Considerations for optimal iron use for anemia due to chronic kidney disease.

BACKGROUND: Availability of recombinant human erythropoietin (rHuEPO) has improved the treatment of anemia due to chronic kidney disease (CKD). Iron deficiency is the most common cause of resistance to rHuEPO therapy, contributing to ineffective erythropoiesis and hematocrit/hemoglobin values below the recommended target range (33%-36%/11-12 g/dL). I.v. iron supplementation is necessary to meet increased iron demands from stimulation of erythropoiesis and chronic blood loss; however, questions remain as to the optimal supplementation strategy to maintain appropriate yet safe iron status. Treatment guidelines for anemia management have been developed through the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI). OBJECTIVE: This review presents the basis of need for the NKF-K/DOQI guidelines and includes detailed information concerning iron physiology, metabolism, iron preparations, and evaluation of iron status. METHODS: This review was based on a MEDLINE search and complemented by references from the NKF-K/DOQI guidelines (whose review extended beyond MEDLINE). References focusing on normal iron physiology and metabolism, alterations in iron physiology in patients with CKD, laboratory evaluation methods, and strategies for iron supplementation were obtained from MEDLINE and reviewed for content. RESULTS: Controversy over appropriate use of iron supplementation has led to disparity in accepted practice procedures. Oral iron (ferrous salts and polysaccharide iron complex) and i.v. iron preparations (iron dextran, sodium ferric gluconate, and iron sucrose) are available. Problems with oral iron supplementation include limited absorption and patient noncompliance. Although most available data on i.v. iron use in the United States are specific to iron dextran preparations, published information based on clinical use of sodium ferric gluconate and iron sucrose products has been promising. The use of chronic i.v. iron administration to sustain iron stores has been more widely accepted to prevent development of absolute and functional iron deficiency. CONCLUSIONS: Although iron therapy is commonly warranted in patients with CKD, questions remain as to the most favorable supplementation strategy to optimize therapy through improvements in hematocrits, efficient use of rHuEPO, and maintenance of appropriate and safe iron levels. Clinicians will need to devise strategies based on the compilation of information from clinical experience and the available literature. Clinical practice guidelines devised by the NKF-K/DOQI have provided a useful tool for the medical community using both these resources.

The pharmacokinetics of subcutaneous enoxaparin in end-stage renal disease.

STUDY OBJECTIVE: To evaluate the pharmacokinetics of enoxaparin in end-stage renal disease (ESRD), and determine if dosage reduction is necessary to maintain antifactor Xa activity concentrations within the therapeutic range. DESIGN: Prospective, single-dose pharmacokinetic study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight nonthrombosed patients with ESRD requiring hemodialysis. INTERVENTION: All subjects received a single dose of enoxaparin sodium 1 mg/kg subcutaneously and had serial plasma antifactor Xa activity concentrations measured over 24 hours. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of enoxaparin were determined from plasma antifactor Xa activity concentrations, and various multiple-dose regimens were simulated. After administration of the drug, total body clearance was 14.6 ml/minute and there was a 2-fold prolongation in antifactor Xa activity half-life compared with values reported in healthy subjects. All other pharmacokinetic parameters were similar to those in healthy subjects and patients with chronic renal insufficiency. An accumulation ratio of 1.6 was estimated for a dosing interval of every 12 hours based on single-dose pharmacokinetics. When various therapeutic regimens were simulated to predict average steady-state antifactor Xa activity, standard enoxaparin dosages of 1 mg/kg subcutaneously every 12 hours and 1.5 mg/kg every 24 hours resulted in average steady-state concentrations within the therapeutic range. CONCLUSIONS: Based on antifactor Xa activity, ESRD has little effect on the pharmacokinetics of enoxaparin, and dosing adjustments are unnecessary.

Nephrology pharmaceutical care preceptorship: a programmatic and clinical outcomes assessment.

