for QCs demonstrated the equivalency between this method and two single-analyte methods which were previously validated for quantitation of daclatasvir in human plasma. This approach of using a multiplexed LC-MS/MS method for the simultaneous quantitation of three DAAs is time- and cost-effective, and can maintain good data quality in sample analysis.

A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban.

Background Currently, there are no direct comparisons of apixaban and rivaroxaban, two new oral direct factor Xa inhibitors approved for management of thromboembolic disorders. Objective Compare the pharmacokinetics and anti-factor Xa activity (AXA) of apixaban and rivaroxaban. Methods In this randomized, open-label, two-period, two-treatment crossover study, healthy subjects (N=14) received apixaban 2.5 mg twice daily (BID) and rivaroxaban 10 mg once daily (QD) for 4 days with a ≥4.5-day washout. Plasma samples were obtained for pharmacokinetic and AXA assessments; parameters were calculated using noncompartmental methods. Results Median time-to-maximum concentration was 2 hours for both compounds, and the mean half-life was 8.7 and 7.9 hours for apixaban and rivaroxaban, respectively. Daily exposure, the area under the curve (AUC(0–24)), appeared similar for rivaroxaban (1,094 ng · h/mL) and apixaban (935 ng · h/mL), whereas mean peak-to-trough plasma concentration ratio was 3.6-fold greater for rivaroxaban (16.9) than apixaban (4.7). Coefficient of variation for exposure parameters (AUC0–24, Cmax, Cmin) was 20%–24% for apixaban versus 29%–46% for rivaroxaban. Peak AXA, AXA AUC(0–24), and AXA fluctuation were ~2.5-, 1.3-, and 3.5-fold higher for rivaroxaban than apixaban, respectively. Trough concentrations and AXA were lower for rivaroxaban (10 ng/mL and 0.17 IU/mL vs 17 ng/mL and 0.24 IU/mL for apixaban, respectively). Rivaroxaban exhibited a steeper concentration–AXA response (slope: 0.0172 IU/ng vs 0.0134 IU/ng for apixaban, P<0.0001). Conclusion Apixaban 2.5 mg BID demonstrated less intersubject variability in exposure, lower AXA AUC, and higher trough and smaller peak-to-trough fluctuations in plasma concentration and AXA, suggesting more constant anticoagulation compared with rivaroxaban 10 mg QD. However, the clinical impact of these differences on the relative efficacy and safety of apixaban and rivaroxaban remains to be determined.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of apixaban in healthy Japanese male subjects.

OBJECTIVE This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of apixaban in healthy Japanese male subjects. METHODS The study was conducted using three sequential dose panels: apixaban 2.5 mg, 5 mg, and 10 mg given twice daily. For each dose panel, subjects were randomly assigned to receive oral apixaban (n = 6) or matching placebo (n = 2) for 7 days. The pharmacokinetics of apixaban and effect on pharmacodynamic variables (clotting assays and anti-Xa activity) were assessed on day 1 and day 7 of treatment. Safety was assessed throughout the study. Only after the preceding dose was confirmed to be safe and well-tolerated subjects were enrolled into the next-higher-dose panel. RESULTS Apixaban was safe and well-tolerated in these healthy Japanese male subjects across the doses evaluated. On day 7, peak plasma concentrations were reached ~ 3 hours postdose, and increases in peak plasma concentration (C(max)), trough plasma concentration, and area under the plasma concentration-time curve across one dosing interval (12 hours) were tested dose-proportional across the dose range. A modest degree of accumulation was observed that was similar for all doses (accumulation index of 1.7 to 2.0), and renal clearance was consistent across doses (0.91 L/h - 1.07 L/h). Exposure-dependent prolongation of prothrombin time, activated partial thromboplastin time, modified prothrombin time, and increases in anti-Xa activity were observed after single and multiple doses of apixaban. CONCLUSIONS Apixaban was safe and well-tolerated in healthy Japanese subjects. The pharmacokinetic profile of apixaban following multiple twice-daily doses was linear, and exposure parameters such as C(max), observed at ~ 3 hours post-dose, and area under the plasma concentration-time curve increased in a dose-proportional manner. Pharmacodynamic profiles closely followed the apixaban plasma concentration-time profiles.

Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban

AIM To assess pharmacokinetic and pharmacodynamic interactions between naproxen (a non-steroidal anti-inflammatory drug) and apixaban (an oral, selective, direct factor-Xa inhibitor). METHOD In this randomized, three period, two sequence study, 21 healthy subjects received a single oral dose of apixaban 10 mg, naproxen 500 mg or co-administration of both. Blood samples were collected for determination of apixaban and naproxen pharmacokinetics and pharmacodynamics (anti-Xa activity, international normalized ratio [INR] and arachidonic acid-induced platelet aggregation [AAI-PA]). Adverse events, bleeding time and routine safety assessments were also evaluated. RESULTS Apixaban had no effect on naproxen pharmacokinetics. However, following co-administration, apixaban AUC(0,∞), AUC(0,t) and Cmax were 54% (geometric mean ratio 1.537; 90% confidence interval (CI) 1.394, 1.694), 55% (1.549; 90% CI 1.400, 1.713) and 61% (1.611; 90% CI 1.417, 1.831) higher, respectively. Mean (standard deviation [SD]) anti-Xa activity at 3 h post-dose was approximately 60% higher following co-administration compared with apixaban alone, 4.4 [1.0] vs. 2.7 [0.7] IU ml(-1) , consistent with the apixaban concentration increase following co-administration. INR was within the normal reference range after all treatments. AAI-PA was reduced by approximately 80% with naproxen. Co-administration had no impact beyond that of naproxen. Mean [SD] bleeding time was higher following co-administration (9.1 [4.1] min) compared with either agent alone (5.8 [2.3] and 6.9 [2.6] min for apixaban and naproxen, respectively). CONCLUSION Co-administration of naproxen with apixaban results in higher apixaban exposure and appears to occur through increased apixaban bioavailability. The effects on anti-Xa activity, INR and inhibition of AAI-PA observed in this study were consistent with the individual pharmacologic effects of apixaban and naproxen.

Metabolism, Excretion, and Pharmacokinetics of Oral Brivanib in Patients with Advanced or Metastatic Solid Tumors*

The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of 14C-labeled brivanib alaninate and the safety and tolerability of brivanib after multiple doses in patients with advanced or metastatic solid tumors. This was a two-part, single-center, open-label, single oral-dose (part A) followed by multiple-dose (part B) study in patients with advanced or metastatic solid tumors. In part A, patients received a single dose of [14C]brivanib alaninate and in part B patients received 800 mg of nonradiolabeled brivanib alaninate every day. Four patients (two white, two black: two with non–small-cell lung cancer, one with ovarian cancer, and one with renal cell carcinoma) were treated in both parts. The median time to reach the maximal plasma concentration of brivanib was 1 h, geometric mean maximal plasma concentration was 6146 ng/ml, mean terminal half-life was 13.8 h, and geometric mean apparent oral clearance was 14.7 l/h. After a single oral dose of [14C]brivanib alaninate, 12.2 and 81.5% of administered radioactivity was recovered in urine and feces, respectively. Brivanib alaninate was completely converted to the active moiety, brivanib, and the predominant route of elimination was fecal. Renal excretion of unchanged brivanib was minimal. Brivanib was well tolerated; fatigue was the most frequent adverse event occurring in all patients and the most frequent treatment-related adverse event in three (75%). The best clinical response in one patient was stable disease; the other three had progressive disease. Brivanib alaninate was rapidly absorbed and extensively metabolized after a single 800-mg oral dose; the majority of drug-related radioactivity was excreted in feces.

LC–MS/MS determination of apixaban (BMS-562247) and its major metabolite in human plasma: an application of polarity switching and monolithic HPLC column

BACKGROUND apixaban (BMS-562247) (Eliquis(®)) is a novel, orally active, selective, direct, reversible inhibitor of the coagulation factor Xa (FXa). A sensitive and reliable method was developed and validated for the measurement of apixaban (BMS-562247) and its major circulating metabolite (BMS-730823) in human citrated plasma for use in clinical testing. METHODOLOGY/RESULTS A 0.100 ml portion of citrated plasma sample was extracted and analyzed by LC-MS/MS. Run times were approximately 3 min. The lower limit of quantification (LLOQ) was 1.00 ng/ml for BMS-562247 and 5.00 ng/ml for BMS-730823. Intra- and inter-assay precision values for replicate QC control samples were within ≤5.36% for both analytes (≤7.52% at the LLOQ). The accuracy for both analytes was within ±9.00%. CONCLUSION The method was demonstrated to be sensitive, selective and robust, and was successfully used to support clinical studies.