Thomas J. Comstock

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.

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.

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

Summary: 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 > 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 < 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 > 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.

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.

Ranitidine pharmacokinetics in continuous ambulatory peritoneal dialysis

SummaryRanitidine kinetics in renal failure were evaluated in six patients undergoing continuous ambulatory peritoneal dialysis (CAPD). On separate occasions each patient received either 50 mg intravenously (i.v.) or 150 mg orally of ranitidine HCl. Following i.v. administration, the plasma concentration vs time curve was best described by a two compartment model with firstorder elimination. The mean ± SD distribution and elimination rate constants were 2.47±0.78 and 0.098±0.013 h, respectively. The area under the serum concentration vs time curve after the i.v. dose was 5979±2870 μg·h· 1−1, resulting in a mean volume of distribution of 76.81 and a total body clearance of 126 ml·min−1. Following oral administration the observed maximum plasma concentration was 904±483 μg·l−1 at 4.2±1.8 h, and the bioavailability was 69.7±35.6%. The peritoneal clerance of ranitidine was 3.2±0.7 and 2.6±0.6 ml·min−1 for the i.v. and oral groups, respectively. The amount of drug removed by dialysis was 561.2±336.2 μg for the i.v. and 1197.1±602.3 μg for the oral group. Four patients in the i.v. group had urine output during the study period with renal ranitidine clearance values of 9.9±9.9 ml· min−1. Two patients in the oral group had urine output and corresponding renal ranitidine clearance values of 5.1 and 20.1 ml·min−1. A dosage regimen for ranitidine is proposed based on ranitidine kinetics in patients undergoing CAPD.

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 pharmacoki-netics 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 / 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 ± 0.008h−1h), Tmax (7.49 ± 2.69 vs. 6.04 ± 2.7 h), AUC 48 h (119 ± 22 vs. 133 ± 13 mg/h/L), or AUCO-∞ (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.

Use and prescribing patterns for erythropoiesis-stimulating agents in inpatient and outpatient hospital settings.

PURPOSEnErythropoiesis-stimulating agent (ESA) use in the outpatient and inpatient settings through pharmacist-conducted, hospital-based chart audits is examined and discussed.nnnMETHODSnData from four hospital chart audits conducted in 250 hospitals between October 2005 and July 2006 were pooled for analyses. Eligible hospitals were categorized by ESA sales volume, with approximately equal numbers randomly selected from each decile. The last five inpatients and outpatients within each specified month receiving either darbepoetin alfa or epoetin alfa were evaluated. Study variables by setting included ESA use, prescriber specialty, and dosage regimen.nnnRESULTSnThe most common hospital locations of ESA administration were a cancer center in the outpatient setting (49%) and general medicine (57%) in the inpatient setting. ESA prescribers were most commonly hematologists and oncologists in the outpatient setting, and nephrologists were the most common prescribers in the inpatient setting. In the outpatient analysis, 2155 patients were prescribed darbepoetin alfa and 3106 were prescribed epoetin alfa. The predominant administration frequencies were every two weeks and once weekly for darbepoetin alfa, and once weekly for epoetin alfa. In the inpatient analysis, 1633 patients were prescribed darbepoetin alfa and 3231 were prescribed epoetin alfa. The predominant administration frequencies were once weekly for darbepoetin alfa and once weekly and three times weekly for epoetin alfa. Common uses for both ESAs were chemotherapy-induced anemia (outpatient setting) and anemia of end-stage renal disease with chronic dialysis (inpatient setting). There was considerable variability in ESA dosages and administration frequencies in both settings within all patient groups when analyzed by specified use.nnnCONCLUSIONnESA use differed between outpatient and inpatient settings in indication, frequency of administration, and specialty of the prescriber.

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

SummaryWe 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 × 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.

Case Report: Pseudoephedrine Accumulation in Renal Failure

ABSTRACT 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.