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• W1569239833 abstract "Low‐molecular‐weight heparin (LMWH) has become an increasingly preferred agent for the acute and long‐term treatment of pediatric thromboembolism. Much of the clinical and research experience with LMWH, particularly in the United States, has involved the use of enoxaparin. The recommended starting dose of enoxaparin in children >2 months of age is 1 mg kg dose−1 administered subcutaneously twice‐daily, with target peak anti‐Factor Xa (anti‐Xa) activity of 0.5–1 U mL−1 [1Monagle P. Chan A. Massicotte P. Chalmers E. Michelson A.D. Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest. 2004; 126: 645S-87SAbstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar]. A large randomized controlled trial in adults demonstrated equal safety and efficacy between once‐daily and twice‐daily enoxaparin in the initial treatment of venous thromboembolism [2Merli G. Spiro T.E. Olsson C.G. Abildgaard U. Davidson B.L. Eldor A. Elias D. Grigg A. Musset D. Rodgers G.M. Trowbridge A.A. Yusen R.D. Zawilska K. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease.Ann Intern Med. 2001; 134: 191-202Crossref PubMed Scopus (349) Google Scholar]. A once‐daily dosage of 1.5 mg kg−1 was chosen because it had a suitable pharmacokinetics profile in healthy volunteers and was well tolerated in patients with thromboembolism [3Collignon F. Darne B. Caplain H. Huet Y. Thiebault J. Frydman Y. Pharmacokinetics of enoxaparin in man given single subcutaneous doses of 1.0‐1.25‐1.50‐2.0 mg kg−1.Thromb Res. 1992; 1: 167Abstract Full Text PDF Google Scholar, 4Parent F. Collignon F. Darne B. Ozoux M.‐.L. Saliba E. Simonneau G. Treatment of venous thrombo‐embolism with a daily subcutaneous injection of enoxaparin: preliminary results of a pharmacokinetic study.Thromb Haemost. 1993; 69: 860Google Scholar]. A meta‐analysis of adult trials comparing once‐daily with twice‐daily administration of various LMWH products in the initial treatment of venous thromboembolism also demonstrated non‐significant differences in recurrent thrombosis, major bleeding, and mortality [5Van Dongen C.J. MacGillavry M.R. Prins M.H. Once versus twice daily LMWH for the initial treatment of venous thromboembolism.Cochrane Database Syst Rev. 2005; 3: CD003074PubMed Google Scholar]. Although adults typically transition from LMWH to oral anticoagulants, smaller studies have demonstrated that once‐daily enoxaparin is also an effective agent for long‐term thromboembolism therapy [6Gonzalez‐Fajardo J.A. Arreba E. Castrodeza J. Perez J.L. Fernandez L. Agundez I. Mateo A.M. Carrera S. Gutierrez V. Vaquero C. Venographic comparison of subcutaneous low‐molecular weight heparin with oral anticoagulant therapy in the long‐term treatment of deep venous thrombosis.J Vasc Surg. 1999; 30: 283-92Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 7Kucher N. Quiroz R. McKean S. Sasahara A.A. Goldhaber S.Z. Extended enoxaparin monotherapy for acute symptomatic pulmonary embolism.Vasc Med. 2005; 10: 251-6Crossref PubMed Scopus (34) Google Scholar, 8Veiga F. Escriba A. Maluenda M.P. Lopez Rubio M. Margalet I. Lezana A. Gallego J. Ribera J.M. Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long‐term treatment of deep venous thrombosis in the elderly: a randomized trial.Thromb Haemost. 2000; 84: 559-64Crossref PubMed Scopus (114) Google Scholar]. Once‐daily enoxaparin has been used anecdotally in children [9Dager W.E. White R.H. Low‐molecular‐weight heparin‐induced thrombocytopenia in a child.Ann Pharmacother. 2004; 38: 247-50Crossref PubMed Scopus (26) Google Scholar], and in a recent study by Schobess et al., children were stratified to receive once‐ or twice‐daily enoxaparin after an acute treatment period (7–14 days) of twice‐daily enoxaparin [10Schobess R. During C. Bidlingmaier C. Heinecke A. Merkel N. Nowak‐Gottl U. Long‐term safety and efficacy data on childhood venous thrombosis treated with a low molecular weight heparin: an open‐label pilot study of once‐daily versus twice‐daily enoxaparin administration.Haematologica. 2006; 91: 1701-4PubMed Google Scholar]. The starting dose of once‐daily enoxaparin in this study was 1.5 mg kg day−1. However, target peak anti‐Xa activity was the same (0.4–0.8 U mL−1) for both treatment arms. Recurrent thrombosis and major bleeding events were similar between the two groups. The pharmacodynamics of once‐daily enoxaparin in pediatrics has yet to be studied formally. A recent report by Manco‐Johnson reveals that dose requirements for twice‐daily enoxaparin are increased not only in the newborn period, but throughout much of childhood [11Manco‐Johnson M.J. How I treat venous thrombosis in children.Blood. 