Robert J. Wills

Interferon kinetics and adverse reactions after intravenous, intramuscular, and subcutaneous injection

Three groups of six subjects each received a single 36 × 106 U dose of recombinant leukocyte A interferon (rIFN‐αA) as a 40‐min infusion, an intramuscular injection, or a subcutaneous injection. Blood samples were collected at specific times after dosing for analysis of rIFN‐αA serum concentrations by an enzyme immunoassay method, ELISA. The rIFN‐αA was rapidly distributed and moderately eliminated (t½ =5.1 hr) after intravenous infusion. The maximum concentrations at the end of intravenous infusion were tenfold the maximum concentrations after intramuscular and subcutaneous injections. Renal tubular secretion or extrarenal elimination was suggested by clearance values of 1.8 times the glomerular filtration rate. After intramuscular and subcutaneous injection, rIFN‐αA was absorbed slowly (time to reach maximum concentration ranged from 4 to 8 hr), which resulted in prolonged serum concentrations. Estimated bioavailability was more than 80% for both intramuscular and subcutaneous injection shares qualitatively the same adverse reactions, the reactions differ in severity and duration. The adverse effects appear to be related to route of administration, of herpes labialis were also noted. There were no significant clinical laboratory abnormalities of medical concern. Although rIFN‐αA injected by intravenous infusion or intramuscular or subcutaneous injection shares qualitatively the same adverse reactions, the reactions differ in severity and duration. The adverse effects appear to be related to route of administration.

Distribution of alpha interferon in serum and cerebrospinal fluid after systemic administration

After intravenous infusion of recombinant leukocyte interferon (rIFN‐αA) to four subjects with an indwelling reservoir, serial serum and cerebrospinal fluid samples were taken over 48 hr and were analyzed for interferon by an enzyme immunoassay method (ELISA). On separate occasions, 18 and 50 × 106 of rIFN‐αA were infused over 10 min. Maximum serum concentrations of rIFN‐αA ranged from 6720 to 11,000 pg/ml and from 32,900 to 43,400 pg/ml after the 18 and 50 × 106 U doses. There was no measurable concentration of rIFN‐αA in the cerebrospinal fluid of subjects who received 18 × 106 U doses. In three of four subjects who received 50 × 106 U rIFN‐αA, concentrations ranged from 17 to 70 pg/ml that were measurable no earlier than 1 hr after the start of the infusion and that in two cases were measurable throughout 24 hr.

The preclinical development of roferon®‐A

Interferon alfa‐2a (Roferon®‐AHoffmann‐La Roche Inc. NutleyNJ) is identical to one of approximately 15 subtypes of interferon alpha made by human leukocytes and is produced in bacteria using recombinant DNA techniques. In its antiviralantiproliferativeand immunomodulatory activities it is similar to leukocyte interferon alpha. These activities are species‐restricted and have been demonstrablethus faronly in humanscertain other primatesbovinesand guinea pigs or cells derived therefrom. The possibility that the toxicity of interferon alfa‐2a would also be species‐restricted appears to have been confirmed by results obtained thus far. Toxicological studies in ratsmice and several species of monkeys have failed to indicate the side effects that have been observed in humans. Howeverstudies in species in which interferon alfa‐2a is active and in others in which it is nothave revealed similar pharmacokinetics and elimination mechanisms.

Prostaglandins and the Protection of the Gastroduodenal Mucosa in Humans: A Critical Review

M ucosal protection ([MP] “cytoprotection”) owes its inception largely to the demonstration by Robert and co-workers1’2 that it was possible to protect the mucosa of the rat from the injurious effects of a variety of noxious agents. These compounds included 6N HC1, iN NaOH, boiling water, absolute ethanol, and nonsteroidal antiinflammatory drugs (NSAIDs).’ Although cytoprotection was born from nonphysiologic experimentation, it is now being used by clinical researchers applying the knowledge of MP in a more physiologic fashion to the human subject. The clinical researcher has the difficult task of experimenting on human subjects, using ideas obtained largely from studies in rats. Thus, MP is a subject in a phase of very rapid advance, and a critical review over a broad clinical front is particularly appropriate at the moment. An immense preclinical literature base has accumulated since the pioneer work by Robert’s group. Recently, a very complete and useful account on the subject of protection of the intestinal mucosal has appeared.3’4 In humans, the bulk of information on MP has been obtained from studies of the upper gastrointestinal (CI) tract. Accordingly, the scope of this review will be restricted to data obtained from the stomach and duodenum. The main objective is to provide the reader with an up-to-date background regarding the interpretation of MP data.

