Melanie S. Joy

Randomized, double-blind, placebo-controlled, dose-titration, phase III study assessing the efficacy and tolerability of lanthanum carbonate: a new phosphate binder for the treatment of hyperphosphatemia.

BACKGROUND Lanthanum carbonate is a novel, non-calcium, non-aluminum phosphate binder under evaluation for the treatment of hyperphosphatemia in end-stage renal disease (ESRD) patients receiving either hemodialysis or continuous ambulatory peritoneal dialysis. METHODS This 16-week study assessed the control of serum phosphorus with lanthanum carbonate, and its effects on serum calcium, calcium x phosphorus product, and parathyroid hormone (PTH). Hemodialysis patients > or =18 years old entered into a 1- to 3-week washout period during which serum phosphorus levels rose to >5.9 mg/dL (1.90 mmol/L). In total, 126 patients were titrated with lanthanum carbonate at doses containing 375, 750, 1,500, 2,250, or 3,000 mg/d elemental lanthanum, given in divided doses with meals over a 6-week period, to achieve serum levels < or =5.9 mg/dL. By the end of dose titration, 11/126 (9%) patients received < or =750 mg/d of lanthanum, 25 (20%) received 1,500 mg/d, 37 (29%) received 2,250 mg/d, and 53 (42%) received 3,000 mg/d. Following titration, patients were randomized to receive either lanthanum carbonate or placebo during a 4-week, double-blind maintenance phase. RESULTS At the study endpoint, the mean difference in serum phosphorus between the lanthanum carbonate and placebo treatment arms was 1.91 mg/dL (0.62 mmol/L) (P < 0.0001). Calcium x phosphorus product (P < 0.0001) and serum PTH levels (P < 0.01) were also significantly lower with lanthanum carbonate versus placebo. The incidence of drug-related adverse events was similar between placebo- and lanthanum carbonate-treated patients. CONCLUSION Lanthanum carbonate is an effective and well-tolerated agent for the treatment of hyperphosphatemia in patients with ESRD.

Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: A systematic overview of randomized placebo-controlled trials

Clinical trials have shown the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in delaying the progression of diabetic renal disease. There is less evidence from primary clinical trials of nondiabetic renal disease. We performed an updated meta-analysis to determine the efficacy of ACE inhibitors in slowing the progression of renal disease over a broad range of functional renal impairment. We included published and unpublished randomized, placebo-controlled, parallel trials with at least 1 year of follow-up available from January 1970 to June 1999. In nine trials of subjects with diabetic nephropathy and microalbuminuria, the relative risk for developing macroalbuminuria was 0.35 (95% confidence interval [CI], 0.24 to 0.53) for individuals treated with an ACE inhibitor compared with placebo. In seven trials of subjects with overt proteinuria and renal insufficiency from a variety of causes (30% diabetes, 70% nondiabetes), the relative risk for doubling of serum creatinine concentration or developing end-stage renal disease was 0.60 (95% CI, 0.49 to 0.73) for individuals treated with an ACE inhibitor compared with placebo. Treatment of individuals with chronic renal insufficiency with ACE inhibitors delays the progression of disease compared with placebo across a spectrum of disease causes and renal dysfunction.

Cutaneous and Systemic Manifestations of Drug-Induced Vasculitis

OBJECTIVE: To evaluate the literature for published cases of drug-induced vasculitis with cutaneous and/or systemic manifestations. DATA SOURCES: The MEDLINE database was searched from 1965 to December 1999 for articles focusing on drugs and vasculitis, using various search terminologies (e.g., Churg-Strauss syndrome, Goodpastures syndrome, Henoch-Schönlein purpura, various drugs suspected to induce vasculitis). Cases were included when they met the established criteria as described in the methodology. DATA SYNTHESIS: Drugs found to be most frequently associated with vasculitis were propylthiouracil, hydralazine, colony-stimulating factors, allopurinol, cefaclor, minocycline, D-penicillamine, phenytoin, isotretinoin, and methotrexate. The interval between the first exposure and appearance of symptoms was reported to be extremely variable (hours to years). Vasculitis has occurred after drug dosage increases and after rechallenge with the suspected drug. In the majority of cases, vasculitis has resolved after discontinuing the drug. Patients with more severe, often life-threatening, manifestations have required treatment with corticosteroids, plasmapheresis, hemodialysis, or cyclophosphamide. Death was the result in 10% of all published cases, with a predominance in patients in whom multiple organ systems were involved. CONCLUSIONS: Clinicians need to be suspect of drug-induced vasculitis to enable prompt diagnosis and treatment. This should improve patient outcomes based on the data referenced for this article.

Comparative evaluation of the Cockcroft-Gault Equation and the Modification of Diet in Renal Disease (MDRD) study equation for drug dosing: an opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy.

Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturer‐recommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft‐Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 1 0–40% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine‐based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.

Phase 1 Trial of Adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) Study Group

BACKGROUND Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end-stage kidney disease. Antifibrotic agents, such as tumor necrosis factor alpha antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data. STUDY DESIGN Phase 1 clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to tumor necrosis factor alpha. SETTING & PARTICIPANTS 10 patients (4 male and 6 female) aged 16.8 +/- 9.0 years with an estimated glomerular filtration rate of 105 +/- 50 mL/min/1.73 m(2) were studied. INTERVENTION Adalimumab, 24 mg/m(2), every 14 days for 16 weeks (total, 9 doses). OUTCOMES Pharmacokinetic assessment, tolerability, and safety. MEASUREMENTS Estimated glomerular filtration rate, proteinuria, and pharmacokinetic assessment after initial dosing and steady state. RESULTS Pharmacokinetic evaluation indicated that the area under the curve was decreased by 54% (P < 0.001) and clearance was increased by 160% (P < 0.01) in patients with resistant FSGS compared with healthy controls and patients with rheumatoid arthritis. Adalimumab was well tolerated with no serious adverse events or infectious complications attributable to the drug. Proteinuria decreased by > or = 50% in 4 of 10 treated patients. LIMITATIONS Insufficient power to assess the safety or efficacy of adalimumab therapy for patients with resistant FSGS. CONCLUSIONS Pharmacokinetic assessment showed increased clearance of adalimumab in patients with resistant primary FSGS and validated the need to evaluate the disposition of novel therapies for this disease to define appropriate dosing regimens. The study provides a rationale to evaluate the efficacy of adalimumab as an antifibrotic agent for resistant FSGS in phase 2/3 clinical trials.