2006; 107: 21-9Crossref PubMed Scopus (123) Google Scholar]. Therefore, therapeutic recommendations for once‐daily enoxaparin should not simply be extrapolated from the adult literature. The purpose of our study was to investigate the dosing requirements and pharmacodynamics of once‐daily enoxaparin in a pediatric population. This study was approved by the University of Pittsburgh Institutional Review Board. Eligible patients were 3 months to 18 years of age with a newly diagnosed thromboembolism. All patients in whom the treating physician chose enoxaparin as the long‐term therapy were eligible, including those initially treated with unfractionated heparin or thrombolysis. Exclusion criteria included treatment for >48 h with twice‐daily enoxaparin, severe renal failure (creatinine clearance <30), BMI >40 kg m−2, active major bleeding, pregnancy, or known hypersensitivity to heparin. After enrollment, patients received a starting dose of 1.5 mg kg−1 enoxaparin administered subcutaneously every 24 h. Peak anti‐Xa activity was measured 4 h after the second dose. Anti‐Xa activity between 1–2 U mL−1 was considered therapeutic, as suggested by the American College of Pathologists for once‐daily dosing of enoxaparin [12Laposata M. Green D. Van Cott E.M. Barrowcliffe T.W. Goodnight S.H. Sosolik R.C. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low‐molecular‐weight heparin, danaparoid, hirudin and related compounds, and argatroban.Arch Pathol Lab Med. 1998; 122: 799-807PubMed Google Scholar]. There is no published nomogram for dosing adjustments in once‐daily enoxaparin. In the event of sub‐ or supra‐therapeutic anti‐Xa activity, dose adjustments were made using a modified version of the nomogram currently used for pediatric patients receiving twice‐daily enoxaparin [13Andrew M. DeVeber G. Pediatric Thromboembolism and Stroke Protocols. B.C. Decker Inc., 1997Google Scholar]. After target anti‐Xa activity was reached, patients were asked to undergo 24‐h inpatient monitoring. Anti‐Xa activity was measured using the Chromogenix Coamatic Heparin Kit (DiaPharma, West Chester, OH, USA) at pre‐dose (hour 0), and post‐dose at hours 2, 4, 8, 12, 18, and 24. The lower limit of quantification for this assay is 0.1 U mL−1, and the coefficient of variation is 2.8% between runs. Participants underwent physical exams and serial ultrasound imaging (if applicable) 1, 3 and 6 months after study entry. Total duration of anticoagulation was determined on an individual basis. Patients were monitored for minor and major bleeding events, and thrombus extension or recurrence. Major bleeding was defined as any hemorrhage causing a significant clinical event, a hemoglobin decrease ≥2 g dL−1, or requiring a blood transfusion. Platelet counts were monitored to assess for heparin‐induced thrombocytopenia. Although anti‐Xa levels measure the anticoagulation activity (i.e. dynamics) of enoxaparin, we were able to apply pharmacokinetic principles to determine the maximum activity (Amax) area under the activity time curve for dosing interval AUC0‐τ (τ = 24 h) by non‐compartmental analysis using WinNonlin (version 5.0.1, Pharsight Corporation, Mountain View, CA, USA). The apparent clearance (CL/F, where F is bioavailability) and apparent volume of distribution (V/F) for anti‐Xa were estimated by the nonlinear mixed effects pharmacokinetic modeling analysis approach using NONMEM (version V). In this analysis, a conversion factor of 102.99 IU anti‐Xa per milligram enoxaparin was used to adjust for the unit difference, and the effect of covariates on CL/F or V/F was explored. We then performed a one‐sample t‐test to compare the mean AUC0‐τ of our study population with the mean AUC0‐τ of 21 healthy adult volunteers receiving 1.5 mg kg−1 of once‐daily enoxaparin reported by Sanderink et al. [14Sanderink G.J. Le Liboux A. Jariwala N. Harding N. Ozoux M.L. Shukla U. Montay G. Boutouyrie B. Miro A. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers.Clin Pharmacol Ther. 2002; 72: 308-18Crossref PubMed Scopus (164) Google Scholar]. We chose to compare our data with Sanderink’s work because this is the largest study of once‐daily enoxaparin pharmacokinetics in a healthy adult population. Fifteen patients (ages 3 months to 16 years) were enrolled into the study (Table 1). One patient was removed from the study on day 2 because anticoagulation was discontinued, and was therefore not available for analysis. Target anti‐Xa activity (1–2 U mL−1) was achieved in all 14 patients. However, only one patient achieved target anti‐Xa activity with the original enoxaparin dose of 1.5 mg kg−1. Eight children required a final dose of >2 mg kg−1 to achieve target activity. One limitation of our study is that during the initial period of dose adjustment, some outpatient anti‐Xa levels were drawn at local laboratories due to the large catchment area of our population, and the comparability of these results with our in‐house assay is not known.Table 1Dose adjustments needed to achieve target anti‐Xa activity (1–2 U mL−1)PatientAgeWeight (kg)Indication for enoxaparinOther diagnosesAnti‐Xa 4 h after 2nd dose (U mL−1)Dose changesFinal dose (mg kg−1) 13 months6.5DVT with CVLFactor V Leiden, Prothrombin gene variant0.7143.8 210 months10DVT with CVLNone0.5844.0 314 months13DVT with CVLDiabetes0.5822.3 42 years14DVT with CVLFactor V Leiden0.6842.7 53 years14DVTInfection, surgery, Prothrombin gene variant0.4422.7 68 years83DVT