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K A DeSante

Publications and source records attributed to K A DeSante.

At least 19 recordsLinked to original sources
PubMed1998

Why rate of absorption inferences in single dose bioequivalence studies are often inappropriate.

PURPOSE: Peak drug concentration (Cmax) measures the extremity of drug exposure and is a secondary indicator of the extent of absorption after area under the concentration time curve (AUC). Cmax serves as the indicator of absorption rate in bioequivalence (BE) studies in the US (1). The use of Cmax, not the time to Cmax (Tmax), as the metric to assess absorption rate causes erratic inferences in BE studies, and incorrect conclusions for some. We can improve BE efficiency (i.e., get the answer right the first time), by properly analyzing the time to Cmax (Tmax) instead of Cmax. METHODS: We have previously redirected attention to Tmax as the unconfounded absorption rate variable, instead of Cmax, and have called for equally spaced sampling times during the suspected absorption phase to improve the performance of the rate metric (2). Equal spacing converts Tmax easily into a count variable and we illustrated an appropriate statistical analysis for counts. This paper provides some measurement theory concepts to help judge which is the more appropriate analysis, and also provides parametric confidence limits for Tmax treatment differences. Three separate BE studies are then analyzed by both methods. RESULTS: By focusing on the differences in conclusions, or inferences, this paper identifies three major issues with the current FDA "recommended" analysis of BE studies. First, Cmax, a continuous variable peak-height or extent measure has usurped Tmax's function and performs erratically as a substitute measure for the rate of absorption. Second, Tmax, should be analyzed as a discrete attribute, not as a continuous variable. Third, since several extent measures (AUC, Cmax), not one, are actually being analyzed, an adjustment for multiple testing is mandatory if we are to maintain the size of the test at the desired alpha level (13), and not inadvertently use a narrower bioequivalence window than is intended. These actions all can have serious unintended consequences on inferences, including making inappropriate ones.

Area Under Curve↗
PubMed1996

Tmax: an unconfounded metric for rate of absorption in single dose bioequivalence studies.

PURPOSE: While peak drug concentration (Cmax) is recognized to be contaminated by the extent of absorption, it has long served as the indicator of change in absorption rate in bioequivalence studies. This concentration measure per se is a measure of extreme drug exposure, not absorption rate. This paper redirects attention to Tmax as the absorption rate variable. METHODS: We show that the time to peak measure (Tmax), if obtained from equally spaced sampling times during the suspected absorption phase, defines a count process which encapsulates the rate of absorption. Furthermore such count data appear to follow the single parameter Poisson distribution which characterizes the rate of many a discrete process, and which therefore supplies the proper theoretical basis to compare two or more formulations for differences in the rate of absorption. This paper urges limiting the use of peak height measures based on Cmax to evaluate only for dose-dumping, a legitimate safety concern with any formulation. These principles and techniques are illustrated by a bioequivalence study in which two test suspensions are compared to a reference formulation. RESULTS: Appropriate statistical evaluation of absorption rate via Tmax supports bioequivalence, whereas the customary analysis with Cmax leads to rejection of bioequivalence. This suggests that the inappropriate use of Cmax as a surrogate metric for absorption rate contributes to the unpredictable and uncertain outcome in bioequivalence evaluation today.

Absorption↗
PubMed1994

Sensitive and specific radioimmunoassay for fialuridine: initial assessment of pharmacokinetics after single oral doses to healthy volunteers.

