The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the Cmax and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This is not expected to have any clinical significance under the conditions of therapeutic use.

The influence of food on the absorption of midazolam, a new benzodiazepine derivative, was investigated in 18 healthy volunteers in a four-way, randomized, crossover study with a one-week washout period between treatments. Single 15-mg oral doses of midazolam were administered one hour before, with, and one hour after a standard meal as well as under fasting conditions (control). Following serial blood sampling over the next 24-hour period, midazolam plasma concentrations were determined by gas chromatography and mass spectrometry for pharmacokinetic evaluation. The maximum plasma concentration (Cmax), time of maximum concentration (tmax), lag time prior to absorption (tlag), area under the plasma concentration-time curve (AUC), and elimination rate constant of midazolam and 1-hydroxymethylmidazolam were determined. Significant changes in these parameters were not found when midazolam was taken one hour before or with a meal as compared with the control condition. Significant changes in the Cmax, tmax, and AUC parameters for both midazolam and its metabolite were seen when midazolam was ingested one hour after a meal: There was a delayed and reduced rate of absorption as well as a small reduction in the extent of absorption. Thus, ingestion of midazolam within one hour after a meal may result in a delay in the onset of the pharmacologic effect. These changes may be of some clinical significance in that they may potentially delay the onset of sleep.

Five healthy volunteers and 31 patients with various degrees of renal impairment received a 10-mg/kg intravenous dose of amdinocillin by infusion over 15 min to establish the disposition profile of the drug in plasma and urine. Both clearance from plasma and elimination rate constant showed a linear relationship with creatinine clearance. It was noted that in subjects with creatinine clearances of greater than 50 ml/min, the elimination half-life remained relatively constant; however, as the creatinine clearance decreased from 50 to 5 ml/min, there was a progressive rise in the elimination half-life. Despite the removal of the drug by hemodialysis (32 to 72% of the dose), concentrations of amdinocillin in plasma remained in the therapeutic range. In patients undergoing peritoneal dialysis, less than 4.0% of the infused dose was removed by dialysis during the hourly exchanges over a 14-to 18-h period. Although the clearance from plasma and the half-life of amdinocllin were altered up to fourfold in patients with creatinine clearances of less than 15 ml/min, the amdinocillin dosage per se may not need to be reduced for these patients if the frequency of dosing is reduced from six to three or four times daily. This is based on drug accumulation estimates of 56% from a regimen of 10 mg/kg every 8 h in these patients as compared with less than 10% from a regimen of 10 mg/kg every 4 h in subjects with normal renal function. In addition, supplemental doses may not be necessary during or at the end of hemodialysis for patients undergoing hemodialysis.Amdinocillin (also known as mecillinam) (recently approved by the Food and Drug Administration for clinical use and soon to be available under the trade name of Coactin) is an amdino penicillinate (6) which is active against a broad range of gram-negative bacteria and acts synergistically with other ,B-lactam antibiotics (2, 9, 12, 13). The pharmacokinetics of amdinocillin in healthy human volunteers have been defined by several investigators (3,4,7,8,10). According to these studies, amdinocillin has a relatively short elimination half-life (t1/20; 47 to 59 min), a small volume of distribution (V; 0.22 to 0.53 liter/kg), and a low clearance from plasma (CLp; 3.0 to 5.3 ml/min per kg). In addition, the fraction of a dose of amdinocillin excreted unchanged in urine (fe) is 50 to 70%, whereas biliary excretion and metabolism represent two minor pathways of elimination for amdinocillin in humans. Preliminary studies, which were limited to patients with severe-to-end-stage renal insufficiency, have shown that t1/2P of amdinocillin is prolonged in such patients (1, 11).

A pharmacokinetic model was developed to describe the disposition of lead in the rat. The model can be used to predict the effect of acute high-dose as well as low-dose exposure to lead. These results suggest that the model should be able to predict the effect of chronic low-dose exposures as well. Plasma, bone, liver, and bile profiles were generated from this model using previously published data. The results obtained supported the existing theory that lead demonstrates a dose-dependent pharmacokinetic profile in the rat.

Interferon is currently being evaluated for the treatment of disseminated cancer and viral diseases. Alpha interferons have shown to be effective in the treatment of a number of malignancies. Recombinant leukocyte A interferon (rIFN-alpha A) is an alpha interferon produced by recombinant DNA techniques. A kinetic evaluation of rIFN-alpha A following intravenous and intramuscular administration has not been adequately defined. The present study was designed to evaluate the kinetics of rIFN-alpha A following intravenous and intramuscular administration of 3, 9 or 18 X 10(6) units to patients with disseminated cancer. A preliminary report of this study was presented at the meeting of the American Society for Clinical Pharmacology and Therapeutics in San Diego, March 1983 (1).