Calcineurin Inhibitor–Induced Nephrotoxicity and Renal Expression of P‐glycoprotein

Study Objective. To evaluate immunohistochemistry staining patterns for P‐glycoprotein (P‐gp) and a marker of early apoptosis (active caspase‐3) in renal biopsy specimens obtained from solid organ transplant recipients with nephrotoxicity and those from a control group.

A long-term, open-label extension study on the safety of treatment with lanthanum carbonate, a new phosphate binder, in patients receiving hemodialysis

ABSTRACT Background: Lanthanum carbonate, a new phosphate binder, is effective in reducing serum phosphorus levels in patients with end-stage renal disease. A 1-year extension study to two randomized controlled studies was conducted to evaluate the long-term safety of lanthanum carbonate in patients who received hemodialysis. Research design and methods: Patients from two previous lanthanum carbonate studies were eligible to continue treatment in a 1-year open-label extension. A total of 77 patients (N = 77; 11 from Study 1, 66 from Study 2) were enrolled in this extension. The mean age of patients was 60.9 years (SD ± 12.5 years); 65% were male and 35% were female. All patients received lanthanum carbonate at the optimal dose for phosphorus control, determined in their previous study. Safety and tolerability were assessed by monitoring adverse events, laboratory parameters, and vital signs. The number of patients who maintained serum phosphorus levels at ≤ 5.9 mg/dL (1.9 mmol/L) was recorded, along with serum calcium, calcium × phosphorus product, and parathyroid hormone levels. Results: Lanthanum carbonate was well tolerated and was associated with few treatment-related adverse events. The most commonly reported adverse events were nausea (26.0%), peripheral edema (23.4%), and myalgia (20.8%). No treatment-related serious adverse events occurred. By Week 4, the mean serum phosphorus level had decreased by approximately 1 mg/dL to 5.7 ± 2.0 mg/dL (1.84 ± 0.7 mmol/L). At the end of the study, the mean pre-dialysis serum phosphorus level was 5.7 ± 1.4 mg/dL (1.84 ± 0.5 mmol/L); 53% of patients had controlled phosphorus levels. Calcium × phosphorus product decreased during Week 1 and remained within a clinically acceptable range thereafter. There were no clinically significant changes in serum calcium, or parathyroid hormone levels. Conclusion: Lanthanum carbonate is well tolerated and is effective for the long-term maintenance of serum phosphorus control in patients with end-stage renal disease.

Darbepoetin Alfa: A Novel Erythropoiesis-Stimulating Protein

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of darbepoetin alfa. DATA SOURCES: Pertinent references were identified by a MEDLINE search (1995–January 2001) of the medical literature, review of English-language literature and references of these articles, product information, and abstracts from professional meetings. STUDY SELECTION: Clinical efficacy data were gathered from all available trial data citing darbepoetin alfa. Additional information concerning pharmacology, pharmacokinetics, and safety was also reviewed. DATA SYNTHESIS: Darbepoetin alfa is a new erythropoiesis-stimulating protein with a threefold longer half-life than recombinant human erythropoietin (r-HuEPO). Darbepoetin alfa is approved for intravenous and subcutaneous administration in patients requiring and not requiring dialysis. Clinical studies in patients with chronic kidney disease (CKD) have shown darbepoetin alfa to be equivalent to r-HuEPO in terms of increases in hemoglobin concentration, percentage of patients obtaining target hemoglobin, and average time to reach target hemoglobin concentration. Trials are currently ongoing in patients receiving cancer chemotherapy. The adverse event profile appears to be similar between the 2 agents. CONCLUSIONS: The equivalent efficacy and safety profile, as well as the longer half-life, may make darbepoetin alfa an attractive alternative to r-HuEPO in patients with CKD. Since these patients need to receive r-HuEPO 1–3 × weekly at the expense of increased healthcare utilization to improve their hemoglobin, agents such as darbepoetin alfa, with longer durations of action, may reduce healthcare expenses. In addition, enhanced patient compliance may be realized with once-weekly or once every-other-week administration.

Determinants of Ceftriaxone Clearance by Continuous Venovenous Hemofiltration and Hemodialysis

Study Objective. To guide individual ceftriaxone dosages in patients receiving continuous renal replacement therapy.

Cinacalcet HCl: a calcimimetic agent for the management of primary and secondary hyperparathyroidism.

Cinacalcet HCl (AMG 073) is an investigational oral calcimimetic drug currently being evaluated for the treatment of primary and secondary hyperparathyroidism (HPT). Calcimimetics bind to the calcium-sensing receptors of the parathyroid glands and lower the sensitivity for receptor activation by extracellular calcium, thereby diminishing parathyroid hormone release. Cinacalcet HCl has demonstrated efficacy in controlling the hypercalcaemia of severe primary HPT and in reducing parathyroid hormone levels in patients with secondary HPT. Asymptomatic dose-dependent hypocalcaemia has occurred in some clinical trials. This drug has a favourable pharmacokinetic profile compared to its precursors and will prove useful as an additional/alternative agent in patients with primary and secondary HPT.