Menger Chung

Study of single and multiple dose pharmacokinetic/pharmacodynamic modeling of the antihypertensive effects of labetalol

This was an open-label, two-phase crossover study of labetalol in 11 patients with mild to moderate hypertension. A two- to four-week outpatient placebo phase was followed by a three-day inpatient placebo period. Patients were then randomly assigned to receive either labetalol, 200 mg, as a single dose and three times a day for three days and, on the final day, another single dose or a similar sequence with 300 mg as the single dose and multiple twice a day treatment. A two-week placebo outpatient period was followed by the second phase of the study in which the treatment regimen was reversed for the two groups. Blood samples for the determination of free and conjugated labetalol plasma levels were collected, and blood pressures and heart rate were recorded sequentially for 24 hours after the first and last dose of labetalol, and during the multiple dose treatment period before and two hours after each dose as well as four times daily with the patient supine and upright. Of the 11 patients analyzed, five were men and six were women, ranging in age from 33 to 62 years. Labetalol (200 mg and 300 mg) was rapidly absorbed with peak concentrations achieved in approximately one hour. The pharmacokinetic data best fit a two-compartment pharmacokinetic model with first order absorption. At steady state, the absorption, distribution, and elimination kinetics were similar for both dosage regimens with elimination half life of 7.65 and 7.92 hours for the 200 mg three times a day and 300 mg twice a day regimens, respectively. During the multiple dosing period average steady-state plasma drug concentrations were 0.149 mg/ml and 0.145 mg/ml for the 300 mg twice a day and 200 mg three times a day regimens, respectively. Approximately 12 percent of total plasma labetalol was free drug. The balance was conjugated. The first dose of 200 mg or 300 mg of labetalol significantly (p less than 0.01) lowered standing and supine mean blood pressure over a period of eight to 12 hours, respectively, with peak effects occurring at two (standing) and four (supine) hours. A significant reduction (p less than 0.01) in supine mean blood pressure was present 24 hours after the initial dose of 300 mg. At steady state the antihypertensive effects of the 200 mg three times a day and the 300 mg twice a day dosage regimens were similar.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical pharmacology of netilmicin in preterm and term newborn infants

Sixty-four neonates, with gestational age ranging from 27 1/2 to 40 weeks, postnatal age from 1 to 15 days, and birth weight from 800 to 3400 gm, were given netilmicin 2.5 mg/kg intramuscularly two or three times per day according to postnatal age, for 5 to 14 days. Serum concentrations were measured before and 1 hour after a dose at least twice during treatment. The serum washout profile of the drug was observed in 22 neonates after discontinuation of therapy. Renal function was studied in 37 infants by measuring serum creatinine concentrations and in 27 by urinary excretion of N-acetyl-glucosaminidase during and up to 15 days after therapy. Behavioral and impedance audiometry, and in infants failing those, auditory brainstem evoked response tests, were performed between 6 and 12 months of age. In 23.5% of the neonates, trough serum levels were greater than 3 micrograms/ml. The serum washout followed a multiexponential decay, accounting for distributional, rapid (initial), and slow (tissue) elimination phases. Linear regression analysis performed between each kinetic parameter and gestational age or birth weight showed that initial elimination half-life, steady-state volume of distribution, and total body clearance were significantly correlated with both variables. Netilmicin did not cause detectable renal or auditory damage.

Effect of sleep on quazepam kinetics

The effect of sleep on quazepam kinetics was studied in 12 normal adult men. In a randomized two‐way crossover design, each subject received one 15‐mg quazepam tablet either at night just before sleep or in the morning after a nights sleep. Blood samples were drawn before and at specified times (to 120 hr) after dosing. To assure that blood collection did not interfere with sleep, blood was drawn by an indwelling catheter from a large arm vein. Plasma concentrations of quazepam and its two major plasma metabolites (which are also active) 2‐oxoquazepam and N‐desalkyl‐2‐oxoquazepam (N‐desalkylflurazepam) were determined by specific GLC methods. Kinetic analysis was by a two‐compartment open model with first‐order absorption/formation kinetics. Quazepam was rapidly absorbed with both administration times; absorption t½ was 0.7 to 0.9 hr. Absorption lag time was slightly longer after the nighttime dose (1.0 and 0.6 hr). Maximum concentration and AUC of quazepam and 2‐oxoquazepam and AUC of N‐desalkyl‐2‐oxoquazepam were somewhat higher after nighttime dosing, most likely a result of decreased apparent volume of distribution of the central compartment after the nighttime dose (5.0 l/kg for nighttime dosing and 8.6 l/kg for morning dosing). The elimination t½s of quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam after the morning dose were 25, 28, and 79 hr, which did not differ from those values after the nighttime dose. In general, time of dosing had no appreciable effect on quazepam kinetics or those of its major active plasma metabolites. The small differences between the two dose times are not expected to have clinical significance.

Multiple‐dose quazepam kinetics

Quazepam, a benzodiazepine hypnotic, was studied in normal subjects to evaluate steady‐state kinetics of quazepam and of its major active plasma metabolites, 2‐oxoquazepam and N‐desalkyl‐2‐oxoquazepam, after 15 mg once daily by mouth for 14 days. The kinetics of quazepam and 2‐oxoquazepam can be best described by a two‐compartment open model with first‐order absorption/formation kinetics. Quazepam was rapidly absorbed and its two major plasma metabolites appeared very quickly in systemic circulation. The elimination t½ of quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam were 41, 43, and 75 hr. Steady‐state levels were predictable from the kinetic data and were reached by the seventh dose for quazepam and 2‐oxoquazepam and by the thirteenth dose for N‐desalkyl‐2‐oxoquazepam. These kinetic profiles may explain the clinical hypnotic effect of quazepam—rapid induction of sleep and long duration of clinical action without appreciable rebound insomnia.

