Paul A. Abraham

Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta

Different recombinant human erythropoietin products have been developed. Although they appear to have similar pharmacokinetics and function, these have not been directly compared. This randomized, double‐blind, four‐period crossover study compared the pharmacokinetics and pharmacodynamics of intravenous and subcutaneous epoetin alfa and epoetin beta in 18 normal male volunteers. As a control, three subjects received placebo treatment. After intravenous administration, the steady‐state volume of distribution and β‐phase volume of distribution of epoetin beta were 7.7% and 16.9% larger than for epoetin alfa (p <0.05). The terminal elimination half‐life after intravenous administration of epoetin beta was 20% longer than the terminal elimination half‐life of epoetin alfa. After subcutaneous administration there was a delayed drug absorption with epoetin beta compared with epoetin alfa (p <0.05). There was a small but significantly greater absolute reticulocyte response after subcutaneous epoetin beta compared with subcutaneous epoetin alfa. The findings support differences in the pharmacokinetics and function of epoetin alfa and beta that are possibly caused by differences in their glycosylation.

Biochemical Effects of Losartan, a Nonpeptide Angiotensin II Receptor Antagonist, on the Renin-Angiotensin-Aldosterone System in Hypertensive Patients

We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.

Pharmacokinetics and pharmacodynamics of codeine in end‐stage renal disease

The pharmacokinetics and pharmacodynamics of codeine and its metabolites codeine glucuronide, morphine, and morphine glucuronide were assessed after the administration of a single 60 mg oral dose of codeine sulfate and a single 60 mg intravenous dose of codeine phosphate in six healthy volunteers and six patients on chronic hemodialysis. Plasma and urine drug and metabolite concentrations were determined by sensitive and specific RIA procedures. Pharmacodynamics were assessed by pupillometry and vital sign determinations. Codeine elimination half‐life and mean residence time were increased significantly in the hemodialysis group (18.69 ± 9.03 hours and 12.77 ± 7.09 hours, mean ± SD, respectively) compared with the healthy volunteer group (4.04 ± 0.60 hours and 3.90 ± 0.52 hours, respectively). The total body clearance and volume of distribution of codeine were not significantly different between groups. Peak concentrations, times to peak concentrations, and AUCs for the three metabolites were also not significantly different between the groups, in part as a result of significant interpatient variability in the hemodialysis group. Examination of pupillometry and vital sign data did not reveal clinically significant differences in pharmacodynamics between the groups. Adjustment of dosage regimen may be required in some patients with uremia receiving multiple‐dose codeine therapy.

Body Fluid Spaces and Blood Pressure in Hemodialysis Patients During Amelioration of Anemia With Erythropoietin

Blood pressure (BP) may increase in hemodialysis patients during treatment of anemia with recombinant human erythropoietin (r-HuEPO). Since fluid volume is a determinant of BP in dialysis patients, changes in body fluid spaces during r-HuEPO therapy could affect BP. Thus, 51Cr-labeled red blood cell (RBC) volume, inulin extracellular fluid (ECF) volume, and urea total body water (TBW), as well as cardiac output, plasma renin activity (PRA), and plasma aldosterone concentration were determined postdialysis before and after r-HuEPO therapy in patients in whom changes in BP could be managed by ultrafiltration alone. Eleven patients entered the study: one had a renal transplant and two required addition of antihypertensive drug therapy and were excluded; eight, of whom two required antihypertensive drug therapy following the study, were included in the analyses. Results revealed an increase in predialysis hemoglobin from 67 to 113 g/L (6.7 to 11.3 g/dL) (P = 0.001) during 18 +/- 6 weeks of therapy. Predialysis diastolic BP increased from 80 to 85 mm Hg (P = 0.07), while postdialysis diastolic BP was unchanged at 73 mm Hg. 51Cr-RBC volume increased, from 0.7 to 1.3 L (P = 0.004). ECF tended to decrease, from 13.7 to 10.8 L (P = 0.064), while TBW decreased to a similar extent, but not significantly, 34.3 to 31.2 L (P = 0.16). Postdialysis ECF volume was positively correlated with mean arterial BP at baseline (r = 0.89, P = 0.007) and after therapy (r = 0.74, P = 0.035). However, the regression lines for this relationship were different (P = 0.022) before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal function during erythropoietin therapy for anemia in predialysis chronic renal failure patients.

Recombinant human erythropoietin (r-HuEPO) therapy for anemia in chronic renal failure patients could have unfavorable renal effects since reversal of anemia can raise blood pressure and accelerate experimental glomerular injury. Thus, the effects of r-HuEPO on renal and systemic hemodynamics and the progression of renal disease were studied in predialysis chronic renal failure patients. The clearances of inulin and p-aminohippurate, fractional excretions of albumin and immunoglobulin G, cardiac output, plasma renin activity and aldosterone concentration were assessed at baseline, after short-term r-HuEPO (n = 4) or placebo (n = 4) therapy, and after long-term r-HuEPO for all patients (n = 8). In addition, the slope of l/serum creatinine with time was determined before and during continued r-HuEPO therapy. In contrast to placebo therapy, hematocrit increased with r-HuEPO from 32 to 37% after 7.6 +/- 2.7 weeks (mean +/- SD). Antihypertensive drug therapy was increased in 2 patients in each group. Renal function, cardiac output, plasma renin activity and aldosterone did not change significantly in either group. After 18 +/- 9 weeks of therapy for all patients, hematocrit increased from 31 to 39%. Antihypertensive drug therapy was increased in 5 patients and decreased in 1. Renal function decreased while proteinuria tended to increase. Cardiac output, plasma renin activity and aldosterone did not change. During 37 +/- 22 weeks of r-HuEPO therapy, the slope of l/serum creatinine did not worsen in any patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of codeine after single- and multiple-oral-dose administration to normal volunteers.