Fialuridine (FIAU) is a halogen-substituted analog of thymidine that was undergoing clinical investigation as a drug for the treatment of chronic hepatitis B viral infection. However, clinical trials of FIAU were terminated after adverse events occurred following chronic oral administration. Prior to the termination of clinical trials, a sensitive assay was needed for the measurement of FIAU because of the anticipated low dose administered to patients. We therefore undertook the development of a radioimmunoassay (RIA). A specific antiserum was raised in rabbits following immunization with a 5'-O-hemisuccinate analog of FIAU coupled to keyhole limpet hemocyanin. Radiolabeled FIAU was synthesized by a destannylation procedure by using sodium [125I]iodide. We developed a competitive-binding procedure and used precipitation with polyethylene glycol as the method for separating the bound and free forms of FIAU. The RIA is sensitive (0.2 ng/ml), specific (negligible interference from known metabolites and endogenous nucleosides), and reproducible (interassay coefficients of variation range from 5 to 19.7% for serum controls). We used the RIA to assess the pharmacokinetics of FIAU in healthy adult volunteers following administration of a single 5-mg oral dose. The sensitivity of the RIA permitted the detection of a prolonged elimination phase for FIAU in healthy volunteers and dogs, with mean elimination half-lives of 29.3 and 35.3 h, respectively. We conclude the RIA is a valid method for the quantification of FIAU in biological fluids.

Administration, Oral↗
PubMed1993

Effects of renal dysfunction on the pharmacokinetics of loracarbef.

Loracarbef, the first carbacephem antibiotic to undergo clinical development, is excreted primarily unchanged in the urine (> 90%). Data analyzed from subjects with various degrees of renal dysfunction who were given single oral doses of loracarbef indicated a linear relationship between creatinine clearance (CLCR) and plasma clearance [CLP (L/hr) = 0.106.CLCR (ml/min/1.73 m2)]. The mean area under the plasma concentration-time curve in normal subjects and in patients with severe renal insufficiency (no dialysis/receiving dialysis) was 32 micrograms.hr/ml and 1085 micrograms.hr/ml/103 micrograms.hr/ml, respectively. Therefore, for individuals with moderate renal insufficiency (CLCR, 10 to 49 ml/min/1.73 m2), the dose should be halved or the dosing interval doubled; patients with severe renal insufficiency who are not receiving dialysis should be treated with the normal dose given once every 3 to 5 days. Loracarbef is readily cleared from plasma by hemodialysis; dosing should be repeated after a hemodialysis treatment.

Adult↗
PubMed1993

Pharmacokinetics of dirithromycin.

Dirithromycin is a new member of the macrolide class of antibiotics and has been developed for oral administration. Dirithromycin is a 14-membered lactone ring macrolide and is the C9-oxazine derivative of erythromycylamine. The human pharmacokinetics and clinical pharmacology of dirithromycin have been studied. Dirithromycin has unique pharmacokinetics which distinguish it from erythromycin. In man, following an oral 500 mg dose of dirithromycin, a mean peak plasma concentration (Cmax) of 0.48 mg/L (range 0.1-1.97) was observed at 4 h. The mean area under the plasma concentration versus time curve (AUC0-24h) measured 3.37 mg.h/L (range 0.39-17.16). No plasma accumulation was observed with multiple-dose administration. Dirithromycin may be taken without regard to meals, although food and H2-receptor antagonists may increase the systemic bioavailability in some patients. Based upon drug interaction studies performed with antipyrine and theophylline, dirithromycin has shown less potential to interact with other drugs metabolized by the cytochrome P450 system that does erythromycin. Plasma concentrations and AUCs were low due to rapid movement of the drug from the vascular space to the extravascular compartment, as reflected by tissue concentrations, which exceeded plasma concentrations 4 h after dosing. Dirithromycin achieves relatively high tissue concentrations (approximately 0.8-5.0 mg/kg) 4-24 h after dosing. The extensive tissue penetration is reflected in a large mean apparent volume of distribution of 800 L (range 504-1041). Dirithromycin is rapidly converted by non-enzymatic hydrolysis during absorption to erythromycylamine, which is microbiologically active. In a 14C-radiolabelled study, 60-90% of the administered dose was hydrolysed to erythromycylamine within 35 min of infusion. After 1.5 h, conversion to erythromycylamine in serum was virtually complete. Plasma protein binding was determined to be 15-30% by ultracentrifugation. Dirithromycin is characterized by a plasma elimination half-life of 44 h (range 16-65 h) that permits once-daily administration. Total body clearance was 226-1040 mL/min in the 14C-radiolabelled study. The primary route of elimination of dirithromycin/erythromycylamine was faecal/hepatic. Following intravenous administration, approximately 17-25% of the radioactivity appeared in the urine and 62-81% appeared in the stool, indicating predominantly hepatic excretion. With oral administration 1.2-2.9% of the radioactivity appeared in the urine and 81-97% in the stool. The major part of urinary excretion occurs within the first 48 h post-administration; however, urinary excretion of radioactivity lasted longer than 240 h. The absolute bioavailability calculated from dose-corrected urinary excretion data was 10% (6-14%).