OBJECTIVE: The University of Pittsburgh Nephrology Pharmaceutical Care Preceptorship (NPCP) program was conceived to acquaint health system pharmacists with the pharmacotherapeutic management of dialysis patients, enhance the delivery of pharmaceutical care, and improve clinical outcomes through the development of specialized professional skills. A survey designed to determine the impact of the NPCP program was sent to all 145 participants of the program. METHODS: The survey, designed to collect demographic information and data about the participants' practice sites, professional activities prior to and after the completion of the program, and markers of disease status, was mailed to all participants in September 1997. The 96 respondents (66.2%) were involved in a wide variety of clinical practices; inpatient management of peritoneal dialysis, hemodialysis, or renal transplant patients were most commonly reported. RESULTS: More than 80% of the participants believed that the educational content of the NPCP program was sufficient to allow them to establish a specialized service for the management of dialysis patients. However, two-thirds would have preferred to have more contact time (an additional 1-2 d) with the preceptorship faculty. The percentage of the pharmacists' time devoted to the provision of pharmaceutical care for dialysis patients almost doubled, from 13.1% to 25.2% (p < 0.001). The components of pharmaceutical care performed by these pharmacists also changed as a result of their completion of the NPCP program. Time devoted to clinical services and the provision of educational programs (inservices) increased significantly, while the time allocated to distributive activities decreased from a mean of 32.4% to 26.4% (almost 20% from baseline). The number of pharmacists who provided some component of pharmaceutical care for ambulatory dialysis patients increased significantly, from 10 to 33, after completion of the program. In the survey given after the preceptorship, almost 70% of these 33 pharmacists self-reported that the mean hematocrit of their ambulatory dialysis patients increased; 45% reported that the epoetin dose was lower. Parenteral iron use was also reported to have increased in 78.8% of the dialysis units, and an increase in serum ferritin and transferrin saturation was observed in 54.5% and 60.6% of the units. respectively. Although far fewer pharmacists (n = 15) initiated a renal osteodystrophy management program, 73.3% of those who did so reported an increase in their patients' compliance with phosphate binder therapy, which was reflected in a drop in serum phosphorous in 40% of the units. CONCLUSIONS: The NPCP program resulted in changes in the professional activities of the participants: fewer distributive activities and increased clinical and educational activities. These significant changes were noted in all areas of outpatient care. Participation in the NPCP program enhanced the delivery of pharmaceutical care to dialysis patients and improved the markers of disease status.

Pharmacokinetics of gabapentin in subjects with various degrees of renal function.

The pharmacokinetics of oral gabapentin (400 mg) was studied in normal subjects and in subjects with various degrees of renal function. Sixty subjects participated in this three-center study. None of the subjects were receiving hemodialysis. Plasma and urine samples were collected for up to 264 hours after dosing, and concentrations of gabapentin were determined by high performance liquid chromatography. Apparent oral plasma clearance (CL/F) and renal clearance (CLR) of gabapentin decreased and maximum plasma concentration, time to reach maximum concentration, and half-life values increased as renal function diminished. Gabapentin CL/F and CLR were linearly correlated with creatinine clearance. Total urinary recovery of unchanged drug was comparable in all subjects, indicating that the extent of drug absorption was unaffected by renal function. There was no evidence of gabapentin metabolism even in subjects with severe renal impairment. In summary, impaired renal function results in higher plasma gabapentin concentrations, longer elimination half-lives, and reduced CL/F and CLR values. Based on pharmacokinetic considerations, it appears that the dosing regimen of gabapentin in subjects with renal impairment may be adjusted on the basis of creatinine clearance.

A dose-response trial of once-daily diltiazem.

This trial was performed to determine the safe and effective dosage range of once daily diltiazem (diltiazem CD) capsules for treatment of essential hypertension. Patients with essential hypertension having supine diastolic blood pressure values greater than or equal to 95 mm Hg and less than or equal to 110 mm Hg were randomly assigned to receive placebo or one of four doses of diltiazem CD: 90, 180, 360, or 540 mg. Blood pressure was measured at trough, 24 hours after the dose, and at the time of peak effect, 10 hours after the dose. Diltiazem CD lowered both supine diastolic and systolic blood pressure. A linear dose response was seen with changes in diastolic and systolic blood pressure and heart rate for trough and peak measurements. Trough/peak ratios for the 180, 360, and 540 mg doses were all greater than 0.50. Adverse effects were dose related; those most commonly reported were headache (8.6%), bradycardia (8.1%), and edema (7%), with bradycardia and edema possibly dose related. It is therefore concluded that diltiazem CD is a safe and effective antihypertensive agent.

Pharmacokinetics and protein binding of methocarbamol in renal insufficiency and normals.