with CVLObesity0.9511.7 79 years37Arterial strokeCarotid artery dissection0.6011.9 813 years67DVT with CVLSickle cell anemia0.6622.1 914 years65DVTProtein S deficiency0.4722.21014 years68DVT with CVLTrauma0.6611.81115 years60Arterial strokeAtrial septal defect0.6811.91215 years60DVT with CVLTrauma0.7411.61315 years77DVT with CVLSickle cell anemia1.2101.51416 years45DVTHypereosinophilic syndrome0.3032.9Data not available for patient 6 because anticoagulation discontinued on day 2. Open table in a new tab Data not available for patient 6 because anticoagulation discontinued on day 2. Eight patients completed 24‐h pharmacodynamic monitoring. Reasons for not completing pharmacodynamic monitoring included: inability to obtain intravenous access (3), early discontinuation or change in anticoagulation (3), and patient refusal (1). The shape of the pharmacodynamics curve for our pediatric population approximates the profile in healthy adult volunteers after administration of 1.5 mg kg−1 once‐daily enoxaparin by Sanderink et al. (Fig. 1) [14Sanderink G.J. Le Liboux A. Jariwala N. Harding N. Ozoux M.L. Shukla U. Montay G. Boutouyrie B. Miro A. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers.Clin Pharmacol Ther. 2002; 72: 308-18Crossref PubMed Scopus (164) Google Scholar]. However, total drug exposure was different, with a mean AUC0‐τ of 10.1 h IU mL−1 in children, compared with 16.4 h IU mL−1 in adults (P < 0.001). Our population also demonstrated faster clearance, with mean individual apparent clearance of 0.88 L h−1, compared with 0.74 L h−1 in adults. In our study population, seven of eight children demonstrated sub‐therapeutic anti‐Xa activity (<0.5 IU mL−1) by hour 12, and four of eight had undetectable levels by hour 18. This contrasts sharply with the adult experience published by Sanderink et al., in which therapeutic anti‐Xa levels (0.5–1 U mL−1) were measurable 13–18 h after administration, and prophylactic levels (0.1–0.3 U mL−1) were measurable at 24 h [14Sanderink G.J. Le Liboux A. Jariwala N. Harding N. Ozoux M.L. Shukla U. Montay G. Boutouyrie B. Miro A. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers.Clin Pharmacol Ther. 2002; 72: 308-18Crossref PubMed Scopus (164) Google Scholar]. Body weight was identified to significantly affect both the apparent clearance (CL/F) and the apparent volume of distribution (V/F) by the log‐likelihood test, where the degree of freedom was the difference in the number of model parameters. Children with BMI >25 showed a tendency towards higher clearance and volume of distribution. The effects of various body habitus measures have been shown to be important in adjusting enoxaparin doses in the adult population [15George‐Phillips K.L. Bungard T.J. Use of low‐molecular‐weight heparin to bridge therapy in obese patients and in patients with renal dysfunction.Pharmacotherapy. 2006; 26: 1479-90Crossref PubMed Scopus (20) Google Scholar]. Based on the final population pharmacokinetics model, CL/F and V/F are described by the following formulae: 1 2 in which 40 is the data‐derived median value of body weight (kg) in our population. Participants were followed for a mean duration of 6.4 months (range 3–10 months). No patient experienced thrombus extension or recurrence. All patients experienced bruising at enoxaparin injection sites, and two reported increased bruising in other locations. Patient 6, who underwent a double lung transplant 2 days prior to starting enoxaparin, developed bloody chest tube drainage on day 2. Anti‐Xa activity was sub‐therapeutic at 0.23 U mL−1. Surgical re‐exploration revealed a bleeding bronchial artery, which was repaired. The highest recorded anti‐Xa levels during the study period were 1.74, 1.84, and 2.02 U mL−1 (patients 7, 13, and 12). None of these levels were associated with bleeding events other than increased bruising in patient 7. No patient demonstrated clinical or laboratory signs of heparin‐induced thrombocytopenia. These are the first reported data on the pharmacodynamics of once‐daily enoxaparin dosing in the pediatric population. In addition to requiring doses >1.5 mg kg−1 in order to reach target peak anti‐Xa activity, our 24‐h pharmacodynamic monitoring revealed significantly lower total drug exposure with the use of once‐daily enoxaparin in a small pediatric/adolescent population compared with published adult data. It is our opinion that once‐daily enoxaparin is probably not feasible in the pediatric population, and twice‐daily administration should remain the standard of care. Alternative agents with longer half‐lives need to be studied. The authors state that they have no conflict of interest. This study was jointly supported by the Children’s Hospital of Pittsburgh General Clinical Research Center (5M01 RR00084) and an unrestricted award from the Hemophilia and Thrombosis Research Society." @default.
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• W1569239833 title "Once‐daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study" @default.
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