William G. Kramer

Effect of cardiopulmonary bypass on fentanyl distribution and elimination

Fentanyl kinetics was studied in two groups of six patients, one group undergoing surgery with and one without cardiopulmonary bypass; the latter served as the controls. Plasma fentanyl concentrations declined biexponentially in the control patients with an average half‐life (t½β) of 3.3 ± 1.1 hr, total plasma clearance of 11.2 ±3.4 ml/min/kg, and volume of distribution (Vdβ) of 3.2 ± 1.5 l/kg. The plasma concentration/time curves were severely disrupted during cardiopulmonary bypass but appeared to regain a log‐linear decay once bypass was complete. This elimination phase had a t½ of 5.2 ± 2.7 hr, longer than that in the control patients. Since fentanyl is eliminated primarily by hepatic metabolism, decreased liver plasma flow observed during and after bypass, as evidenced by a 30% decrease in indocyanine green clearance, may contribute to the extended t½. The prolonged t½ has clinical importance because of potentially prolonged effects and their relation to other drugs and the clinical management of the patient.

The pharmacodynamics of intravenous and oral torsemide in patients with chronic renal insufficiency

The pharmacodynamics of intravenous and oral torsemide were determined in two randomized crossover clinical trials in patients with chronic renal insufficiency. There was no significant difference in the rate or magnitude of the diuretic response between oral and intravenous administration. As has been shown with other loop diuretics, patients with chronic renal insufficiency have a reduced diuretic response compared with healthy subjects. This diuretic resistance is primarily related to a diminished delivery of drug to the urinary site of action. The response of torsemide at the tubular level is not different from that seen in subjects with normal renal function. Metabolites of torsemide do not appear to contribute to the diuretic response. A dose of 50 to 100 mg dependent on renal function is required to obtain a maximal response. A ceiling dose of approximately 100 mg in patients with chronic renal insufficiency is therefore recommended.

Safety, tolerability, and pharmacokinetics of eliglustat tartrate (Genz-112638) after single doses, multiple doses, and food in healthy volunteers.

Three phase 1 studies of eliglustat tartrate (Genz‐112638), an oral inhibitor of glucosylceramide synthase under development for treating Gaucher disease type 1 (GD1), evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after escalating single doses (n = 99), escalating multiple doses (n = 36), and food (n = 24). Eliglustat tartrate was well tolerated at single doses ≤20 mg/kg and multiple doses ≤200 mg bid, with 50 mg bid producing plasma concentrations in the predicted therapeutic range. No serious adverse events occurred. Mild to moderate events of nausea, dizziness, and vomiting increased in frequency with escalating single and multiple doses. Single doses ≥10 mg/kg caused mild increases in electrocardiogram PR, QRS, and QT/QTc intervals. Single‐dose pharmacokinetics showed dose linearity but not proportionality. Maximum plasma concentrations occurred at ∼2 hours, followed by a monophasic decline with a ∼6‐hour terminal half‐life. Unchanged drug in 8‐hour urine collections was <1.5% of administered doses. Food did not significantly affect the rate or extent of absorption. Multiple‐dose pharmacokinetics was nonlinear, showing higher than expected plasma drug concentrations. Steady state was reached ∼60 hours after bid dosing. Higher drug exposure occurred in slower CYP2D6 metabolizers. Based on favorable results in healthy participants, a phase 2 trial of eliglustat tartrate was initiated in GD1 patients.

Safety, Tolerability, and Pharmacokinetics of KNS-760704 (Dexpramipexole) in Healthy Adult Subjects

Dexpramipexole (KNS‐760704; [6R]‐4,5,6,7‐tetrahydro‐N6‐propyl‐2,6‐benzothiazole‐diamine) is a novel synthetic amino‐benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single‐dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half‐life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%–90% of dose). Food had no effect on the single‐dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compounds therapeutic potential in other neurodegenerative diseases.

The Effect of Obesity on Acetaminophen Pharmacokinetics in Man

Abstract: This study examined the absorption and disposition of orally administered acetaminophen in morbidly obese patients as compared to subjects of normal weight, and possible changes in disposition as the patients underwent weight reduction through dietary modification. The overall disposition of acetaminophen was not affected by a weight loss of 8 to 30 kg; elimination half‐life, time to reach the peak, and peak plasma concentration varied within each subject but not in a systematic way. The half‐life was the same in the obese patients (2.6 ± 0.85 hours) and normal subjects (2.6 ± 0.12 hours). However, maximum plasma concentrations were reached at a significantly later time and were significantly lower in the obese patients as compared to the normals, implying an apparently lower absorption rate. The area under the plasma concentration‐time curve for the obese patients when normalized to ideal body weight was more consistent with that in the normal subjects than when normalized to total body weight. Administration of a normal dose of acetaminophen to an obese patient should yield plasma levels in the same range as persons of normal weight. As total weight may exceed 200 per cent of the ideal weight in this patient group, dosing according to total rather than ideal weight could lead to toxic or lethal effects when using the 10 mg/kg dosing recommendation.