Multiple‐Dose Albuterol Kinetics

Albuterol a beta‐adrenergic agonist bronchodilator, was studied in 12 healthy male volunteers to evaluate the steady‐state pharmacokinetics following oral administration of 4‐mg tablets, given every six hours for five days. The kinetics of albuterol were best described by a two‐compartment open model with first‐order absorption kinetics. Steady‐state plasma levels were predictable from the kinetic data and were reached by the third day of dosing (ninth and tenth dose). Small accumulation ratios of approximately two were seen based on area under the plasma concentration‐time curve and maximal and minimal concentration data. The elimination phase half‐life was determined to be 6.5 hours, which is similar to the values reported following single‐dose administration.

Quazepam kinetics in the elderly

The kinetics of quazepam, a benzodiazepine hypnotic, was studied in 10 geriatric subjects. Each received one 15‐mg tablet of quazepam. Blood samples were collected before and at specified times (up to 672 hr) after dosing. Plasma concentrations of quazepam and its two major active plasma metabolites, 2‐oxoquazepam and N‐desalkyl‐2‐oxoquazepam (N‐desalkylflurazepam), were determined by specific GLC methods. Kinetics were best described by a two‐compartment open model with first‐order absorption/formation kinetics and standard equations. Quazepam was rapidly absorbed, with a t½ of 0.8 hr. The mean maximum plasma level (Cmax) was 29.3 ng/ml. The disposition t½s in the distribution (t½α) and elimination (t½β) phases were 3.5 and 53.3 hr. 2‐Oxoquazepam was rapidly formed with quazepam, with an apparent formation t½ of 0.8 hr. Mean Cmax was 14.5 ng/ml. The t½α and t½β of 2‐oxoquazepam were 4.2 and 43.1 hr, of the order of those of quazepam. The t½β of N‐desalkyl‐2‐oxoquazepam, formed from 2‐oxoquazepam, was 189.7 hr, much longer than that of its precursor. Comparison of these data with reported kinetic data in young subjects shows that t½βs of quazepam and 2‐oxoquazepam increased only slightly or not at all with age, but that the t½β of N‐desalkyl‐2‐oxoquazepam in the elderly was more than twice that in young subjects.

Rising Multiple-Dose Pharmacokinetics of Labetalol in Hypertensive Patients

Labetalol a drug possessing both alpha‐ and beta‐adrenergic blocking activities, is used in the treatment of hypertension. The current study was undertaken to elucidate the steady‐state pharmacokinetics of labetalol following a rising oral multiple‐dosage regimen. Twelve patients received oral labetalol every 12 hours for 18 days. An initial dose of 100 mg was increased at three‐day intervals to 200, 300, 400, and 600 mg q12h. Selected blood samples were taken at various times following drug administration at each dose level and analyzed for labetalol levels by a specific high‐performance liquid chromography assay. The pharmacokinetics of labetalol are best described by a two‐compartment open model with first‐order absorption. The half‐lives of the absorption, distribution, and elimination phases are 0.6, 1.3, and 8.3 hours, respectively. The steady‐state plasma drug concentrations are predictable from the pharmacokinetic data and are in good agreement with the observed values. Steady‐state levels are reached by the third day at each dose level studied and increase proportionally with dose.

Multiple‐dose halazepam kinetics

Halazepam is a benzodiazepine used in the management of anxiety disorders or short‐term relief of anxiety. Our study was undertaken to evaluate its steady‐state kinetics and those of its major active plasma metabolite N‐desalkylhalazepam. Eleven healthy men aged 19 to 35 yr were given oral, 40‐mg halazepam tablets every 8 hr for 14 days. Plasma samples were analyzed by gas chromatography to determine levels of halazepam and N‐desalkylhalazepam. Halazepam kinetics can best be described by a two‐compartment open model with first‐order absorption kinetics. The elimination phase t½s of halazepam and N‐desalkylhalazepam were 34.7 and 57.9 hr. Steady‐state levels were predictable from kinetic data and were reached by the third day for halazepam and by the eleventh day for N‐desalkylhalazepam.

Pharmacokinetic study of sisomicin in humans

Detailed analyses of the pharmacokinetics of sisomicin administered at doses of 25, 50, and 100 mg intravenously and intramuscularly to healthy volunteers established that the drug is handled by a two-compartment open model system with a disposition (elimination) half-life of 2.6 hr. The kinetic estimates over this dose range are linear and independent of dose and were verified by a 60-min infusion experiment in which dose and the maximum serum concentration achieved (5 μg/ml) were predicted correctly. Sisomicin was rapidly distributed to the tissue compartment, and equilibrium between the central and the tissue compartment was established by 30 min after dosing. Renal clearance (55 ml/min) of sisomicin was about 30% less than total body clearance (78 ml/min). Total urinary excretion of sisomicin during a 24-hr period following drug administration was about 70% of the dose. The disposition kinetics of sisomicin following intramuscular administration are similar to those obtained following rapid intravenous administration. Intramuscular bioavailability of sisomicin for the doses of 25, 50, and 100 mg was greater than 95%. Based on these results, various initial loading infusion doses and maintenance infusion rates were calculated to provide specific desired peak and steady-state serum sisomicin concentrations rapidly. The purpose was not to expose patients to potentially toxic high peak concentrations of drug while maintaining these concentrations during the current therapeutic dosing intervals of 8 to 12 hr.