Absorption↗
PubMed1992

Pharmacokinetic profile of loracarbef.

Loracarbef, the first beta-lactam antibiotic of the carbacephem class to undergo clinical evaluation, has been the subject of extensive clinical pharmacology studies. Loracarbef is well absorbed: virtually all of an orally administered dose is excreted in the urine unchanged. Following administration of a 400 mg capsule to adults twice a day for 10 days, no accumulation of drug is noted. In one study in children, following the administration of 15 mg/kg of loracarbef suspension, the mean maximum plasma concentration (Cmax) was 20.3 micrograms/mL. In adults, the Cmax following administration of the suspension or solution formulations is higher than that achieved following administration of the capsule formulation, and the time to reach peak concentration (Tmax) is increased when loracarbef is administered as a capsule; however, the area under the curve, plasma half-life, and percentage of oral dose excreted in the urine are comparable among all formulations. The ingestion of food decreases the Cmax and delays the Tmax compared with the fasting state. The pharmacokinetic profile of loracarbef in adults is comparable with that in children or the elderly. Because loracarbef is eliminated primarily by the kidney, dosage must be reduced in patients with moderate-to-severe renal insufficiency. Loracarbef achieves middle-ear and interstitial-fluid levels that generally exceed the minimum inhibitory concentrations for common bacterial pathogens. Loracarbef possesses a pharmacokinetic profile consistent with the efficacy and safety profile documented in controlled clinical trials.

Adult↗
PubMed1992

Pharmacokinetics of cefaclor AF: effects of age, antacids and H2-receptor antagonists.

The pharmacokinetics and bioavailability of cefaclor advanced formulation (cefaclor AF) were investigated in two studies, one comparing healthy elderly and younger volunteers and the other assessing the effects of an antacid and H2-receptor antagonist on cefaclor AF bioavailability. The pharmacokinetics of a 750 mg dose of cefaclor AF were studied in 30 subjects ranging in age from 65 to 84 years and 10 control subjects 21-45 years of age. Compared with controls, elderly subjects exhibited higher plasma concentrations of cefaclor which were attributed to lower plasma clearance. There was a strong association between age and renal function, and the plasma clearance of cefaclor was highly dependent upon renal function. Thus, elderly patients with impaired renal function had a reduced ability to eliminate cefaclor. Due to a short elimination half-life and wide therapeutic index, dosage adjustments are not necessary in patients exhibiting moderate renal dysfunction. The 15 healthy men in the second trial were crossed over to receive five treatments, including cefaclor AF (500 mg) alone, cefaclor AF with or preceded by cimetidine, cefaclor AF followed by Maalox TC and cefaclor immediate release (500 mg) alone. Cefaclor AF and immediate release cefaclor had similar bioavailability, but plasma concentrations were maintained for a longer period of time when cefaclor AF was administered. Cimetidine did not alter the bioavailability of cefaclor AF but Maalox TC, coadministered with cefaclor AF, reduced the extent of absorption. This suggests that cefaclor AF bioavailability is influenced by the antacid Maalox TC but not by H2-receptor antagonist cimetidine.

Adult↗
PubMed1992

Sensitive, specific radioimmunoassay for quantifying pergolide in plasma.

