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Antimicrobial Agents and Chemotherapy, April 2006, p. 1130-1135, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1130-1135.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Maribavir Pharmacokinetics and the Effects of Multiple-Dose Maribavir on Cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-Acetyltransferase-2, and Xanthine Oxidase Activities in Healthy Adults

Joseph D. Ma,1,{dagger} Anne N. Nafziger,1,2,{ddagger} Stephen A. Villano,3 Andrea Gaedigk,4 and Joseph S. Bertino Jr.1,2*

Clinical Pharmacology Research Center, The Research Institute,1 Department of Medicine, Bassett Healthcare, Cooperstown, New York,2 ViroPharma Incorporated, Exton, Pennsylvania,3 Division of Clinical Pharmacology and Experimental Therapeutics, Children's Mercy Hospital and Clinics, Kansas City, Missouri4

Received 22 July 2005/ Returned for modification 8 September 2005/ Accepted 9 January 2006


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ABSTRACT
 
Maribavir (1263W94, VP-41263) is an oral anticytomegalovirus agent under clinical development. The pharmacokinetics and safety of maribavir and the effects of maribavir on the activities of cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) were evaluated in a randomized, double-blind, placebo-controlled study. Twenty healthy subjects received a five-drug phenotyping cocktail of caffeine (CYP 1A2, NAT-2, XO), warfarin plus vitamin K (CYP 2C9), omeprazole (CYP 2C19), dextromethorphan (CYP 2D6), and midazolam (CYP 3A) 4 days before and after 7 days of treatment with maribavir at 400 mg twice daily (16 subjects) or placebo (4 subjects) for 10 days. Maribavir did not affect the CYP 1A2, CYP 2C9, CYP 3A, NAT-2, or XO activities. Bioequivalence was not demonstrated for CYP 2C19 and CYP 2D6, suggesting a decrease or inhibition of CYP 2C19 and CYP 2D6 activities. The pharmacokinetics of maribavir following a single dose and after 10 days of treatment were similar, with minimal accumulation at steady state. Maribavir was safe and well tolerated. Taste disturbance was the most frequently reported adverse event. These results will further guide evaluation of the drug interaction potential and clinical development of maribavir.


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INTRODUCTION
 
Maribavir (1263W94, VP-41263) is a benzimidazole L-riboside antiviral compound currently in clinical development (19). Preclinical studies suggest that maribavir is a potent and selective inhibitor of several laboratory and clinical isolates of human cytomegalovirus (HCMV) (8, 30). In one study, the mean 50% inhibitory concentrations for the AD169 and Toledo strains of HCMV were 3.0 and 2.1 µM, respectively (30). Inhibition of several ganciclovir-resistant isolates of HCMV has also been reported (30). Maribavir's mechanism of action may explain the activity against ganciclovir-resistant isolates of HCMV. Maribavir inhibits both UL97 kinase and viral DNA synthesis (8, 15). This is in contrast to the mechanisms of action of current antiviral therapies, including ganciclovir, which inhibit DNA polymerase.

The pharmacokinetics of maribavir have been evaluated in both animal models and humans. Maribavir demonstrates rapid absorption, linear pharmacokinetics, and in vivo anti-CMV activity (16). Nearly dose-proportional increases in maribavir exposure and peak concentrations have been observed, with mean oral bioavailabilities of >90% in rats and ~50% in monkeys (14). In humans, approximately 25 to 45% of oral maribavir was found to be absorbed, based on the urinary recovery of maribavir (28).

