Susan A. Willavize

Single- and multiple-dose administration, dosing regimens, and pharmacokinetics of trovafloxacin and alatrofloxacin in humans

A simplified dosing algorithm for trovafloxacin was evaluated following a single-dose infusion of alatrofloxacin at trovafloxacin equivalent doses of 30, 100, 200, 300 and 400 mg (57 subjects), and multiple doses of 200, 300 and 400 mg (30 subjects). Maximum serum concentration and area under the concentration-time curve for trovafloxacin increased with dose. Trovafloxacin clearance (82–85 ml · h/kg) and volume of distribution (1.3–1.6 l/kg) were independent of dose. Infusion of alatrofloxacin at a trovafloxacin equivalent dose of 300 mg at 1, 2 or 3 mg/ml over 1 h did not alter the pharmacokinetics of trovafloxacin. A plot of the weight-adjusted dose of trovafloxacin in individual subjects against the maximum serum concentration following single and multiple dosing, indicated that the maximum serum concentration increased 1 μg/ml for each 1 mg/kg of trovafloxacin administered. Thus, a prior knowledge of the desired serum concentration will permit appropriate dosing without the use of complex nomograms in patients with normal hepatic function.

A double-blind, placebo-controlled, parallel group study of oral trovafloxacin on bowel microflora in healthy male volunteers.

BACKGROUND Treatment with oral antibiotic drugs generally influences normal fecal flora. These changes can be both beneficial (eg, elimination of aerobic, gram-negative bacilli) and detrimental (eg, the appearance of resistant pathogenic micro-organisms). Trovafloxacin, a new fluoroquinolone with in vitro activity against anaerobes, and gram-negative, gram-positive, and atypical pathogens, is a potentially beneficial antimicrobial for bowel sterilization. This double-blind trial investigated the effect of trovafloxacin on the normal microbial bowel flora of healthy male subjects. METHODS Subjects were randomized (in a 2:1 ratio) to receive either 200 mg trovafloxacin once daily for 10 days or a matching placebo. Fecal samples were collected at two baseline occasions, on visit days 4, 7, 10, and 17, and at follow-up. Bacterial species were identified and quantified in the fecal samples. RESULTS Twelve subjects received the active drug and seven received placebo. No Enterobacteriaceae were found in samples from days 4 to 10 in subjects receiving trovafloxacin. No changes in Enterobacteriaceae were found throughout the study in subjects receiving placebo. Incidental Enterobacteriaceae were isolated from subjects in the trovafloxacin group at the end of the study. No clinically significant differences were found in either group with respect to prevalence, appearance, or disappearance of aerobic gram-positive cocci, anaerobic bacteria, or yeasts. All tested Enterobacteriaceae were highly susceptible to trovafloxacin. No increase in minimum inhibitory concentration values was seen in day 17 and follow-up samples for isolated Escherichia coli strains. No Clostridium difficile was found in day 17 or follow-up samples from subjects in the trovafloxacin group. All tests for clostridium toxin were negative. CONCLUSIONS During the treatment period, E. coli could not be cultured from the feces of the 12 healthy subjects receiving 200 mg trovafloxacin daily during days 4 to 10. All isolated Enterobacteriaceae were susceptible to trovafloxacin and no changes in susceptibility were found after the treatment period. In subjects treated with trovafloxacin, the prevalence and number of gram-positive bacteria were rapidly reduced. Trovafloxacin is able to selectively and reversibly suppress bowel flora.

The bioavailability of nasogastric versus tablet-form oral trovafloxacin in healthy subjects

