Creatinine clearance dose calculation

Because LMWHs are eliminated renally and patients with renal insufficiency generally have been exclnded from clinical trials, some practice protocols recommend UFH for patients with creatinine clearance rates of less than 30 mL/min. (Creatinine clearance is calculated based on total patient body weight.) However, recent recommendations for dosing adjnstment of enoxaparin in patients with creatinine clearances between 10 and 30 mL/min are now listed in the product manufacturer s label (see Table 16 ). Administration of LMWHs should be avoided in dialysis patients. UFH is monitored and the dose adjusted to a target aPTT, whereas LMWHs are administered by a fixed, weight-based dose. Other dosing information and contraindications are described in Table 16. ... 

Obtain a baseline serum creatinine measurement. Calculate the estimated creatinine clearance and adjust the dose of H2RAs and sucralfate according to package insert recommendations. 

To minimize the risk of induced arrhythmia, patients initiated or reinitiated on Betapace or Betapace AF should be placed for a minimum of 3 days (on their maintenance dose) in a facility that can provide cardiac resuscitation, continuous electrocardiographic monitoring, and calculations of creatinine clearance. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see Administration and Dosage. 

Maintain normal sinus rhythm after conversion from atrial fibrillation or flutter PO Individualized using a seven-step dosing algorithm dependent upon calculated creatinine clearance and QT interval measurements. 

Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus infections. Intravenous cidofovir must be administered with high-dose probenecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours after), which blocks active tubular secretion and decreases nephrotoxicity. Cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or for the presence of urine protein before each infusion, and aggressive adjunctive hydration is required. Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. Direct intravitreal administration of cidofovir is not recommended because of ocular toxicity. 

The risk interpretation of biomonitoring results will tend to have additional uncertainties. That is because, in addition to the standard uncertainties encountered in risk assessment, there is the uncertainty of extrapolating from a blood or urinary concentration to an external dose. There will be variability both in the timing between sample draw and most recent exposure and in the relationship between blood concentration and dose. Those kinds of variability are compounded by uncertainty in the ability of a PK calculation or model to convert biomarker to dose accurately. For example, reliance on urinary biomarker results expressed per gram of urinary creatinine leads to an uncertain calculation of total chemical excretion per day because of the considerable variability in creatinine clearance per day. That complicates an otherwise simple approach to estimating dose. Furthermore, the conversion requires knowledge of fractional excretion via various pathways, which may not be present for a large sample of humans. The uncertainties created by these factors can be bounded via sensitivity and Monte... 

A concern with AUC-targeting based on renal function surrounds the measurement of creatinine clearance. The formulas of Calvert et al. were developed using EDTA clearance, measurement of which is not widely available. They have shown that neither standard measured creatinine clearance, nor the calculation of this index are as accurate or as reproducible. To circumvent this difficulty an alternative dosing strategy has been developed by Chatelut, Canal and co-workers [226], This dosing approach is being tested in clinical trials. 

A 24 h urine sampling was performed during the IV dosing period of the study that started on Day 1 and ended on Day 2. The volume of urine collected and the concentration of creatinine were determined to allow the creatinine clearance to be calculated. 

The safety and efficacy of amphotericin colloidal dispersion have been evaluated in 148 immunocompromised patients with candidemia (20). ABCD was given intravenously in a median daily dose of 3.9 (range 0.1-9.1) mg/kg for a median of 12 (range 1-72) days. In the safety analysis (n = 148 patients), nephrotoxicity occurred in 16% of the patients, with either doubling of the baseline serum creatinine concentration or an increase of 88 pmol/l (1.0 mg/dl) or a 50% fall in calculated creatinine clearance. Severe adverse events were believed to be probably or possibly related to ABCD in 36 patients (24%), including chills and fever (9.5%), hypotension and abnormal kidney function (4%), tachycardia, asthma, hypotension (3%), and dyspnea (2%). ABCD was withdrawn in 12%... 

The safety and efficacy of ABCD have been stndied in 220 bone marrow transplant recipients enrolled in the same five phase I or phase II stndies (23). The median dose in this population was 4 (range 0.4—8.0) mg/kg, and the median duration of treatment was 16 (range 1-409) days. Overall, 37 (19%) of the patients had nephrotoxicity, defined as a doubling of serum creatinine from baseline, an increase of 88 pmol/l from baseline, or at least a 50% fall in calculated creatinine clearance. There were no significant changes in hepatic transaminases, alkaline phosphatase, or total bilirubin. Fever and chills were reported by 12 and 11% of patients respectively. Other acute, severe, infusion-related adverse events were hypoxia (4.1%), hypertension (2.7%), and hypotension (2.7%). 

The adverse effects of mycophenolate mofetil in children have been reviewed retrospectively in 24 renal transplant patients (mean age 14 years) switched from azathioprine to mycophenolate mofetil a mean of 4.8 years after transplantation (42). The mean dose of mycophenolate mofetil was 560 mg/m. After a mean of 9.6 months, 13 had to discontinue treatment because of adverse effects, namely severe and partially reversible anemia (10 patients, of whom three required transfusions), neutropenia n — 1), and diarrhea n — 2). The anemia was normocytic and normochromic in nine patients, and such a high incidence of severe anemia was unexpected from the available adult data. Although patients who discontinued treatment had a lower pretreatment-calculated creatinine clearance, this was not significant and probably not the major cause of anemia. The author speculated that the anemia resulted from a disproportionately high unbound plasma concentration of mycophenolate mofetil, due to reduced protein binding and impaired renal clearance. 

A 14-month-old girl with chronic renal insufficiency due to renal dysplasia was empirically treated with ceftazidime and vancomycin for fever. Her calculated creatinine clearance was 10 ml/minute/1.73 m. She erroneously received vancomycin 1.5 g in 3 doses 6 hours apart. Her serum creatinine concentration increased and her vancomycin concentrations remained markedly high (338 mg/1 5 hours after the third dose). The half-Ufe of vancomycin was 145 hours. Hearing loss developed. Continued charcoal hemoperfusion and hemodialysis were used to treat the disorder. Thrombocytopenia was noted as significant consequence of hemoperfusion. The patient did not fully recover her previous renal function and became dialysis dependent. The audiogram normalized by 6 months. 

The dose administered should be adjusted in proportion to the reduction of creatinine clearance for patients with renal impairment since they require lower doses to achieve AUCs comparable with those seen with patients with normal renal function. Calvert et al. [64] have proposed the following formula for calculation of dose ... 

The Hull and Sarrubi aminoglycoside dosage nomogram (Table 5-5) is based on this dosage-calculation method and includes precalculated doses and dosage intervals for a variety of creatinine clearance values. The nomogram assumes that Vd = 0.26 L/kg and should not be used to compute doses for disease states with altered V. ... 

Why would one consider creatinine clearance in dose calculation ... 

Algorithm for Dose Reduction of Aminoglycosides Based on Calculated Creatinine Clearance... 

In Equation 1.36, Dg is the adjusted maintenance dose for the patient with renal failure, D is the maintenance dose for a normal individual,/is the fraction excreted, and C/r is the patient s creatinine clearance, which can be determined from the serum creatinine value using the Cockcroft and Gault Equation 1.42. If a new dosing interval for the patient with renal failure (x ) is calculated, a reciprocal of the bracketed term in Equation 1.45 is used and the new equation becomes Equation 1.46. ... 

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