The potential effect of maribavir on drug-metabolizing enzyme activity in healthy adults has not been evaluated. The use of multiple, concurrently administered drug probes, known as a "cocktail," is one method of assessment of the activities of multiple drug-metabolizing enzymes. Upon administration of a drug probe cocktail, specified phenotyping parameters (e.g., metabolic ratios, area under the concentration-time curve [AUC], and total body clearance) are determined. The use of a phenotyping cocktail enables evaluation of real-time, independent enzyme activity since a specific drug probe can determine the activity of a drug-metabolizing enzyme involved in its metabolism. Several phenotyping cocktails have been reported (26). The Cooperstown 5 + 1 cocktail was used in this study, with slight modification (5). An advantage of the Cooperstown 5 + 1 cocktail is the use of caffeine as a probe drug. The use of different phenotyping parameters for caffeine allows the simultaneous measurement of the cytochrome P450 (CYP) 1A2, N-acetyltransferase (NAT-2), and xanthine oxidase (XO) activities.

The purposes of this study were to examine the effects of repeated doses of oral maribavir on CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, NAT-2, and XO activities by using a multiple-drug-probe cocktail and to evaluate the pharmacokinetics and safety of maribavir in healthy adults.


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MATERIALS AND METHODS
 
Study population. The Institutional Review Board of The Mary Imogene Bassett Hospital, Cooperstown, NY, approved this study. Written informed consent was obtained from each subject prior to study procedures. The subjects were healthy nonsmoking men and women between the ages of 18 and 55 years. Women were surgically sterile or, if they were of childbearing potential, were using an acceptable nonhormonal method of birth control. During the course of the study, the subjects did not take any prescription medications (including estrogen- and/or progestin-containing products) or nonprescription drugs (including herbal preparations or vitamins) and did not receive vaccinations. The subjects were instructed to refrain from consuming Seville oranges, grapefruits (including grapefruit juice), broccoli, brussels sprouts, charcoal-grilled meats, alcoholic beverages, and caffeine- and theobromine-containing beverages and foods for the duration of the study.

Subjects were excluded if they had any surgical or medical condition that could interfere with the administration of the study drug; were women who were pregnant or breastfeeding; had known intolerance to benzodiazepines, the active and/or inactive ingredients in caffeine, warfarin, vitamin K, omeprazole, or dextromethorphan; had an elevated international normalized ratio (INR) time (INR > 1.3); had taken any nicotine-containing or nicotine replacement devices within 6 months before the screening visit; had taken any prescription drugs during the 3 months before the screening visit; had taken any nonprescription drugs during a period of 3 days prior to the screening visit; had received an immunization during the 2 weeks prior to the screening visit (to minimize acute immune system changes potentially affecting drug-metabolizing enzyme activity); had any acute or chronic respiratory disease (e.g., asthma); had hemorrhagic tendencies or blood dyscrasia; had known hepatitis B or C; had known immune deficiency disease or were positive for human immunodeficiency virus; had participated in any other investigational drug study within 30 days before the screening visit; or had participated in any maribavir clinical trial.

Study design. Screening visit procedures included a medical history, physical examination, blood and urine collections for laboratory safety, urine drug screen, serum pregnancy test for each woman, 12-lead electrocardiogram, and vital sign measurements. Twenty subjects were randomized in a 4:1 allocation ratio (16 subjects received maribavir plus cocktail, and 4 subjects received placebo plus cocktail). Oral maribavir was administered at 400 mg twice daily on day 1 through day 10. On the morning of day –4, the subjects reported to the research center, where the modified Cooperstown 5 + 1 cocktail (5) was administered 4 days prior to the start of maribavir or placebo administration. On the morning of day 7 of maribavir or placebo dosing, the subjects returned to the research center, where administration of the modified Cooperstown 5 + 1 cocktail was repeated. Upon complete recovery of the sedative effects of midazolam on day –4 and day 7, the subjects were allowed to leave the research center and return for their scheduled visits. Study diaries were collected for each subject on day 1 through day 11. The subjects were instructed to record the date and time of self-administration of study medication (maribavir or placebo). During each scheduled outpatient visit, the subjects were asked if they were taking any new medications.

