Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.

AIMApixaban 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. METHODFifty-four healthy subjects were enrolled [18 each into low (Յ50 kg), reference (65-85 kg) and high (Ն120 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. RESULTSCompared 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. CONCLUSIONThe 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.

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. Key Points Apixaban, a direct factor Xa inhibitor, has predictable pharmacokinetic and pharmacodynamic properties that are consistent across a wide range of patients, including the elderly and those with moderate renal impairment. The fast onset of action, low potential for food or drug interactions, and lack of requirement for routine monitoring during clinical use make apixaban a potentially useful option to simplify anticoagulation treatment.

RESULTSThe Pfizer Population Pharmacokinetic Analysis Guidance is included as Supplementary Appendix S1 online. The full content of the guidance and a general workflow are presented in Figure 1 and Figure 2, respectively, and general recommendations are summarized below. It should be noted that the recommendations in the guidance were based on current best practice and state of knowledge. The guidance will be updated and revised on a regular basis as new methodologies are developed and the model-building process is refined. The guidance was written with internal and external references to avoid in-depth technical and theoretical discussion within the guidance itself: the full list of references applicable to the guidance can be found in the Reference section of the Supplementary Appendix S1 online.The guidance itself does not address tool-specific implementation but is primarily focused on outlining the expected population pharmacokinetic (Pop PK) modeling-related processes and procedures that should be undertaken by the analyst. However, guidance recommendations are based on standard tools and relevant terminology, including NON-MEM (ICON Development Solutions, Ellicott City, MD), 1 Perl speaks NONMEM (PsN), 2 and Xpose. 3 Points to consider before conducting a Pop PK analysisPopulation modeling analysis plan. It is recommended that a population modeling analysis plan (PMAP) be developed to prospectively outline the modeling approach before conducting a Pop PK analysis. In addition, the PMAP should be finalized before database lock if the analysis results are to be included in a regulatory submission. A well-prepared PMAP should provide an overview of the purpose of the modeling, prior information used, the choice of studies/data to be included for analysis, the proposed modeling approach, and assumptions made. The level of detail required in the PMAP depends on the intended use of the modeling analysis, as the plan in some cases can be considered a "living document," i.e., updates to the plan can be made as more information becomes available. A PMAP should facilitate writing of the population modeling analysis report (PMAR) in a timely manner upon completion of model development and should be an effective planning tool both for the analyst and for any reviewer to assess whether the original objectives of the analysis were met. cal and statistical summaries of dependent variables and demographics, including covariates, should be completed to help with identifying potential errors. In addition, this will help to identify the base structural model and components of the statistical model, as well as potential covariate relationships and outliers.Below the limit of quantification. It is not uncommon that some concentration data are censored as below the limit of quantification (BLQ) by the bioanalytical laboratory and reported qualitatively in Pop PK data sets. Commonly used approaches for handling BLQ concentrations have been shown to introduce bias in the parameter estimates and to result in model misspecification...

Aim Apixaban is an orally active inhibitor of coagulation factor Xa and is eliminated by multiple pathways, including renal and non‐renal elimination. Non‐renal elimination pathways consist of metabolism by cytochrome P450 (CYP) enzymes, primarily CYP3A4, as well as direct intestinal excretion. Two single sequence studies evaluated the effect of ketoconazole (a strong dual inhibitor of CYP3A4 and P‐glycoprotein [P‐gp]) and diltiazem (a moderate CYP3A4 inhibitor and a P‐gp inhibitor) on apixaban pharmacokinetics in healthy subjects. Method In the ketoconazole study, 18 subjects received apixaban 10 mg on days 1 and 7, and ketoconazole 400 mg once daily on days 4–9. In the diltiazem study, 18 subjects received apixaban 10 mg on days 1 and 11 and diltiazem 360 mg once daily on days 4–13. Results Apixaban maximum plasma concentration and area under the plasma concentration–time curve extrapolated to infinity increased by 62% (90% confidence interval [CI], 47, 78%) and 99% (90% CI, 81, 118%), respectively, with co‐administration of ketoconazole, and by 31% (90% CI, 16, 49%) and 40% (90% CI, 23, 59%), respectively, with diltiazem. Conclusion A 2‐fold and 1.4‐fold increase in apixaban exposure was observed with co‐administration of ketoconazole and diltiazem, respectively.