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.

Thorough QT/QTc study of ritonavir-boosted saquinavir following multiple-dose administration of therapeutic and supratherapeutic doses in healthy participants.

The effect of saquinavir-boosted ritonavir at therapeutic (1000/100 mg twice daily [bid]) and supratherapeutic (1500/100 mg bid) doses was evaluated in a double-blind, placebo- and positive-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT/QTc study. Least squares mean estimated study-specific QTc (QTcS) change from dense predose baseline (ddQTcS(dense)) was the primary endpoint. Greatest mean increase in ddQTcS(dense) occurred 12 hours postdose for the 1000/100-mg group (18.9 ms) and 20 hours for the 1500/10-mg group (30.2 ms). The upper 1-sided 95% confidence interval was >20 ms from 2 to 20 hours postdose in both groups. ddQTcB(dense) and ddQTcF(dense) were similar to ddQTcS(dense). No QTcS, QTcF, or QTcB measurements were >500 ms. One participant receiving 1000/100 mg and 3 receiving 1500/100 mg had a maximum ddQTcS(dense) >60 ms. More participants with ≥1 adverse event received saquinavir/ritonavir. PubMed search and Roche postmarketing data did not reveal publications or reports directly presenting the effect of saquinavir on QT/QTc or causing torsade de pointes.

Comparison of 30-min and 3-h infusion regimens for imipenem/cilastatin and for meropenem evaluated by Monte Carlo simulation.

Imipenem/cilastatin and meropenem are carbapenem antibiotics that are infused intravenously (IV) over 30 to 45 min. We evaluated probability of target attainment and cumulative probability of target attainment of 30-min and 3-h infusions for imipenem/cilastatin and meropenem. Eighteen healthy adults in a randomized, 4-phase, crossover study received 1000 mg of imipenem/cilastatin or meropenem as a single-dose IV over 30 min or 3 h. A population pharmacokinetics analysis using a 2-compartment IV infusion model was performed. Monte Carlo simulations using various dosage regimens at steady-state and 30-min and 3-h infusion rates were performed to evaluate the probabilities of attaining 20% (bacteriostatic), 30%, and 40% (maximum kill) time above the MIC. Three-hour infusions of imipenem/cilastatin and meropenem improved the cumulative probability of target attainment for a variety of populations of microorganisms compared to 30-min infusions. Prolonged infusions have the potential to optimize efficacy of imipenem/cilastatin and meropenem.

Evaluation of a sex-based difference in the pharmacokinetics of digoxin.

STUDY OBJECTIVE: To determine whether a sex-based difference in digoxin pharmacokinetics exists in patients receiving long-term digoxin therapy for chronic heart failure or atrial fibrillation. DESIGN: Single-center, retrospective review of medical records. SETTING: University-based teaching hospital and outpatient clinic. PATIENTS: Sixty-seven adults (32 men, 35 women) with chronic heart failure or atrial fibrillation who were receiving digoxin therapy. MEASUREMENTS AND MAIN RESULTS: Serum digoxin concentrations and daily digoxin doses were obtained from patients' medical records. Daily doses were adjusted for patients' actual and ideal body weight and body mass index (BMI). The ratio between the serum digoxin concentration and each of the adjusted daily doses of digoxin was compared between men and women. The mean +/- SD serum digoxin concentration was 0.85 +/- 0.51 ng/ml for men compared with 1.02 +/- 0.51 ng/ml for women. Mean +/- SD unadjusted doses of digoxin were 0.180 +/- 0.063 and 0.164 +/- 0.059 mg/day for men and women, respectively; the difference was not statistically significant. Ratios of serum digoxin concentration to daily digoxin doses did not differ by sex when doses were estimated with actual or ideal weight. Only the ratio of the digoxin concentration to the BMI-adjusted dose was significantly different between men and women (0.14 +/- 0.09 and 0.19 +/- 0.11, respectively, p<0.05). CONCLUSION: Sex-based differences in digoxin pharmacokinetics were absent when actual or ideal body weight was used. However, the ratio of serum digoxin concentration to daily digoxin dose adjusted for BMI differed by sex. Because digoxin is distributed to lean body mass, use of the BMI could have overadjusted body weight, leading to inaccurate pharmacokinetic assumptions and calculations. The pharmacokinetics of digoxin do not appear to differ by sex.

Limited sampling models for oral midazolam: midazolam plasma concentrations, not the ratio of 1-hydroxymidazolam to midazolam plasma concentrations, accurately predicts AUC as a biomarker of CYP3A activity.

Oral midazolam is used as a phenotyping probe for cytochrome P450 (CYP) 3A activity and requires multiple plasma samples to measure drug exposure. Limited sampling is a useful strategy for optimizing sampling and reducing costs and labor. We studied limited sampling models using multiple linear regressions to predict the area under the concentration versus time curve (AUC) of midazolam using either midazolam plasma concentrations or the ratio of 1-hydroxymidazolam (1-OH MDZ) to midazolam plasma concentrations. CYP3A baseline activity data for oral midazolam from previous studies were used (45 healthy adults for models using midazolam plasma concentrations and 41 healthy adults for models using the ratios of 1-OH MDZ to midazolam plasma concentrations). Limited sampling models were derived, validated, and evaluated for precision and bias. Two equations using the time points at 0.5 and 6 hours and 0.5, 2, and 6 hours were acceptable and predictive of midazolam AUC using midazolam plasma concentrations. No 1-OH MDZ to midazolam plasma concentration ratios accurately predicted midazolam AUC.