Population Pharmacokinetic Analysis of Dalteparin in Pediatric Patients With Venous Thromboembolism.

This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label study was conducted in children who required anticoagulation for the treatment of VTE. The study population included children with and without cancer. The goal was to describe the pharmacokinetics of dalteparin using anti-Xa as a surrogate marker and to determine the dose required to achieve therapeutic anti-Xa levels (0.5-1.0 IU/mL). The anti-Xa data were supplemented with 2 published studies and analyzed using population pharmacokinetic approaches. The pharmacokinetics of dalteparin following subcutaneous injection in pediatric patients was described by a 1-compartment model with linear absorption and elimination. Body weight was added as a covariate on both CL/F and Vd/F as a power function with fixed exponents of 0.75 and 1.0, respectively. The estimates of CL/F and Vd/F in the full model were 929 mL/h and 7180 mL, respectively, for a reference female patient aged 12 years with body weight of 43 kg. Body weight-normalized CL/F decreased with age. Cancer status and sex did not have significant effects on CL/F and Vd/F. Simulations were conducted to select starting doses of dalteparin that would rapidly achieve therapeutic anti-Xa levels. These simulations suggested that the recommended starting doses of dalteparin administered subcutaneously in pediatric patients of different age cohort groups for treatment of VTE were 150 IU/kg every 12 hours (1 month to <2 years), 125 IU/kg every 12 hours (≥2 to <8 years), and 100 IU/kg every 12 hours (≥8 to <19 years).

A post hoc analysis of dalteparin versus oral anticoagulant (VKA) therapy for the prevention of recurrent venous thromboembolism (rVTE) in patients with cancer and renal impairment.

Venous thromboembolism (VTE) is a common and serious complication in patients with cancer; treatment guidelines recommend extended therapy of ≥6 months with low-molecular-weight heparin (LMWH) for treatment and prevention of recurrent VTE (rVTE) in this population. This post hoc analysis used data from the CLOT study-a phase III, randomized, open-label, controlled study (N = 676)-to compare the efficacy and safety of dalteparin, a LMWH, versus vitamin K antagonist (VKA) for prevention of rVTE in patients with cancer and renal impairment (creatinine clearance <60 ml/min). Overall, 162/676 (24 %) patients had renal impairment at baseline. Patients received subcutaneous dalteparin 200 IU/kg once daily during month 1, followed by 150 IU/kg once daily for months 2-6; or VKA once daily for 6 months, with initial overlapping subcutaneous dalteparin 200 IU/kg once daily for ≥5 days until international normalized ratio was 2.0-3.0 for 2 consecutive days. Endpoints included the rates of rVTE (primary) and bleeding events. Overall, fewer dalteparin-treated patients (2/74 [2.7 %]) experienced ≥1 adjudicated symptomatic rVTE compared with VKA-treated patients (15/88 [17.0 %]; hazard ratio = 0.15 [95 % confidence interval 0.03-0.65]; p = 0.01). Bleeding event rates for both treatments were similar (p = 0.47). In summary, compared with VKA, dalteparin significantly reduced risk of rVTE in patients with cancer and renal impairment (p = 0.01) while exhibiting a comparable safety profile. This analysis supports dosing patients with renal impairment in accordance with patients with normal renal function; however, anti-Xa monitoring could be considered to further support safety in selected patients, particularly those with very severe renal impairment.

Population pharmacokinetics of atorvastatin and its active metabolites in children and adolescents with heterozygous familial hypercholesterolemia: selective use of informative prior distributions from adults.

The population pharmacokinetics (PPK) of atorvastatin and its principal active metabolite, o-hydroxyatorvastatin, were described in 6-17 years old pediatric hypercholesterolemia patients with a 2-compartment model for both parent and metabolite. Informative prior distributions on selected parameters, based on adult data, were required to stabilize the model and were implemented using a Bayesian penalty term on the likelihood function in the nonlinear mixed effects model (NONMEM VI with PRIOR). Concentrations below the limit of quantitation were treated as censored data using a conditional likelihood function. Atorvastatin apparent oral clearance (CL/F) was described as a function of body weight using an allometric equation. Based on the final model, the typical CL/F estimates for a Tanner Stage 1 patient (35 kg weight) and Tanner Stage ≥2 (50 kg weight), would be 553 and 543 L/hour, respectively. When scaled allometrically, CL/F was similar to values reported for adults. Variability in atorvastatin PK was primarily affected by weight.

Safety of intravenous nitroglycerin after administration of sildenafil citrate to men with coronary artery disease: a double-blind, placebo-controlled, randomized, crossover trial.

OBJECTIVE: Although contraindicated, there are situations when a patient who has recently taken a phosphodiesterase 5 inhibitor (e.g., sildenafil) might need intravenous nitroglycerin (NTG) treatment. This study determined if, and at what dose, intravenous NTG could be administered safely to men with coronary artery disease who had recently ingested sildenafil. DESIGN: Double-blind, placebo-controlled, randomized, crossover trial. SETTING: Four clinical practice sites in Canada, Scotland, and the United States. PATIENTS: A total of 34 men (>or=35 yrs) with a history of angina pectoris and coronary artery disease (>50% stenosis of at least one coronary artery), most of whom were taking antihypertensives. INTERVENTIONS: Sildenafil (100 mg) or placebo (single dose; crossover after 3-7 days) followed 45 mins later by escalating doses of intravenous NTG (160 microg/min maximum). MEASUREMENTS AND MAIN RESULTS: After sildenafil, there were slightly greater maximum (supine) blood pressure decreases and heart rate increases (e.g., 4 to 6 mm Hg [systolic] and