Rimantadine pharmacokinetics in healthy subjects and patients with end‐stage renal failure

The single‐dose (two 100 mg doses) pharmacokinetics of rimantadine hydrochloride were compared in eight patients with end‐stage renal disease who were on hemodialysis and seven age‐matched healthy subjects. Plasma and urine rimantadine concentrations were determined by a GC/MS method. The plasma half‐life (43.6 vs 27.5 hours) and AUC (9.9 ± 2.1 vs 6.0 ± 1.6 μg · hr/ml) were significantly (p < 0.05) increased in the patient population. No significant differences were noted in the maximum rimantidine concentration, time of maximum concentration, or apparent volume of distribution. Urinary excretion of unchanged rimantadine accounted for 16% of the dose in the healthy subjects. Hemodialysis did not appreciably remove rimantadine. These findings suggest that rimantadine dosage may need to be reduced in patients with end‐stage renal disease but supplemental doses on dialysis days are not required.

Pharmacokinetics and Pharmacodynamics of Intravenous Cibenzoline in Normal Volunteers

The pharmacokinetics of intravenous (IV) cibenzoline were studied in six healthy male volunteers ranging in age from 51 to 78 years. The subjects received intravenous (IV) cibenzoline 100 mg over 20 minutes, and plasma and urine specimens were collected for 48 hours. Cibenzoline plasma concentrations at the end of the infusion ranged from 730 to 1,420 ng/mL and exhibited triexponential decline thereafter. The following mean model independent pharmacokinetic parameters were calculated from the plasma and urine concentration data: terminal half‐life, 9.8 hours (range, 8.5–11.9); plasma clearance, 523 mL/min (range, 387–687); volume of distribution, 445 L (range, 328–506); and renal clearance, 289 mL/min (range, 202–334). Approximately 31% to 59% of the dose was recovered unchanged in the urine in 48 hours. A triexponential pharmacokinetic equation with zero order input was used to curve fit the plasma and urine data, and the model‐dependent parameters agreed well with the model‐independent estimates. A hysteresis loop was observed in the relationship between cibenzoline plasma concentration and QRS prolongation, indicating an initial lag between plasma concentration and effect after IV administration. Based on these results, the following preliminary dosing regimen was proposed to rapidly achieve and maintain therapeutic plasma concentrations equal to or slightly greater than 200–400 ng/mL: 0.25 mg/kg/min IV bolus over one minute followed by 1‐1.5 mg/kg/hr for one hour and 0.2‐0.4 mg/kg/hr for long‐term infusion.

Continuous Intravenous Infusion Pharmacokinetics of Interferon to Patients With Leukemia

R ecombinant human alpha A interferon (rIFN-aA), a single protein moiety derived by recombinant DNA techniques,1 is being evaluated in disseminated cancers and viral diseases. In a recent report involving healthy volunteers,2 it was shown that a single dose of rIFN-aA given by intravenous infusion was much better tolerated than by either intramuscular or subcutaneous injections. Therefore, the route of administration may be an important factor in determining tolerance. In addition, early clinical studies suggested that patients with acute leukemia were responsive to interferon when administered by intravenous bolus3 or infusion.4 This study assessed the pharmacokinetics of rIFNaA in patients with relapsed and/or refractory acute leukemia or blast crisis myelogenous leukemia following a 14-day continuous intravenous infusion. Thirteen patients (eight men and five women) having relapsed and/or refractory acute leukemia or blast crisis chronic myelogenous leukemia were entered into this study after giving written informed consent. Study approval was obtained from the Baltimore Cancer Research Center, University of Maryland Hospital, Institutional Review Board. Dr. R.D. Leavitt conducted the study. The entrance criteria included those patients who were previously treated with chemotherapy, immunotherapy, or radiation therapy, had an evaluable disease, and an expected survival of eight weeks. Entry criteria did not require palliative radiation therapy at the time of entry into the study, chemotherapy, immunotherapy, or hormonal therapy, other than the treatment regimen prescribed by this protocol. Patients did not suffer from any severe heart disease, intercurrent infections, impaired renal or hepat-