Table 1 summarizes the drug probes used. The modification of the Cooperstown 5 + 1 cocktail involved the use of oral midazolam to assess the combined effects of intestinal and hepatic CYP 3A activity. Midazolam was administered 3 h prior to the concomitant administration of caffeine, warfarin, vitamin K, omeprazole, and dextromethorphan on day –4 and day 7. The specific phenotyping measures used to determine drug-metabolizing enzyme activities are shown in Table 2. The subjects fasted overnight and continued to fast for at least 4 h after midazolam administration. The subjects avoided meals or snacks for at least 2 h before and after maribavir or placebo administration. Safety was evaluated by physical examination, clinical laboratory testing, vital sign measurements, electrocardiograms, and determination of the incidence of adverse events.


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  		TABLE 1. Description of the modified Cooperstown 5 + 1 cocktail


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  		TABLE 2. Assessment of drug-metabolizing enzyme activity by the modified Cooperstown 5 + 1 cocktaila

Plasma sampling and urine collection. At each sampling time point for each substrate, approximately 7 ml of venous blood was collected via venipuncture or through an indwelling venous catheter in a tube containing EDTA. The tubes containing EDTA were gently inverted, placed on ice, and centrifuged at 2,500 rpm for 15 min; and the resultant plasma was stored at –70°C until analysis. The sampling time points for blood collection for the drug probes are summarized in Table 1. Plasma samples were analyzed for maribavir, midazolam, S-warfarin, omeprazole, and 5-hydroxyomeprazole concentrations. Plasma maribavir concentrations were obtained on day 1 and day 10 at 0.5, 1.5, 2, 3, 4, 6, 8, and 12 h after the morning dose of maribavir. To determine trough maribavir concentrations, a blood sample was collected on day 3 and day 7 prior to the morning dose of maribavir.

Prior to the start of the 12-h urine collection, 3 g of ascorbic acid was added to the collection container to minimize spontaneous conversion of caffeine metabolites. Subjects were instructed on the importance of complete urine collection. To ensure complete urine collection, urine volumes and start and stop times were recorded for each subject for each 12-h collection period. Urine samples were analyzed for determination of 1-methylxanthine, 1-methylurate, 5-acetylamino-6-formylamino-3-methyluracil, 1,7-dimethylurate, dextromethorphan, and dextrorphan. The collection containers were refrigerated between urine collections. Upon completion of the 12-h collection period, two aliquots (15 ml) were removed during each collection period and stored at –70°C until analysis.

Analytic methods. Urinary 1-methylxanthine, 1-methylurate, 5-acetylamino-6-formylamino-3-methyluracil, 1,7-dimethylurate, dextromethorphan, and dextrorphan were determined by Prevalere Life Sciences (Whitesboro, NY) by using tandem liquid chromatography-mass spectrometry (LC/MS/MS). The linear range of the assay for the caffeine metabolites was 0.5 to 100 ng/ml; and the interday precision was ≤9% with quality control samples of 1.5, 20, 60, and 75 ng/ml. The linear range of the assay for dextromethorphan and dextrorphan was 1 to 500 ng/ml; and the interday precision was ≤12% with quality control samples of 3, 100, and 375 ng/ml.

Plasma concentrations of omeprazole, 5-hydroxyomeprazole, and S-warfarin were determined by Prevalere Life Sciences by using LC/MS/MS. The linear range of the assay for omeprazole and 5-hydroxyomeprazole was 10 to 1,000 ng/ml; and the interday precision was ≤9% with quality control samples of 30, 150, and 750 ng/ml. The linear range of the assay for S-warfarin was 10 to 1,500 ng/ml; and the interday precision was ≤15% with quality control samples of 30, 300, and 1,200 ng/ml. Plasma concentrations of midazolam were determined by Tandem Laboratories (Salt Lake City, UT) by using LC/MS/MS. The linear range of the assay for midazolam was 0.2 to 10 ng/ml, and the interday precision was ≤6%. Plasma maribavir concentrations were determined by MDS (Montreal, Quebec, Canada) by the LC/MS/MS procedure developed by MDS. Details of this procedure, with slight modifications, are described elsewhere (16).