Pergolide, a synthetic ergoline with potent dopaminergic activity, is used to treat Parkinson disease. The low plasma concentrations of pergolide achieved during therapy complicate the development of a method for its analysis. Because radioimmunoassay successfully measures other structurally related ergolines in physiological fluids, we undertook the development of a radioimmunoassay of pergolide. The detection limit of the radioimmunoassay is 21 ng/L with an optimal working range from 100 to 1000 ng/L. We maximized assay specificity by using a monoclonal antibody that displayed low cross-reactivity with pergolide sulfoxide, a major metabolite found in animals. The radioimmunoassay has performed acceptably for > 2 years during toxicology studies with rats and rhesus monkeys and in clinical studies involving patients with Parkinson disease. We consider the radioimmunoassay a valid method for quantifying therapeutic concentrations of pergolide in plasma.

Animals↗
PubMed1989

Clinical pharmacokinetics of pinacidil, a potassium channel opener, in hypertension.

Pinacidil is a potassium channel opener that decreases blood pressure by reducing peripheral arterial resistance. In two multicenter trials, we studied the concentrations and apparent clearance of pinacidil (406 patients) and concentrations of its pyridyl-N-oxide metabolite (147 patients). Responding patients had plasma samples collected hourly for 12 hours on 2 occasions after weeks to months of treatment. Pinacidil dose was titrated from 12.5 to 75 mg b.i.d. The peak concentration of pinacidil and N-oxide and the area under the concentration-time curve (AUC) were proportional to the dose of pinacidil, with an average pinacidil concentration of 268 micrograms/L (1.02 microM) and N-oxide concentration of 172 micrograms/L (0.65 microM) for every 1 mg/kg pinacidil administered. Clearance of pinacidil (Clp = Dose/AUC) was 31 L/hr in patients younger than 45 years and 27 L/hr in those older than 60. Clp was significantly smaller in white patients compared with other races (Clp = 28 vs. 34 L/hr). Clp was significantly less in patients taking hydrochlorothiazide (27 vs. 31 L/hr) and greater in smokers (33 vs. 29 L/hr). Concomitant propranolol use did not influence Clp.

Adult↗
PubMed1988

Disposition of [14C]pinacidil in humans.

Pinacidil [(+/-)-2-cyano-1-(4-pyridyl)-3-(1,2,2-trimethylpropyl)guanidine monohydrate] is a novel, direct-acting vasodilator antihypertensive agent. The cyano 14C-labeled drug is rapidly and completely absorbed after an oral 12.5-mg dose in solution. The blood:plasma concentration ratios (0.8-0.9) indicate transient penetration of radioactivity into blood cells. Blood and plasma tmax (0.5 h) and t 1/2 (4 h) of [14C]pinacidil equivalents are similar. Pinacidil (51%), pinacidil N-oxide (28%), and unidentified polar metabolites (21%) comprise the plasma radioactivity. The plasma t 1/2 of pinacidil is 2-3 h, and that of pinacidil N-oxide is 4-5 h. Renal excretion of radioactivity is the major route (80-90% dose) of drug elimination; fecal elimination accounted for 4% of the dose. Renal clearance of the N-oxide is 10 times the renal clearance of the parent drug and exceeds the creatinine clearance. Biotransformation products in 0-24-h urine samples include pinacidil (10%), pinacidil N-oxide (60%), and free and conjugated analogues of pinacidil and metabolites (30%). Stereoselective metabolism is not a major biotransformation pathway of pinacidil or the N-oxide metabolite.

Adult↗
PubMed1982

Benoxaprofen kinetics in renal impairment.

To establish therapeutic guidelines, benoxaprofen kinetics were examined in 26 adult subjects with normal and decreased renal function. Mean peak plasma concentrations after a single 600-mg dose ranged from 58 to 72 mg/l, independent of renal function. Elimination half-life and benoxaprofen plasma clearance correlated with creatinine clearance. Hemodialysis did not remove benoxaprofen from plasma. A dosage nomogram was derived from which a dose one half of the normal maintenance dose was suggested for patients with severe renal failure.

