Thromboprophylaxis with Rivaroxaban in Acutely Ill Medical Patients with Renal Impairment: Insights from the MAGELLAN and MARINER Trials.

Patients with renal impairment are at higher risk of thrombosis and bleeding than those with normal renal function. The optimal rivaroxaban dose for thromboprophylaxis in acutely ill medical patients with renal impairment is unknown. MARINER and MAGELLAN were multicenter, randomized clinical trials of rivaroxaban in acutely ill medical patients. Efficacy and safety outcomes in patients with renal impairment in MARINER (7.5 mg once daily) were compared with those in patients with normal renal function in MARINER (10 mg once daily) and in a subpopulation of MAGELLAN that excluded patients at high risk for bleeding at baseline (10 mg once daily). Compared with enoxaparin/placebo in the MAGELLAN subpopulation, the relative risk (RR) of symptomatic venous thromboembolism (VTE) and VTE-related death with rivaroxaban 10 mg in patients with renal impairment (RR = 0.62; 95% confidence interval [CI] 0.27-1.44) was similar to that in those with normal renal function (RR = 0.78; 95% CI 0.44-1.40), while in MARINER, the 7.5 mg dose did not reduce the risk in patients with renal impairment (hazard ratio = 1.00; 95% CI 0.52-1.92). Major bleeding with rivaroxaban 10 mg once daily was higher in patients with renal impairment than in those with normal renal function in MAGELLAN (1.54% vs. 0.98%) and in the MAGELLAN subpopulation (0.94% vs. 0.61%). At a dose of 10 mg once daily, rivaroxaban is effective for thromboprophylaxis in acutely ill medical patients with impaired or normal renal function. The safety of this regimen is enhanced without loss of efficacy by excluding patients at high risk for bleeding, but not by using a reduced-dose strategy. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00571649 for the MAGELLAN trial, NCT02111564 for the MARINER trial.

Pharmacokinetics and pharmacodynamics of canagliflozin in pediatric patients with type 2 diabetes.

OBJECTIVE: Canagliflozin, a sodium glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes (T2D), increases urinary glucose excretion (UGE) and lowers plasma glucose (PG) levels by reducing the renal threshold for glucose (RTG ). This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of canagliflozin in pediatric T2D patients. METHODS: Patients, aged 10 to 17 years with mean weight 107.2 kg and body mass index 38.2 kg/m2 , underwent PK and PD assessments after receiving a single daily dose of canagliflozin 100 mg (n = 8) or 300 mg (n = 9) for 14 days. Data are presented as mean (SD). RESULTS: There were dose-dependent increases in the PK of canagliflozin 100 and 300 mg, with maximum plasma concentrations and areas under plasma concentration curves that were similar to the corresponding values in adults. Mean 24-hour RTG fell to 84.6 (13.8) mg/dL with canagliflozin 100 mg and to 69.1 (9.6) mg/dL with canagliflozin 300 mg; also consistent with reductions in RTG in adults. Mean 24-hour UGE increased from 5.3 (10.5) g at baseline to 74.1 (37.4) g with canagliflozin 100 mg and from 0.1 (0.04) g to 68.6 (26.5) g with canagliflozin 300 mg. Both doses were well tolerated and the tablets had acceptable taste, smell, and swallowability. CONCLUSIONS: In pediatric T2D patients, canagliflozin 100 and 300 mg had PK and PD characteristics similar to those in adults with T2D, which is likely due to the relative maturity and increased body weight of youth affected with this disorder.

Summary workshop report: Facilitating oral product development and reducing regulatory burden through novel approaches to assess bioavailability/bioequivalence.

This summary workshop report highlights presentations and over-arching themes from an October 2011 workshop. Discussions focused on best practices in the application of biopharmaceutics in oral drug product development and evolving bioequivalence approaches. Best practices leverage biopharmaceutic data and other drug, formulation, and patient/disease data to identify drug development challenges in yielding a successfully performing product. Quality by design and product developability paradigms were discussed. Development tools include early development strategies to identify critical absorption factors and oral absorption modeling. An ongoing theme was the desire to comprehensively and systematically assess risk of product failure via the quality target product profile and root cause and risk analysis. However, a parallel need is reduced timelines and fewer resources. Several presentations discussed applying Biopharmaceutics Classification System (BCS) and in vitro-in vivo correlations in development and in post-development and discussed both resource savings and best scientific practices. The workshop also focused on evolving bioequivalence approaches, with emphasis on highly variable products (HVDP), as well as specialized modified-release products. In USA, two bioequivalence approaches for HVDP are the reference-scaled average bioequivalence approach and the two-stage group-sequential design. An adaptive sequential design approach is also acceptable in Canada. In European Union, two approaches for HVDP are a two-stage design and an approach to widen C (max) acceptance limits. For some specialized modified-release products, FDA now requests partial area under the curve. Rationale and limitations of such metrics were discussed (e.g., zolpidem and methylphenidate). A common theme was the benefit of the scientific and regulatory community developing, validating, and harmonizing newer bioequivalence methodologies (e.g., BCS-based waivers and HVDP trial designs).