CYP genotype analyses. CYP 2C9, CYP 2C19, and CYP 2D6 genotyping was performed retrospectively for all subjects according to procedures described elsewhere (5, 10, 11). The subjects were genotyped for the CYP 2C9*2 and *3 alleles; the CYP 2C19*2, *3, *4, and *5 alleles; and the CYP 2D6*2, *3, *4, *5, *6, *9, *10, *17, *29, *40, and *41 alleles and *1, *2, and *4 gene duplications. Subjects possessing at least one functional allele for CYP 2C9 and CYP 2C19 were identified as extensive metabolizers, while those possessing at least one functional allele for CYP 2D6 were identified as extensive or intermediate metabolizers.

Pharmacokinetic analyses. S-Warfarin, midazolam, and maribavir pharmacokinetics were determined by noncompartmental analysis with WinNonlin 4.1 (Pharsight Corporation, Cary, NC). The S-warfarin AUC from time zero to infinity (AUC0-{infty}) was calculated as the sum of the AUC from time zero to the time of the last measurable concentration (AUC0-last) plus the ratio of the last measurable concentration and the elimination rate constant. Midazolam and maribavir systemic clearance were calculated as F · dose/AUC0-{infty}, where F is bioavailability. A log-linear trapezoidal method was used to calculate AUC0-last. The maribavir elimination half-life was estimated by linear regression. The maribavir AUCratio was calculated as the day 10 AUC0-last/day 1 AUC0-last.

Statistical analyses. Twenty subjects were enrolled in the study. Based on in vitro data showing that maribavir is not a significant inhibitor or inducer of CYP 3A (investigator brochure; ViroPharma, Inc.), 16 subjects were randomized to detect a 25% difference (80% power) of CYP 3A activity. The four additional subjects randomized to receive placebo provided safety data for comparison with the data for subjects who received maribavir. Statistical analyses were performed by using SAS version 6.12 (SAS Institute, Cary, NC). Data were log transformed prior to the analyses. Analysis of variance and a general linear model that included subject and treatment effects as factors were performed, and least-squares geometric mean ratios (LS-GMRs) were calculated. Ninety percent confidence intervals (CIs) were calculated and expressed as a percentage relative to the LS-GMR of the phase with cocktail alone. No significant drug interaction is present if the 90% CIs are within the interval from 0.8 to 1.25 (29). This statistical method has previously been used to assess drug interactions (21). Maribavir pharmacokinetic parameters are presented as descriptive statistics and are reported as the arithmetic means ± standard deviations (SDs) unless otherwise noted. The maribavir AUCratio is presented as a geometric mean ± asymmetric SD.


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RESULTS
 
All 20 subjects completed the study. All of the 16 subjects who received maribavir completed the dosing. The mean ± SD age and weight were 36.8 ± 8.5 years and 80.1 ± 15.3 kg, respectively. All subjects were genotyped as CYP 2C9 and CYP 2C19 extensive metabolizers and CYP 2D6 extensive or intermediate metabolizers. One subject had levels of 1-methylxanthine, 5-acetylamino-6-formylamino-3-methyluracil, and 1,7-dimethylurate that were below the limit of quantitation and was excluded from the CYP 1A2, NAT-2, and XO analyses.

Figures 1A through G compare the individual drug-metabolizing enzyme activity before (day –4) and after (day 7) maribavir administration. Table 3 summarizes the least-squares geometric mean ratios and the 90% confidence intervals for each phenotyping measure for the 16 subjects who received maribavir. The least-squares geometric mean ratio for the ratio of omeprazole to 5-hydroxyomeprazole was 1.71 (90% CI, 1.50 to 1.92), and that for the ratio of dextromethorphan to dextrorphan was 1.18 (90% CI, 0.94 to 1.41). Thus, bioequivalence for CYP 2C19 and CYP 2D6 was not demonstrated. Maribavir did not affect the activity of CYP 1A2, CYP 2C9, CYP 3A, NAT-2, or XO (Table 3).