Adult↗
PubMed1982

Effect of probenecid on the pharmacokinetics of moxalactam.

The effects of probenecid on the pharmacokinetics of moxalactam were studied in normal volunteers administered a 2-min l-g intravenous infusion. The results showed that probenecid did not alter the plasma or urinary concentrations of moxalactam, its apparent volume of distribution, plasma elimination half-life, elimination rate constant, or plasma and renal clearances. Therefore, moxalactam appears to be eliminated primarily by the kidney via glomerular filtration.

Adult↗
PubMed1982

Single- and multiple-dose pharmacokinetics of moxalactam in normal subjects.

The pharmacokinetics of moxalactam were studied in 86 normal adult male volunteers who received single or multiple doses intravenously or intramuscularly. The short absorption half-times and lag times indicate that the intramuscular dose is rapidly absorbed. The mean plasma half-life was 1.85 +/- 0.24 h for intravenous doses and 2.24 +/- 0.44 h for intramuscular doses. The mean renal clearances for intravenous doses were 0.052 and 0.067 liters/kg per h for intramuscular doses. Although moxalactam is eliminated primarily by the kidney a chromatogram of the feces from volunteers who received multiple doses showed that it is also excreted as the parent compound in to the feces via the biliary tract. The pharmacokinetics parameters of moxalactam when administered intravenously or intramuscularly in single and multiple doses clearly show the kinetics of moxalactam are linear over the dosage ranges studied and are independent of dose.

Adult↗
PubMed1982

Clinical pharmacology of benoxaprofen.

Eating does not modify benoxaprofen blood concentrations. Combining benoxaprofen with tolbutamide does not significantly change plasma glucose, insulin, or tolbutamide concentrations. Probenecid, by blocking renal tubular secretion of benoxaprofen, increases the benoxaprofen half-life and decreases its renal clearance and urinary excretion. Excretion rate is halved in patients with severe renal impairment. Hemodialysis inefficiently lowers benoxaprofen plasma concentrations. Neither glomerular nor renal tubular function is affected by benoxaprofen, even after five years of therapy. The incidence in urine of microscopic spheroids (benoxaprofen glucuronide complexes) is related to urinary drug concentration and osmolality; increasing the fluid intake decreases incidence.

Adult↗
PubMed1981

Lincomycin serum and saliva concentrations after intramuscular injection of high doses.

Serum and saliva levels of lincomycin were determined in 15 normal adult male volunteers after a single intramuscular injection of 600, 1000, or 1500 mg lincomycin in a three-way crossover study. The area under the serum concentration-time curve did not increase in proportion to the increase in dose. The increase in concentration of lincomycin in saliva was greater than expected for the increase in dose. There were not significant differences in elimination half-life between doses. These results suggest that the apparent clearance of lincomycin increases with increasing dose possibly because of a decrease in serum protein binding of lincomycin at high serum concentrations.

Adult↗
PubMed1980

Pharmacokinetic interpretation of plasma cortisol and cortisone concentrations following a signle oral administration of cortisone acetate to human subjects.

The pharmacokinetic and biopharmaceutic profiles of a single dose of oral cortisone acetate were developed for 23 healthy normal adult volunteers using cortisone and cortisol plasma concentration data. Cortisone acetate was rapidly absorbed and converted to the therapeutic moiety cortisol. There was a linear increase in plasma concentrations and, therefore, areas under plasma concentration-time curves with increasing doses of 5, 10, and 25 mg. Twenty-five-mg doses given as 1 x 25 mg or 5 x 5 mg were found to be bioequivalent. The increased efficacy of oral over intramuscular cortisone acetate can be attributed to the increased conversion to cortisol as a result of first-pass metabolism following oral dosing.

Administration, Oral↗