Patricia R. Audet

Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment

To characterize the pharmacokinetics of a single 500 mg oral dose of famciclovir in subjects with varying degrees of renal impairment.

Pharmacokinetics of Testosterone in Hypogonadal Men After Transdermal Delivery: Influence of Dose

To assess the pharmacokinetics of testosterone after application of one, two, or three testosterone transdermal delivery systems to hypogonadal patients, 12 hypogonadal men (mean age 46.6 ± 10.5 years) were enrolled in an open‐label, randomized, crossover study. Each application period comprised 4 days: a 2‐day washout period with no exogenous testosterone therapy followed by 2 days of therapy with one, two, or three transdermal systems applied daily to the patients back. On day 4 of each period, serial blood samples were collected for determination of total and non‐sex hormone binding globulin (non‐SHBG) bound serum testosterone concentrations. Serum concentrations of testosterone were determined using validated radioimmunoassay methods. Residual testosterone analysis of used transdermal systems was used to estimate testosterone delivery through the skin. In general, serum concentrations of testosterone rose in accordance with an increase in dose. Using a strict bioequivalence approach to dose proportionality, the increases in area under the concentration—time curve (AUC) and morning concentrations were proportional to the increase in dose from two to three transdermal systems, but somewhat less than proportional with an increase from one to two transdermal systems. Results from the non‐SHBG bound serum testosterone concentrations closely paralleled those of total serum testosterone. Use of three transdermal systems yielded serum concentrations of testosterone that tended to be above the upper limit of the normal range. The AUC and cumulative release of testosterone were linearly related to the number of applied systems. If necessary, the standard recommended dose of two testosterone transdermal delivery systems can be modified to accommodate interindividual differences in testosterone requirements of hypogonadal men.

Comparative Effects of Nabumetone, Sulindac, and Indomethacin on Urinary Prostaglandin Excretion and Platelet Function in Volunteers

Nonsteroidal antiinflammatory drugs differ with respect to their effects on prostaglandin metabolism in various tissues, a property that may be partly responsible for some of the differences in the pharmacologic activities and side‐effect profiles that are associated with their use. The effects of nabumetone on urinary prostaglandin excretion have not been reported. Fourteen healthy females, age 21–43 years, were treated with nabumetone (NAB) 1000 mg daily, sulindac (SUL) 200 mg every 12 hours, and indomethacin (IND) 50 mg every 12 hours for 7 days in a randomized period‐balanced crossover study. The effects of drug treatment on urinary prostaglandin excretion (PGE2, 6‐keto‐PGF1α, PGF2α, thromboxane [TX] B2) and platelet function (collagen‐induced whole blood platelet aggregation [CIPA] and template bleeding time) were determined on day 1 and day 7. For each treatment regimen, mean baseline urinary PG excretion values were comparable for each prostanoid, but the pattern of excretion differed in response to each drug. Treatment with NAB significantly increased the urinary excretion rates of PGE2 and PGF2α, but 6‐keto‐PGF1α and TXB2 excretion were unchanged. IND treatment did not result in a significant change in PGE2 excretion but did significantly reduce urinary 6‐keto‐PGF1α and TXB2 excretion rates. Reduced excretion of PGF2α was observed on both study days during treatment with IND and SUL. SUL treatment also resulted in increased urinary PGE2 excretion while significantly reducing 6‐keto‐PGF1α excretion on day 7. Significant differences were observed between the NAB and SUL regimens with respect to PGF2α excretion and between the NAB and SUL regimens for PGE2, PGF2α, 6‐keto‐PGFα1 (on day 1 only) and TXB2 (on day 1 only). Neither NAB nor SUL caused inhibition of CIPA or bleeding time although platelet aggregation was inhibited during IND treatment. That NAB treatment was neither associated with alterations in platelet function nor decreases in the urinary excretion of the vasodilatory prostaglandins, PGE2 and 6‐keto‐PGF1α, suggests that NAB possesses renal sparing properties.