Comparative Bioavailability of Intravenous and Oral Chloramphenicol in Adults

Abstract: The comparative bioavailability of chloramphenicol from intravenous succinate, oral palmitate, and oral base preparations was studied in a crossover manner in 12 adult patients. Chloramphenicol was administered at a dose of 1 Gm every 6 hours, and blood samples were collected at steady state. For the succinate study, total urine output was also collected. The bioavailability of active chloramphenicol from the succinate preparation averaged 85.8 ± 42.3 and 78.8 ± 50.1 per cent of the free base and palmitate forms, respectively. This lower availability appeared to be due to variable excretion of unchanged succinate in the urine, averaging 27 ± 11 per cent of the dose. Regardless of dosage form or route of administration, plasma chloramphenicol concentrations remained in the therapeutic range (5 to 25 mg/liter) for the entire dosage interval, implying that no change needs to be made when changing dosage form or route of administration. The interpatient variability, however, supports the need for monitoring of plasma chloramphenicol concentrations, especially in newborn infants, persons with liver disease, or those receiving other medications that alter chloramphenicol metabolism.

The pharmacokinetics of bleomycin in man.

A series of studies were carried out to investigate the pharmacokinetics of the antineoplastic antibiotic bleomycin in patients with neoplastic disorders. Drug was administered by long (four to five days) and short (10 minutes) zero-order infusions, and serial plasma and urine samples were collected. Serum and urine bleomycin concentrations were determined by radioimmunoassay. The disposition of bleomycin after the 10-minute infusion was described by a two-compartment open model. However, following multiple-day infusion estimates were obtained that were inconsistent with those from the short infusion. Parameters from the long infusions agreed with those from the short infusion when terminal plasma bleomycin levels less than 10 microunits/ml were excluded. The time to reach steady state following the long infusion (ca. 12 hours) was consistent with the half-life (3 hours) predicted by the short infusion and the long infusion excluding levels less than 10 microunits/ml. Possible explanations include assay interference by an unknown metabolite or strong binding of drug to tissues with release at a rate much less than the apparent rate of elimination of drug from the body.

Clinical significance of day-night differences in serum theophylline concentration with special reference to Theo-Dur.

In two studies, 25 diurnally active patients with asthma (6 to 17 years of age) were evaluated at steady state for day-night differences in serum theophylline concentration (STC) by frequent blood sampling over two consecutive 12-hour dosing intervals while being given treatment with Theo-Dur. In both studies findings were similar; Cmax was greater and Tmax shorter after dosing at 7 A.M. or 8 A.M. versus 7 P.M. or 8 P.M., with Cmax-C min approximately 7 micrograms/ml. For the morning dosing, 22 of 25 patients exhibited Cmax within 4 hours; 23 of 25 exhibited C min 12 hours after dosing. For the evening ingestion, the situation was very different: C min occurred within the initial 4 hours in 22 of 25 patients, whereas Cmax occurred in 22 of 25 patients just before the next (morning) dose. The findings indicate that the most appropriate time to estimate Cmax in patients given Theo-Dur is within the 4 hours after morning ingestion. The best time to estimate C min is a few hours after the evening ingestion. Sampling at these times is likely to represent within 10% to 20% the actual Cmax or C min.

Pharmacokinetics and Bioavailability of Dilevalol in Normotensive Volunteers

The bioavailability and pharmacokinetics of dilevalol following oral and intravenous administration were investigated in 12 healthy male volunteers. Dilevalol HCl was administered as a 200‐mg oral tablet and a 50‐mg intravenous infusion using a randomized cross‐over design. Blood and urine samples were collected over 60 hours and analyzed for unchanged and total (unchanged plus Glusulase‐released) dilevalol using an high performance liquid chromatography (HPLC) assay. After intravenous administration, total body clearance and volume of distribution of unchanged dilevalol were determined to be 23.2 mL/min/kg and 24.6 L/kg, respectively. After oral administration, a mean maximum concentration of 62 ng/mL was reached at an average peak time of 1.4 hours. Drug was eliminated with a half‐life of 8.3 hours after oral administration and 12 hours after intravenous administration. Based on plasma levels and urinary excretion of total dilevalol, the drug was completely absorbed; however, due to first‐pass metabolism, the absolute bioavailability of unchanged drug was 11 to 14%.

Multiple-dose amikacin kinetics in pediatric oncology patients.

Amikacin kinetics was studied in 8 pediatric oncology patients who received the drug by intravenous infusion over 30 or 60 min at a dose of 5 mg/kg every 6 or 8 hr. This regimen is recommended but, due to patient variability, patients should be monitored. Dosing intervals during 1 or 2 and 3 or 4 days of therapy were studied with serum samples collected before and at the end of the infusion and serially to the end of the dosing interval. The data appeared consistent with and were analyzed according to a l‐compartment model. An equation describing serum concentration with time for the multiple‐dose case was fit to each patients multiple‐interval data with nonlinear regression. Half‐life averaged 1.2 hr, volume of distribution 0.24 l/kg, and total body clearance 109 ml/min/1.73 m2 or 2.51 ml/min/kg. The volume of distribution and the clearance are greater than reported for adults and probably account for the larger dose needed to achieve and maintain therapeutic levels. Although the total daily dose was greater than previously reported, there were no signs of toxicity, although therapeutic concentrations were maintained.