Influence of a Meal on the Bioavailability of Rimantadine · HCl

R imantadine (a-methyl-1-adamantane-methylamine hydrochloride), an analog of amantadine with more potent antiviral activity, is currently being evaluated for prophylaxis and therapy against influenza-A viral infection by use of a dosing regimen of 100 mg bid. To date, very little pharmacokinetic information has been published. Hayden et al.1 reported on the pharmacokinetics of rimantadine following a single 200-mg dose in both young and elderly adults. No age-related alterations in the disposition of rimantadine were evident. Maximum concentrations ranged from 170 to 340 ng/mL at 1.5 to 7.0 hours. The apparent volume of distribution was exceedingly large, greater than 10 L/kg, and the apparent elimination t1/2 ranged from 20 to 50 hours. It is well documented that absorption of drugs can be altered by the presence of food.23 If an interaction with food occurs, it generally results in a decrease or delay in drug absorption. However, increased absorption of drugs have been reported.4’5 Therefore, it becomes important to assess the influence of food on the absorption of drugs intended for clinical use. The current study was conducted to determine the influence of food on the absorption of rimantadine . HC1.

Multiple-dose pharmacokinetics of diazepam following once-daily administration of a controlled-release capsule.

The study was designed to determine the steady-state pharmacokinetic profile of diazepam and desmethyldiazepam following a 15-mg controlled-release capsule dosed once daily at either 7 a.m. or 11 p.m. compared with the respective profiles of the conventional 5-mg tablet dosed three times a day at 7 a.m., 12 p.m., and 5 p.m. Plasma concentrations of diazepam and desmethyldiazepam were assayed by an electron-capture gas-liquid chromatographic method. Plasma concentrations indicated that there were no differences between the pharmacokinetic profiles following the 7 a.m. or 11 p.m. dosings of the controlled-release capsule. Steady-state concentrations of diazepam were attained between days 7 and 9 during the controlled-release dosing, and the accumulation profiles are similar to those observed for the conventional tablet given three times a day. Nearly identical areas under the diazepam plasma concentration-time curves (AUC) on day 1 and at steady state for both regimens indicate equal extents of absorption from the two formulations. In addition, the steady-state AUCs for desmethyldiazepam were independent of formulation. The data indicate that a single daily dose of the 15-mg controlled-release capsule results in accumulation and steady-state profiles comparable to those observed following a regimen of the 5-mg conventional tablet three times a day. During the first few days of dosing, peak diazepam concentrations were reduced and trough concentrations were increased following the controlled-release capsule, which results in less variable concentrations during a 24-h interval.

Influence of Food on the Bioavailability of Trimoprostil: An Overview

Abstract: The influence of food on the bioavailability of trimoprostil, a new antiulcer prostaglandin E2 derivative, was investigated in healthy male volunteers in four separate studies. Doses of 0.75, 1.5, and 3.0 mg were administered orally in both the presence and absence of food followed by serial blood sampling through 24 hours. Plasma trimoprostil concentrations were determined by a gas chromatographnegative chemical ionization‐mass spectrometric method for pharmacokinetic evaluation. Food decreased the absorption rate of trimoprostil as indicated by a later tmax (P < 0.01) and corresponding lower Cmax at each dose. However, the food effect on tmax diminished as the dose increased. Although Cmax was reduced, food did not alter the extent of absorption, indicated by similar AUC (P > 0.05) between fed and fasted states. Both Cmax and AUC increased proportionately with an increase in dose. The harmonic mean half‐lives of elimination were similar (P > 0.05) across all doses and ranged from 27 to 55 minutes.