We determined plasma methocarbamol concentrations over 24 h following a 1.5 g methocarbamol dose (off-dialysis day) to 8 chronic haemodialysis patients and compared these results to those from 17 healthy male volunteers. The harmonic mean elimination half-life was similar between the two groups, 1.24 and 1.14 h, respectively. tmax and the weight-adjusted Cmax were 1.1 h and 27.0 mg.m-1 for haemodialysis patients and 1.1 and 23.1 mg.l-1 for normals. Relative systemic availability was assessed by comparing weight-normalized AUC x k10 products. These results indicate no significant differences with respect to methocarbamol absorption, with the relative systemic availability in patients being 113%. These data suggest that absorption and elimination of methocarbamol is similar between normal subjects and patients undergoing maintenance haemodialysis.

Pseudoephedrine accumulation in renal failure.

Neuropsychiatric complications, such as metabolic encephalopathy, are common occurrences in end-stage renal disease (ESRD) patients. Frequently, metabolic encephalopathy develops in relationship to the multiple pharmacologic therapies routinely employed in this population. Such polypharmacy often leads to adverse drug reactions, drug-drug interactions, or dosage error. In this regard, over-the-counter (OTC) medications are commonly perceived as being "somewhat benign" when, in fact, their potential for adverse effect may be significant. The authors describe the course of a 64-year-old hemodialysis patient who became intoxicated on conventional doses of pseudoephedrine only to regain neurologic integrity upon discontinuation of the medication.

Ranitidine bioavailability and disposition kinetics in patients undergoing chronic hemodialysis.

The absorption and disposition of single-dose intravenous (i.v.) and oral ranitidine were evaluated in 6 patients undergoing chronic hemodialysis. Ranitidine was given as either 50 mg (0.16 mM) i.v. or 150 mg (0.48 mM) tablets 4 h prior to hemodialysis according to a randomized cross-over design with tests separated by 2 weeks. Following i.v. administration, the peak serum ranitidine concentration was 761 +/- 207 micrograms/l (mean +/- SD) and the observed peak after the oral dose was 833 +/- 206 micrograms/l at 3.5 +/- 1.2 h. To convert micrograms/l to microM/l, divide by 314. The terminal elimination rate constants for the i.v. and oral doses were 0.062 +/- 0.013 and 0.058 +/- 0.004 h-1, respectively, with an apparent volume of distribution of 139.6 +/- 35.3 liters and total body clearance 8.5 +/- 1.6 liters/h for the i.v. dose. Hemodialysis clearances during the i.v. and oral studies were 3.2 +/- 0.9 and 3.1 +/- 1.0 liters/h, respectively, and the mean amount removed by hemodialysis following i.v. administration was 3.9 +/- 2.7 mg. The bioavailability of ranitidine was 54.3 +/- 13.5%. Based on these single-dose data, a daily oral dose of 150 mg ranitidine in patients with end-stage renal disease should provide a mean ranitidine serum concentration of approximately 350 micrograms/l with less than 10% of body stores of ranitidine being lost during any dialysis session.

Ranitidine accumulation in patients undergoing chronic hemodialysis.

Ranitidine accumulation was assessed in 20 patients undergoing chronic hemodialysis following oral daily doses of 150 mg ranitidine for 10 days. Serum ranitidine concentrations prior to dialysis were 191 +/- 115 mcg/l and 207 +/- 172 mcg/l for patients dialyzed three and two times per week, respectively. The amount of ranitidine recovered in the dialysate during the final dialysis session of the study was negligible and ranged from 308-3036 mcg, representing less than 3% of the administered dose. Clearance by hemodialysis was 3.0 +/- 1.1 l/hr. Once daily dosing of 150 mg ranitidine does not result in excessive accumulation, and drug loss during hemodialysis is small. These data suggest that supplemental dosing after hemodialysis is not indicated.

Temperature dependence of phenytoin-protein binding in serum: effects of uremia and hypoalbuminemia.

Phenytoin-protein binding was determined as a function of temperature in uremic patients with normal albumin and in uremic patients with hypoalbuminemia. Free phenytoin levels were determined in ultrafiltrates (MPS-1; Amicon, Lexington, MA, U.S.A.) from serum equilibrated at either 20, 25, 30, 35, or 40 degrees C. Scatchard analyses showed significant differences in phenytoin-protein binding affinity as a function of temperature. Linear regression plots of free phenytoin versus temperature showed the slopes of the uremic and uremic with hypoalbuminemia patients (0.546 and 0.535, respectively) to be 3 times that of patients with normal renal function (0.174). Free phenytoin was analyzed in 150 patients with normal renal function in whom the total phenytoin was in the range of 38.0-80.8 mumol/L. The ultrafiltrate, prepared at 22 +/- 0.5 degrees C, resulted in free phenytoin levels in the range of 3.2-8.3 mumol/L. We have established this as the therapeutic range for the patient population seen at this medical center.