Figure 1
Figure 1
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  		FIG.1. Day –4 (baseline) versus day 7 (after administration of repeated doses of maribavir) comparison of (A) CYP1A2 activity ([1-methylxanthine + 1-methylurate + 5-acetylamino-6-formylamino-3-methyluracil]/1,7-dimethylurate; [1X + 1U + AFMU]/17U); (B) CYP 2C9 activity (S-warfarin AUC0-{infty}); (C) CYP 2C19 activity (omeprazole/5-hydroxyomeprazole; OMP/5-OH); (D) CYP 2D6 activity (dextromethorphan/dextrorphan; DM/DX); (E) CYP 3A activity (midazolam clearance; CL/F); (F) N-acetyltransferase-2 activity (5-acetylamino-6-formylamino-3-methyluracil/[1-methylxanthine + 1-methylurate]; AFMU/[1X + 1U]); and (G) xanthine oxidase activity (1-methylurate/[1-methylxanthine + 1-methylurate]; 1U/[1X + 1U]). Solid bars indicate median values.


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  		TABLE 3. LS-GMRs and 90% confidence intervals for subjects who received maribavir

The arithmetic mean ± SD plasma maribavir concentrations on day 3 and day 7 were 3.6 ± 2.6 µg/ml and 3.0 ± 2.0 µg/ml, respectively. The pharmacokinetics of maribavir are summarized in Table 4. The geometric mean (±asymmetric SD) AUCratio was 1.12 (0.68, 1.84).


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  		TABLE 4. Maribavir pharmacokinetics on day 1 and day 10 for subjects who received maribavira

Assessment of clinical safety laboratory parameters, electrocardiograms, physical examinations, and vital signs revealed no clinically significant changes from the baseline. No serious adverse events were reported. Fifteen of 16 subjects (94%) who received maribavir reported a taste disturbance, whereas 1 of 4 placebo subjects (25%) reported a taste disturbance. Twelve of 16 subjects (75%) who received maribavir and 3 of 4 placebo subjects (75%) reported sedation during the phenotyping procedure. The sedation was determined by the investigators to be due to midazolam.


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DISCUSSION
 
This was a randomized, double-blind, placebo-controlled study evaluating the effects of maribavir on the in vivo activities of CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, NAT-2, and XO using a modified Cooperstown 5 + 1 cocktail. Bioequivalence was observed for CYP 1A2, CYP 2C9, CYP 3A, NAT-2, and XO, while bioequivalence was not demonstrated for CYP 2C19 and CYP 2D6.

A lack of bioequivalence may not necessarily correlate with clinical significance. Additional factors that may be of clinical significance include an individual's CYP 2C19 and CYP 2D6 genotypes and the dose and therapeutic window of the concomitantly administered medication (18). Depending on these factors, patients who receive maribavir concomitantly with medications predominantly metabolized by CYP 2C19 (1, 4) or CYP 2D6 (22, 25) may need additional monitoring. Overall, the clinical significance of the effect of maribavir on these CYP enzymes remains to be fully understood.

The day 7 increase in the ratio of omeprazole to 5-hydroxyomeprazole (Fig. 1C) compared to the ratio on day –4 (baseline) suggests a decrease or inhibition of CYP 2C19 activity after maribavir administration. These results appear to represent the true effect of maribavir on CYP 2C19 activity, as the contribution of intra- and interindividual variability of CYP 2C19 was minimal. Over a 12-week period, the intraindividual variability of CYP 2C19, as assessed by the percent coefficient of variation, is approximately 18% (interquartile range, 14.8% to 23.5%) (13). In addition, a large degree of interindividual variability is due to a subject's CYP 2C19 genotype (gene-dose effect). This study included only subjects genotyped as CYP 2C19 extensive metabolizers. Interindividual variability was also minimized, as the subjects in this study served as their own controls.

