Dyal C. Garg

Fluconazole Penetration into Cerebrospinal Fluid in Humans

One hour after intravenous doses of 50 mg/d fluconazole for 6 days or 100 mg/d for seven days to healthy subjects, the cerebrospinal fluid concentrations of fluconazole were 1.26 mg/L and 2.74 mg/L, respectively. These values were approximately 52% and 62% those of serum. Four patients with an initial clinical diagnosis of meningitis also had significant concentrations of fluconazole in the cerebrospinal fluid.

Nalmefene: Intravenous safety and kinetics of a new opioid antagonist

In a placebo‐controlled, double‐blind study we evaluated the safety and kinetics of a new narcotic antagonist, nalmefene, after 2, 6, 12, and 24 mg intravenous doses to healthy men. At each dose level four subjects received active drug and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, the most common of which was lightheadedness. The plasma concentration‐time data were best fit with a triexponential equation, and the terminal elimination phase had a harmonic mean t1/2of 8 to 9 hours. Only about 5% of the dose was excreted in the urine as intact nalmefene, with up to 60% excreted as nalmefene glucuronide. Although intersubject differences were noted, mean or dose‐normalized mean kinetic parameters such as clearance, steady‐state volume of distribution, terminal t1/2, and AUC showed no consistent trends related to increasing doses, indicating that nalmefene has linear pharmacokinetics.

Ranitidine bioavailability and kinetics in normal male subjects

Ranitidine is a potent histamine H2‐receptor blocker that inhibits histamine‐ and pentagastrin‐induced gastric acid secretion. After doses of 100 mg both intravenously and orally ranitidine kinetics and bioavailability were investigated in a single dose two‐way crossover study in 12 normal men. Serum concentrations of ranitidine were determined by radioimmunoassay and urine concentrations by an ion‐pair HPLC method. Intravenous data were fitted to exponential equations with the computer program NONLIN; model‐independent kinetic parameters were calculated. Elimination t½, plasma clearance, renal clearance, hepatic clearance, and volume of distribution for ranitidine after intravenous injection were 2 hr, 10.4 ml/(min × kg), 7.2 ml/(min × kg), 3.1 ml/(min × kg), and 1.82 l/kg, respectively; after oral doses mean t½ was 2.7 hr and mean bioavailability was 52%. The average cumulative urinary‐excretion of ranitidine as percent of dose was 69.4 ± 6.1% and 26.7 ± 7.2% after intravenous and oral doses.

Nalmefene: Safety and Kinetics After Single and Multiple Oral Doses of a New Opioid Antagonist

The aim of these two studies was to evaluate the safety and pharmacokinetics of oral nalmefene, a new orally effective opioid antagonist. In the first study, single ascending doses of 50, 100, 200, and 300 mg of nalmefene HCl were administered in double‐blind fashion to four groups of healthy men. There were six subjects in each group; four received nalmefene and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, such as lightheadedness, at the higher doses. Model‐independent pharmacokinetic analysis of the plasma concentration‐time dathowed that nalmefene was rapidly absorbed and had an elimination half‐life that ranged from seven to 15 hours (mean, 10.7 hr). There was a good linear relationship (r = .97) between administered dose and total area under the curve at each dose level. Only about 4% of the dose was excreted in the urine as unchanged nalmefene, whereas up to 60% was excreted as a β‐glucuronidase/sulfatase hydrolysable conjugate(s) of nalmefene. In the second study, six healthy men were initially administered a single 50‐mg dose of drug, and plasma samples were obtained at selected time intervals for 48 hours. A dosing schedule of 20 mg q12h was then started and continued for seven days. Plasma samples were collected immediately before each dose and at selected times for up to 48 hours after the last dose. The drug was well tolerated by all subjects, and no clinically significant adverse effects were observed during the seven‐day administration period. In most instances, the steady‐state plasma concentrations could be reasonably predicated from the single dose data and had a moderate accumulation factor (about 1.6). There was no significant difference in the mean half‐life following the first and last dose. Both studies indicate that orally administered nalmefene has a wide margin of safety in healthy men and exhibits a linear pharmacokinetic profile at the doses tested.