Effect of Intravenous Fenoldopam on Intraocular Pressure in Ocular Hypertension

Intravenous fenoldopam, a selective dopamine‐1 receptor agonist, was compared with placebo in this randomized, double‐blind, two‐period crossover study to evaluate its effects on intraocular pressure, aqueous dynamics, and macular blood flow in patients with elevated intraocular pressure or primary open‐angle glaucoma. Doses of fenoldopam were titrated up to a maximum of 0.5 μg/kg/min. Intraocular pressure, measured by pneumotonometry, was the primary outcome variable. Other outcomes included macular blood flow assessed by blue field examination, visual field examined by automated perimetry, aqueous outflow facility measured by tonography, and aqueous humor production determined by fluorophotometry. During infusions of fenoldopam, intraocular pressure increased from a mean baseline level of 29.2 mmHg to a mean maximum level of 35.7 mmHg. During the placebo infusions, pressure increased from a mean baseline of 28.4 mmHg to a mean of 29.0 mmHg at the time point that corresponded to the mean maximum intraocular pressure on the day intravenous fenoldopam was administered, to yield a mean difference in pressure between study days of 6.7 mmHg (P <0.05). There were no apparent changes in macular blood flow, visual fields, or production or outflow of aqueous humor associated with fenoldopam infusion. The increase in intraocular pressure seen in this population of patients with ocular hypertension during infusions of fenoldopam is consistent with fenoldopam‐associated increases in intraocular pressure reported in previous studies of healthy volunteers and of patients with accelerated systemic hypertension. These results further suggest that dopamine‐1 receptors play a role in the regulation of intraocular pressure.

Effect of renal impairment on disposition of pentopril and its active metabolite

Disposition of pentopril was studied in 15 male volunteers with varying renal functions. Mild to moderate compromise in renal function did not demonstrate any appreciable changes in plasma concentration of pentopril, the prodrug ester of the active angiotensin–converting enzyme (ACE) inhibitor CGS 13934. This is consistent with the known elimination pattern for pentopril, which is eliminated primarily by hydrolysis to the active inhibitor. In contrast, the plasma concentration of the active ACE inhibitor was sensitive to moderate changes in renal function. Because of the reciprocal relationship of AUC and clearance, AUC did not change to any appreciable extent until creatinine clearance (CLCR) dropped to about 50 ml/min. Below 50 ml/min of CLCR, AUC and half‐life increased sharply with reduced kidney function. Because of the significant contribution of the renal secretion process to total renal elimination of both pentopril and the active metabolite, prediction of renal clearance from CL CR was poor at relatively normal kidney function (CL CR > 80 ml/min). However, renal secretory clearances for both pentopril and metabolite were well correlated to p‐aminohippuric acid clearance. In patients with moderately compromised renal function (glomerular filtration rate < 40 ml/min), tubular secretion rate of creatinine approaches its glomerular filtration rate and hence CLCR could be used as a predictor of renal clearance and other disposition parameters. Plasma ACE activity also demonstrated prolonged inhibition with decreased renal function. Based on the prolonged blockade of plasma ACE activity, some correction in dose or dosing interval is anticipated in patients with moderately compromised renal function (CLCR < 50 ml/min).

Multiple-Dose Kinetics and Dialyzability of Oxazepam in Renal Insufficiency

7 patients with chronic renal insufficiency (4 of whom were on maintenance hemodialysis) and 6 healthy controls received single 15-mg oral doses of oxazepam for 7 consecutive days. Multiple venous blo

Controlled study of renal osteodystrophy in patients undergoing dialysis: Improved response to continuous ambulatory peritoneal dialysis compared with hemodialysis

To assess the effect of different dialysis modalities on renal osteodystrophy, a controlled study was performed in six patients undergoing continuous ambulatory peritoneal dialysis and six hemodialysis-treated patients. All patients were enrolled at the initiation of dialysis, and age, sex, cause of renal failure, prior treatment of renal osteodystrophy, and baseline serum and bone histologic variables were similar in the two groups. After initial blood samples and bone biopsy specimens (with double-tetracycline labels) were obtained, renal osteodystrophy in both groups received comparable treatment with aluminum hydroxide to maintain serum phosphorus levels between 3.5 and 5.5 mg/dl, and with calcium carbonate and calcitriol to maintain total serum calcium levels between 10 and 11 mg/dl. Blood and bone samples were obtained again after nine months. All patients were asymptomatic at the beginning and end of the study. Phosphorus values were well controlled, and total calcium increased similarly in both groups. Although ionized calcium levels increased in both groups, the final level was higher in hemodialysis-treated patients than in patients undergoing continuous ambulatory peritoneal dialysis (2.82 +/- 0.07 meq/liter and 2.5 +/- 0.05 meq/liter, respectively; p = 0.005). Amino-terminal parathyroid hormone levels normalized in both groups, and histologic improvement of osteitis fibrosa occurred in a similar proportion of patients in both groups; however, quantitative improvement was greater in the hemodialysis-treated patients. Osteomalacia, assessed qualitatively and by dynamic histomorphometric measurements, was ameliorated to a much greater degree in patients undergoing continuous ambulatory peritoneal dialysis compared with hemodialysis-treated patients. Bone aluminum staining was absent in all biopsy specimens. Overall, bone histologic findings improved to a greater degree in patients undergoing continuous ambulatory peritoneal dialysis. When patients undergoing continuous ambulatory peritoneal dialysis or hemodialysis and receiving similar treatment for renal osteodystrophy were compared, patients treated with continuous ambulatory peritoneal dialysis appeared to have a greater improvement in their metabolic bone disease.