BACKGROUND Patients in the hospital, as well as those in home care settings, often require nutritional supplementation with enteral feeding solutions. In addition, patients with serious infections who are clinically unstable often cannot maintain adequate intake by mouth and may require an alternative to oral antibiotic administration. However, delivery of crushed oral formulations of drugs via nasogastric tubes is often carried out without adequate bioavailability data, and this method of administration may not always be equivalent to oral drug delivery. METHODS In an open-label, randomized, four-period, four-treatment, cross-over study, 24 healthy volunteers were given one dose of each of the following treatments, with a 7-day wash-out between dosing periods: Treatment A: two 100-mg trovafloxacin tablets given orally with 240 mL water; Treatment B: two crushed 100-mg trovafloxacin tablets suspended in water and administered through a nasogastric tube into the stomach; Treatment C: two crushed 100-mg trovafloxacin tablets suspended in water and administered through a nasogastric tube into the duodenum; or Treatment D: two crushed 100-mg trovafloxacin tablets suspended in water and given through a nasogastric tube into the stomach concomitantly with an enteral feeding solution (240 mL full-strength Osmolite). RESULTS Pharmacokinetic analyses showed that the bioavailability of trovafloxacin after administration of crushed tablets into the stomach with or without concomitant enteral feeding was not significantly different from that of the orally administered whole tablets: the 90% confidence limits of the area under the concentration-time curve (AUC(0-infinity)) for Treatment B versus Treatment A (91.3%, 109.5%) and Treatment D versus Treatment A (91.6%, 109.9%) were well within the bioequivalence criteria of 80% to 125%. Results of analysis of variance (ANOVA) indicated no significant sequence, period, or treatment-by-period interaction effects. Administration of trovafloxacin into the duodenum (Treatment C) resulted in reduced systemic exposure to trovafloxacin, with a 31% decrease in AUC(0-infinity) and a 30% decrease in peak serum concentration (Cmax) compared to oral administration. Time to peak serum concentration (Tmax) was 1.7 hours after oral administration of trovafloxacin and 1.1 hours after administration directly into the stomach or duodenum through a nasogastric tube in the absence of concomitant enteral feeding. All four treatments were well tolerated; no participant discontinued the study due to adverse events and no serious adverse events were reported. CONCLUSIONS These results showed that administration of crushed trovafloxacin tablets through a nasogastric tube into the stomach, with or without concomitant enteral feeding, achieves absorption and tolerability comparable to those of orally administered trovafloxacin tablets.

Disease progression of cognitive impairment in Alzheimer's disease: A model-based approach

P1-260 DISEASE PROGRESSION OF COGNITIVE IMPAIRMENT IN ALZHEIMER’S DISEASE: A MODEL-BASED APPROACH Susan Willavize, Miia Kivipelto, D. Larry Sparks, Roy W. Jones, Andrei Breazna, David A. DeMicco, Judith Hey-Hadavi, Rachel J. Schindler, Brian Corrigan, Pfizer Global Research and Development, New London, CT, USA; Aging Research Centre, Karolinska Institute, Stockholm, Sweden; Ralph & Muriel Roberts Laboratory for Neurodegenerative Research, Sun Health Research Institute, Sun City, AZ, USA; The Research Institute for the Care of Older people, Royal United Hospital, Bath, United Kingdom; Pfizer Global Pharmaceuticals, New York, NY, USA. Contact e-mail: susan. a.willavize@pfizer.com

An open, controlled, crossover study on the effects of cimetidine on the steady-state pharmacokinetics of trovafloxacin

Twelve healthy male volunteers participated in this open, randomized, placebo-controlled, two-way crossover study to investigate the effects of cimetidine on the steady-state pharmacokinetics of oral trovafloxacin. Volunteers were randomized to receive either 400 mg cimetidine twice daily or placebo for 5 days. From day 3–5, volunteers received 200 mg trovafloxacin once daily in addition to either cimetidine or placebo. After a minimum 7-day washout period, the study was repeated; those volunteers who received placebo during the first study period were administered cimetidine, and vice versa. The maximum observed serum trovafloxacin concentration, the area under the concentration-time curve of trovafloxacin within the dosing interval of 24 h and the earliest time to the maximum serum concentration for trovafloxacin in volunteers receiving concomitant cimetidine were 2.4 (μg/ml, 27.8 μg·h/ml and 1.4 h, respectively, compared with 2.5 μg/ml, 27.1 μg·h/ml and 1.5 h, respectively, in volunteers receiving concomitant placebo. Thus, multiple dosing with cimetidine had no significant effect on the absorption or disposition of trovafloxacin at steady state. Co-administration of cimetidine and trovafloxacin was also well tolerated and without serious adverse effects.