The pharmacokinetics of codeine, codeine glucuronide, morphine, and morphine glucuronide were assessed after single‐(60 mg) and multiple‐dose (60 mg every six hours for nine doses) oral administration of codeine sulfate to six normal volunteers. Multiple blood and urine samples were collected after administration of the single‐ and last multiple‐oral doses. Drug concentrations were analyzed using radioimmunoassay techniques. No significant alterations in codeine pharmacokinetics were noted after multiple‐dose oral administration. However, accumulation of morphine during multiple dosing was significant (AUC24 = 102 ± 33 ng/mL/hr after single dose versus 212 ± 118 ng/mL/hr after the last multiple dose). Peak concentration and AUC24 data for morphine glucuronide indicated that significant accumulation of this compound occurs upon multiple‐dose administration. These data indicate that morphine and morphine glucuronide serum concentrations are significantly increased during chronic oral codeine therapy and suggest that morphine, and perhaps morphine glucuronide, contribute significantly to the analgesic activity of chronic oral codeine therapy.

Disposition of Famotidine in Renal Insufficiency

The disposition of famotidine was evaluated in 18 patients; Group 1, mild renal insufficiency, [creatinine clearance (CLCR): 30–60 mL/min]; Group 2, moderate to severe renal insufficiency (CLCR: 10–30 mL/min); Group 3, end‐stage renal disease requiring maintenance hemodialysis (anuric). Blood and urine samples were obtained over a 72‐hour period. Plasma concentration‐time data demonstrated biexponential decay. The terminal elimination half‐life was prolonged in Group 3 (18.6 ± 5.7 hr) compared with Groups 1 (9.3 ± 2.3 hr) and 2 (9.7 ± 1.7 hr), P < .05. Steady‐state volume of distribution ranged from 0.80 to 1.26 L/kg but did not differ among the groups. Total body clearance (CLP) and renal clearance were significantly lower in Groups 2 and 3 patients compared with Group 1 patients. Nonrenal clearance was not related to CLCR. The CLP correlated well with CLCR (CLP = 1.59 CLCR + 33.8, r = 0.830, P < .05). These data indicate that dosage adjustment may be necessary in patients who have renal insufficiency.

Medical evaluation and management of calcium nephrolithiasis.

Stone disease is a common medical problem, frequently recurs, and is associated with significant morbidity. Because appropriate medical therapy significantly decreases stone recurrence, this disorder must not be ignored by nonurologists. Even the single stone-former should be offered a metabolic evaluation.

Epoetin enhances erythropoiesis in normal men undergoing repeated phlebotomies

Epoetin may enhance autologous blood donation, but efficacy and dose response have not been established. This multicenter, double‐blind trial compared intravenous placebo (n = 23) with epoetin beta, 250 U/kg (n = 23), 500 U/kg (n = 19), and 1000 U/kg (n = 22), administered three times weekly for 26 days. Normal men (age, 28 ± 7 years; mean ± SD) received phlebotomies up to three times weekly as long as the hemoglobin remained ≥12 gm/dl. Subjects treated with epoetin donated 32% more units of blood (p < 0.05) compared with placebo. A dose response was not observed. Platelet counts increased with epoetin compared with placebo, but platelet function and bleeding time did not change. Prothrombin times increased and partial thromboplastin times decreased with both epoetin and placebo. The supernatant of packed red blood cells collected after multiple phlebotomies and stored 42 days had slightly lower glucose concentrations and pH after therapy with epoetin. Blood pressure did not change with epoetin or placebo. These findings support the efficacy and safety of epoetin for enhancing the erythropoietic response of normal subjects during intensive phlebotomy.

Cefotaxime and desacetyl cefotaxime kinetics in renal impairment

Cefotaxime and desacetyl cefotaxime kinetics after a single, 1 gm intravenous dose were evaluated in five groups of subjects: group I, normal creatinine clearance (CLCR >90 ml/min); group II, mild renal insufficiency (CLCR 30 to 89 ml/min); group III, moderate renal insufficiency (CLCR 16 to 29 ml/min); group IV, severe renal insufficiency (CLCR 4 to 15 ml/min); and group V, end‐stage renal disease requiring maintenance hemodialysis (CLCR <6 ml/min). The steady‐state volume of distribution (Vss) ranged from 10% to 55% of body weight but was not related to CLCR. The terminal t½ values of cefotaxime and desacetyl cefotaxime were 0.79 and 0.70, 1.09 and 3.95, 1.55 and 5.65, 2.54 and 14.23, and 1.63 and 23.15 hours in groups I to V, respectively. There were no significant changes in Vss or t½ after multiple dosing, but there were significant correlations between CLCR and cefotaxime total body clearance, cefotaxime and desacetyl cefotaxime renal clearance, and cefotaxime nonrenal clearance. Dosage regimens for the use of cefotaxime in patients with renal impairment are proposed.