Pharmacokinetics of Single‐Dose Oral and Intramuscular Ketorolac Tromethamine in the Young and Elderly

The elderly are likely candidates to receive analgesics for pain from a variety of etiologies. Ketorolac tromethamine is a nonsteroidal, analgesic, anti‐inflammatory, antipyretic investigational drug with anti‐prostaglandin synthetase activity. Sixteen healthy, young men (mean age 30 years and mean weight 75 kg) and 13 healthy, elderly subjects (11 men and two women; mean age 72 years and mean weight 75 kg) participated in an open‐label, parallel single‐dose study. On each day of ketorolac tromethamine administration the subjects fasted overnight and for 2 hours post‐dose. A single intramuscular (IM) dose of 30 mg of ketorolac tromethamine was administered followed by an oral dose (PO) of 10 mg after a 1 week washout period for the elderly subjects. Plasma samples were taken from 0 through 48 hours post‐dose and analyzed for ketorolac by HPLC. The elimination of ketorolac was decreased slightly in the elderly following both doses, as evidenced by a prolongation in half‐life (4.7 to 6.1 hours for PO and 4.5 to 7.0 hours for IM) and a reduced total plasma clearance compared to the young adult subjects. These differences were statistically significant (P < .001). Considerable overlap frequently was observed when comparing the range of values obtained for the young and elderly for plasma half‐life, clearance, AUC, Tmax and Cmax. The absorption of ketorolac tromethamine was not altered substantially in the elderly following either dose route. Ketorolac plasma protein binding was not altered substantially in the elderly. The present results show that the elderly may need slightly less frequent dosing of ketorolac than young adults to maintain similar plasma levels. In these studies there has been no evidence of drug accumulation in the elderly after long‐term ketorolac tromethamine administration when given in a tid or qid regimen.

Short-Term Comparison of Once- versus Twice-Daily Administration of Glimepiride in Patients with Non-Insulin-Dependent Diabetes Mellitus

OBJECTIVE: To investigate the metabolic effects and frequency of adverse events with 6 mg of glimepiride, a new oral sulfonylurea, given both in once- and twice-daily dosages to patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: This 15-week study involved 161 subjects with NIDDM. Subjects were randomized into two groups. For 4 weeks, group 1 received glimepiride 3 mg twice daily, and group 2 received glimepiride 6 mg once daily. After a 3-week placebo-washout period, twice- and once-daily regimens were crossed over for a second 4-week treatment period. Subjects were hospitalized at the end of each placebo or active-treatment phase. Their glucose concentrations were recorded at 20 time points over a 24-hour period, and their insulin and C-peptide concentrations were recorded at 16 time points over the same period. Parameters that were calculated included fasting, 24-hour, and postprandial concentrations of glucose, insulin, and C-peptide. RESULTS: One hundred six patients were randomized to receive treatment; 94 completed the entire study. Existing physiologic mechanisms of glucose control were apparently unimpaired by glimepiride treatment. Insulin concentrations increased more during the postprandial glucose peaks than when subjects were fasting. Both twice- and once-daily regimens proved equally effective in reducing concentrations of fasting, postbreakfast, postlunch, and postdinner plasma glucose. Twenty-four-hour mean glucose concentrations showed a slightly greater decrease from baseline for the twice-daily regimen; the difference between the regimens was statistically significant but not clinically meaningful. The incidence of adverse events with glimepiride approximated that obtained with placebo, with both groups reporting only one adverse event, headache, in more than 5% of the subjects. CONCLUSIONS: Glimepiride is equally effective whether administered once or twice daily. Glimepiride seems to stimulate insulin production primarily after meals, when plasma glucose concentrations are highest, but controls blood glucose throughout the day.

Mechanisms of Impaired Potassium Handling With Dual Renin-Angiotensin-Aldosterone Blockade in Chronic Kidney Disease

The combination of an aldosterone receptor antagonist added to an angiotensin-converting enzyme inhibitor has been demonstrated to reduce cardiovascular and renal end points in hypertensive humans but can produce hyperkalemia in the common clinical setting of impaired renal function. We investigated the effects of dual therapy on acute and chronic potassium handling in hypertensive humans with renal impairment by conducting a randomized crossover clinical trial of 4 weeks of 40 mg lisinopril/25 mg spironolactone versus placebo in 18 participants with a glomerular filtration rate of 25 to 65 mL/min. Study end points, following an established protocol, were hourly determinations of dynamic renal potassium excretion (mmol/h) and serum potassium (mmol/L) after 35 mmol oral potassium challenge in addition to ambulatory potassium concentration. After 4 weeks, ambulatory potassium concentration was 4.87 mmol/L with lisinopril/spironolactone versus 4.37 with placebo (P<0.001). Lisinopril/spironolactone produced only a modest 0.44 mmol/h reduction in stimulated potassium excretion (P=0.03) but a substantial 0.67 mmol/L increase in serum potassium (P<0.001) in response to 35 mmol potassium; these findings are consistent with impaired extrarenal/transcellular potassium disposition. We found the increase in serum potassium after an oral potassium challenge to be a strong predictor of the increase in ambulatory potassium with lisinopril/spironolactone. Our study suggests that dual renin-angiotensin-aldosterone blockade may impair extrarenal/transcellular potassium disposition in addition to reducing potassium excretion in humans with renal impairment, and that acute changes in dynamic potassium handling are predictive of chronic changes in ambulatory potassium concentration with dual renin-angiotensin-aldosterone blockade.