Effect of two administration schedules of an enteral nutrient formula on phenytoin bioavailability.

Continuous nasogastric (NG) administration of enteral nutrient formulas (ENFs) reportedly lowers phenytoin (PHT) concentrations. We studied the effects of two administration schedules of an ENF on the bioavailability of PHT. Eight healthy volunteers received 400 mg PHT suspension after fasting (A), with hourly Ensure (B), and with 4-hourly Ensure (C) in a randomized, crossover design. Data obtained from 13 serum samples collected over 80 h were analyzed using ESTRIP. Area under the serum concentration-time curve (AUC), time to maximum serum concentration (Tmax), and urinary excretion of 5-(p-hydroxyphenyl) 5-phenylhydantoin (HPPH) were compared by analysis of variance (ANOVA) and Bonferroni t tests of differences between means. AUCs (mg x h/L) were not different (p greater than 0.05) for A (222.1 +/- 86.9), B (233.9 +/- 92.9), and C (226.0 +/- 95.7). Tmax (h) was significantly shorter (p less than 0.05) when PHT was administered with Ensure (B = 8.5 +/- 3.0, C = 5.3 +/- 2.0) than without Ensure (A = 18.5 +/- 10.5). The HPPH excretion (mg/80 h) was not different (p greater than 0.05) for A (225.6 +/- 48.5), B (238.6 +/- 26.6), and C (229.9 +/- 45.6). Clearance and maximum concentration correlated with AUC, obviating the need for analysis. Relative bioavailability was B/A = 1.07 +/- 0.21, C/A = 1.01 +/- 0.14. The bioavailability of PHT was not decreased by either ENF administration schedule. Factors other than direct contact may be responsible for the observed decreases in PHT concentrations by coadministered ENFs.

Effect of antacid suspension on the pharmacokinetics of ibuprofen.

The effect of antacid administration on the pharmacokinetics of ibuprofen was evaluated in a randomized, crossover study of eight healthy volunteers. Doses of 62 mL of aluminum and magnesium hydroxide suspension and single doses of ibuprofen 400 mg were used. Subjects received each of the following treatments at one-week intervals: ibuprofen alone; ibuprofen administered concurrently with one dose of antacid; antacid administered one hour after the ibuprofen dose; and antacid administered concurrently with the ibuprofen dose, plus three more antacid doses given every five hours. Blood samples were taken at various time intervals up to 24 hours after the ibuprofen dose. Serum samples were assayed for ibuprofen content using high-performance liquid chromatography. Values for AUC, Cmax, tmax, and k were not significantly different among treatment groups. The ranges of mean (+/- S.D.) values were 113.97 +/- 21.5 to 127.53 +/- 29.3 micrograms.hr/mL for AUC, 35.30 +/- 6.40 to 41.00 +/- 10.00 micrograms/mL for Cmax, 0.95 +/- 0.30 to 1.28 +/- 0.54 hr for tmax, and 0.346 +/- 0.026 to 0.388 +/- 0.040 hr-1 for k. For the doses used, concurrent administration of aluminum and magnesium hydroxide suspension and ibuprofen does not alter ibuprofen pharmacokinetics.

Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers.

A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.

A comparative bioavailability study of carbamazepine tablets and a chewable tablet formulation.

Differences in product formulations have been shown to affect the therapeutic response by altering the relative bioavailability and pharmacokinetics of a drug. The relative bioavailability and pharmacokinetics of carbamazepine tablets (CBZ) and a chewable tablet formulation were evaluated in 10 normal healthy subjects (five men and five women). The study utilized a randomized, crossover design with a 4-week washout period between doses. Blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 14, 24, 30, 36, and 48 h following a 200-mg dose. Plasma samples were assayed by fluorescence polarization immunoassay. Ke, Cmax, Tmax, area under the curve (AUC), and relative bioavailability were estimated using traditional pharmacokinetic methods and compared by paired t test. A statistically significant higher Cmax (3.81 +/- 81 vs. 4.64 +/- .80 mg/L) was observed with the chewable tablet formulation but was not thought to be clinically relevant. No significant differences between formulations for Ke (0.022 +/- 0.007 vs. 0.025 +/- 0.008 h-1 h), Tmax (7.49 +/- 2.69 vs. 6.04 +/- 2.7 h), AUC 48 h (119 +/- 22 vs. 133 +/- 13 mg/h/L), or AUCO--infinity ( 221 +/- 40 vs. 203 +/- 41 mg/h/L) were noted. Absorption was variable for both preparations. The relative bioavailability using the tablet as the standard formulation was (0.92 +/- 0.22). Transient, mild side effects were noted in three subjects with the chewable tablet alone, and one subject experienced side effects with both formulations. It was concluded that CBZ tablets and chewable tablets may be used interchangeably; however, considerable intra- and intersubject variability exists, and the need for patient monitoring is emphasized.