Pharmacokinetics of enoxaparin in patients undergoing percutaneous coronary intervention with and without glycoprotein IIb/IIIa therapy.

The pharmacokinetic profile of enoxaparin was established in a substudy involving 1054 patients undergoing percutaneous coronary intervention. Patients enrolled in the National Investigators Collaborating on Enoxaparin 1 (NICE-1) trial received enoxaparin as a 1.0-mg/kg intravenous bolus. Patients enrolled in the NICE-4 trial received enoxaparin as a 0.75-mg/kg intravenous bolus followed by abciximab as a 0.25-mg/kg bolus and a 0.125-mcg/kg/min 12-hour infusion. Blood samples were collected at six time points over 12 hours and analyzed for plasma anti-Xa, anti-IIa, and Heptest (Haemachem Inc., St. Louis, MO) activity using specific and sensitive assay methods. Data were similar in both trials. Plasma anti-Xa, anti-IIa, and Heptest activity peaked shortly after the enoxaparin bolus and declined in parallel over the ensuing 12 hours. Area under the curve and peak activity were greatest for Heptest activity and least for anti-IIa activity. Values for clearance, volume of distribution, volume of distribution at steady state, and elimination rate constant were on the order of 10 mL/h/kg, 48 mL/kg, 45 mL/kg, and 0.22/h, respectively. These measures suggest that the use of abciximab in combination with enoxaparin during percutaneous coronary intervention is unlikely to affect the pharmacokinetics of enoxaparin.

Comparative Pharmacokinetics and Bioavailability of Dilacor XR and Cardizem CD in Healthy Volunteers.

The objective of this investigation was to compare the single-dose and steady-state pharmacokinetic profiles of Dilacor XR to Cardizem CD. The study enrolled 24 healthy males and was divided into three parts: a single intravenous 25-mg bolus dose of diltiazem HCl (Cardizem Injectable) followed by a two-way crossover comparison of single and multiple once-daily 240-mg oral doses of Dilacor XR and Cardizem CD. Plasma samples were analyzed for diltiazem using a specific and sensitive HPLC assay. Statistical analysis and deconvolution were performed on the data. A 1- and 3-hour lag time in diltiazem absorption was noted following the administration of Dilacor XR and Cardizem CD, respectively. Statistically significant differences were noted in mean single- and multiple-dose t(max) values with Cardizem CD taking approximately twice as long as Dilacor XR to reach C(max). Dilacor XR was equivalent to Cardizem CD with respect to AUC((0--infty infinity)) and C(max). Equivalent minimum and average steady-state plasma diltiazem concentrations were noted after multiple-dose administration. Deconvolution of the single-dose data also showed similar mean bioavailabilities for the respective formulations but revealed dissimilarities in each product's absorption profile that may reflect observed differences in absorption lag time and t(max).

The Pharmacokinetics of Once-Daily Diltiazem SR (Sustained-Release) in Young Versus Elderly Hypertensive Patients.

The objective of this open-label, outpatient, parallel-group investigation was to compare the single-dose and steady-state pharmacokinetic profiles of young (n = 12; x = 41 ± 6 years) and elderly (n = 12; X = 69 ± 4 years) hypertensive patients following administration of a once-daily formulation of diltiazem. The study was comprised of two phases. The first phase was a lead-in phase used to establish hypertensive status. In the second phase, patients were administered a single- and multiple-daily dose regimen of 240 mg of diltiazem SR. Plasma samples were obtained at selected times and analyzed for diltiazem using a specific and sensitive HPLC assay. Biopharmaceutic parameter estimates were determined and analyzed for statistical differences. Qualitatively similar concentration-time profiles were observed between groups, suggesting similar release characteristics of the sustained-release formulation. However, significantly higher overall concentrations of diltiazem were observed following single-dose administration in the elderly, possibly as a result of an age-related decrease in the apparent oral clearance of diltiazem. A further reduction in the apparent oral clearance of diltiazem with multiple-dose administration was observed in the elderly resulting in even higher than projected concentrations of diltiazem. Thus, greater oral systemic availability of diltiazem in the elderly hypertensive patients may warrant closer clinical monitoring and possibly a reduction in dosage.