Pharmacokinetics of Ranitidine Following Oral Administration With Ascending Doses and With Multiple‐Fixed Doses

The aim of these studies was to further delineate pharmacokinetic characteristics of ranitidine, a new histamine H2‐receptor antagonist In one study, ranitidine was administered orally to six normal men in increasing doses of 100 mg, 150 mg, 250 mg, and 400 mg weekly over a four‐week period. The peak serum concentrations increased with the corresponding increases in dose but the time needed to reach peak serum concentration did not vary significantly with increased doses. The pharmacokinetic parameters were calculated for each subject at each of the four dose levels. The total area under the curve (AUC) at the four different doses was linearly related to the dose for each individual subject; and a plot of AUC versus dose had a correlation coefficient of .886 (P < .001). The apparent plasma clearance did not vary with the increase in dose; and the average corrected clearance values ranged between 6.7 and 10 mL/(min × kg). Elimination half‐life was between 2.6 and 3.0 hours; and the volume of distribution (Vd area) was between 1.6 and 2.4 L/kg. About 35% of the ranitidine dose was excreted in the urine in the unchanged form over a 12‐hour excretion interval. In the second study, ranitidine was administered orally to 12 normal subjects in doses of 150 mg and 200 mg twice daily for 28 days. The pharmacokinetic parameters for ranitidine with multiple‐dose treatment were similar to those obtained with single‐dose administration. Predose ranitidine concentrations (trough levels) did not increase with multiple dose administration. These studies indicate that the pharmacokinetics of ranitidine are linear in the dose range of 100 mg to 400 mg, and were similar with both single‐ and multiple‐dose administrations.

Pharmacokinetics of ranitidine in patients with renal failure

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6–54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378–808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half‐life following oral administration was 8.5 ± 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% ± 10.5%. After IV administration, the elimination half‐life, plasma clearance, renal clearance, and volume of distribution were 7.0 ± 1.0 hours, 170 ± 38 mL/min, 36.0 ± 25.0 mL/min, and 1.3 ± 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P < .05) after IV administration. The elimination half‐life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2‐blocking activity.

PHARMACOKINETICS OF CEFPROZIL IN HEALTHY SUBJECTS AND PATIENTS WITH HEPATIC IMPAIRMENT

The pharmacokinetics of cefprozil were studied in 12 (9 men, 3 women) subjects with hepatic impairment and in 12 healthy subjects who were matched for age, sex, and weight. Each subject received a single 1000 mg oral dose of cefprozil, which consists of cis and trans isomers in approximately a 90:10 ratio. Serial blood and urine samples were collected and analyzed using validated HPLC/UV methods for the concentration of each isomer. The results of the plasma and urine analyses were subjected to noncompartmental pharmacokinetic analysis. The values for the peak plasma concentrations (Cmax), area under the plasma concentration versus time curve (AUC0–∞), apparent total body clearance (Clt/F), renal clearance (Clr), and percent of drug excreted in urine (% UR) of each isomer were not significantly different in healthy subjects and patients with hepatic impairment. The only parameters that were significantly (P ≤ .05) longer in patients with hepatic impairment were mean residence time in the body (MRT) and half‐life; the MRT for the cis isomer in healthy subjects and subjects with hepatic impairment were 3.33 hr and 3.88 hr, respectively, and for the trans isomer 3.17 hr and 3.68 hr; the half‐life for the cis isomer was 1.62 hr and 2.22 hr, respectively, and for the trans isomer 1.21 hr and 1.54 hr. The pharmacokinetics of the cis and trans isomers of cefprozil were virtually identical in healthy subjects as well as those with hepatic impairment. The results of the study showed that the pharmacokinetics of cefprozil are not significantly affected in patients with hepatic dysfunction, and as a result, the dosage of cefprozil does not require adjustment in patients with hepatic dysfunction.