Single dose comparison of the relative bioavailability of phenytoin suspension and extended capsules.

There is presently only one preparation of phenytoin approved for once-daily dosing--extended phenytoin sodium capsules. We have observed many hospitalized patients switched from either this preparation or the intravenous form of phenytoin to phenytoin oral suspension. The bioavailability and single dose pharmacokinetics of extended phenytoin sodium capsules (Dilantin Kapseals) and phenytoin oral suspension (Dilantin oral suspension) were compared in seven healthy adult volunteers. Each subject was administered both three 100-mg Dilantin Kapseals (276 mg free acid) and 11 ml (275 mg) Dilantin-125 oral suspension in a randomized cross-over design with a 1-week washout period between preparations. Blood samples were drawn over 78 h after the administration of each preparation for determination of serum phenytoin concentration. In addition, total urinary output was collected for 48 h. Statistical analysis consisted of a comparison of the area under the curve (AUC) from time zero to 48 h and time-to-peak concentration using a two-tailed paired t test at a level of significance of p less than 0.05. The total alpha level was 0.10. No significant differences were found between the two preparations. The power of detecting a 15% difference in AUC was 0.80, and the power of detecting a 5-h difference in time to peak was 0.52. Following is a summarization of the pharmacokinetic parameters (capsules mean +/- 1 SD; suspension mean +/- 1 SD).(ABSTRACT TRUNCATED AT 250 WORDS)

Lidocaine anesthesia: comparison of iontophoresis, injection, and swabbing.

The duration and depth of anesthesia produced by lidocaine with three methods of administration were studied. To test duration of anesthesia, either lidocaine or placebo was administered by iontophoresis, subcutaneous infiltration, or swabbing to each of three sites 3 cm apart on the flexor surface of each forearm of 27 subjects. To test for feeling, the tip of a 21-gauge hypodermic needle was pressed on each application site every five minutes until feeling returned. The depth of anesthesia achieved with iontophoresis or infiltration of lidocaine was tested on the flexor surface of each forearm of 12 subjects, with a random assignment of application methods to each arm. Lidocaine iontophoresis produced local anesthesia of significantly longer duration (p less than 0.001) than topical application of lidocaine or placebo by any route of administration, but of significatnly shorter duration (p less tahn 0.001) than lidocaine infiltration. The results showed that lidocaine iontophoresis is an effective method of producing local anesthesia for about five minutes without requiring the use of a hypodermic needle and syringe.

Rapid high-pressure liquid chromatographic determination of quinidine and dihydroquinidine in plasma samples.

A high-pressure liquid chromatographic assay for quinidine and dihydroquinidine was developed. A cation-exchange column was utilized with an eluting solvent pH of about 9. The internal standard was cinchonine. The reproducibility and precision of this method were evaluated by analyzing replicate samples and by comparing results with those obtained from a TLC-fluorometric procedure. In addition, several drugs were evaluated to ascertain whether they interfered with the analysis of quinidine and dihydroquinidine.

Binding of quinidine to plasma proteins in normal subjects and in patients with hyperlipoproteinemias.

Quinidine in the plasma binds to various lipoproteins as well as to albumin. With the use of computer simulations the effect of varying the serum level of each of the lipoproteins as well as albumin was examined. The results suggested that the overall binding of quinidine is relatively insensitive to changes in any one serum protein provided the others are present in normal concentrations. Evaluation of the degree of protein binding of quinidine in plasma from normal subjects and patients with types IV and IIa hyperlipoproteinemias supported the computer predictions. The degree of protein binding in plasma from normal subjects and patients with types IV and IIA hyperlipoproteinemias were 71.2% +/- 11.4%, 75.9% +/- 8.7%, and 69.9% +/- 15.0%, respectively. The quinidine binding in plasma of patients with hyperlipoproteinemias did not differ statistically from that in the normal subjects.