The day 7 increase in the ratio of dextromethorphan to dextrorphan (Fig. 1D) compared to the ratio on day –4 (baseline) suggests a decrease or inhibition of CYP 2D6 activity after maribavir administration. Given that the intraindividual variability of CYP 2D6 has been reported to be 50.4% (mean coefficient of variation; range, 12.1 to 136%) (12), it is unclear if our finding is an effect due to maribavir or CYP 2D6 intraindividual variability. Wide inter- and intraindividual variabilities of CYP 2D6 were observed in this study (Fig. 1D), with one subject displaying a decrease rather than an increase in the ratio of dextromethorphan to dextrorphan after maribavir administration. There is also a suggestion that to detect an effect size of 30%, the use of the dextromethorphan to dextrorphan urinary ratio as a CYP 2D6 phenotyping parameter would require a sample size of 56 for crossover studies (3). This study included only 20 subjects (16 who received maribavir and 4 who received placebo), as sample size calculations were based on CYP 3A data.

Subjects were not genotyped for CYP 1A2, NAT-2, or XO. Genetic polymorphisms have been identified for these enzymes, but their functional significance is poorly understood (2, 6). We do not believe that the polymorphism of CYP 1A2, NAT-2, or XO affected our results. Subjects were also not genotyped for CYP 3A4 and CYP 3A5. Genetic polymorphisms for CYP 3A4 and CYP 3A5 have been identified, but conflicting evidence exists regarding the functional significance of these polymorphisms (9, 20, 23, 27, 31). Based on these studies, it is inconclusive whether CYP 3A genetic polymorphisms affected our results.

CYP 3A4 is the primary enzyme responsible for the metabolism of maribavir to its N-dealkylated inactive metabolite (14). In a human microsome study, the rate of formation of the N-dealkylated metabolite correlated with the rate of formation of testosterone 6-ß-hydroxylation (a marker for CYP 3A activity). No correlations were observed for CYP 1A2, CYP 2C9, CYP 2C19, or CYP 2D6 (14). These results seem to be in contrast to our reported interaction of maribavir with omeprazole (CYP 2C19) and dextromethorphan (CYP 2D6). Although in vitro human microsome studies can be a useful model for prediction of in vivo metabolism, caution is warranted in extrapolating in vitro results to in vivo models. In vitro hepatic microsome studies may represent an oversimplification of in vivo hepatic metabolism (7). Additional factors to be considered include human microsome sample-to-sample variation, the duration of the incubation period of maribavir exposure to the microsome samples, and the concentrations of probe drugs and maribavir (50 µM) used in the in vitro study.

Treatment with maribavir at 400 mg twice daily for 10 days was chosen because of the expectation that antiviral activity would be achieved when the drug is dosed in a target population. Previous studies observed in vivo anti-CMV activity at lower total daily doses (300 to 600 mg/day) and higher total daily doses (1,200 to 2,400 mg/day) of maribavir in comparison to the total daily maribavir dose (800 mg/day) used in this study (16). In human immunodeficiency virus-infected men with asymptomatic HCMV shedding, mean reductions in semen HCMV titers of 2.9 to 3.7 log10 PFU/ml were observed among all 28-day maribavir dosing regimens (16). The decrease in mean HCMV titers reported with maribavir are comparable to the approved doses for the anti-HCMV activities of ganciclovir and cidofovir (17, 24).

Maribavir was rapidly absorbed, with maximum plasma concentrations occurring 1 h after dosing. Other studies have reported maximum plasma concentrations of maribavir occurring 1 to 3 h after administration (28). Maribavir maximum concentrations were similar after administration of the first dose and the last dose, suggesting that predicted steady-state concentrations were reached after the first dose. The mean plasma half-life of maribavir on day 1 was 3.7 ± 0.9 h, which is also consistent with that from single-dose studies with healthy subjects (28). There was minimal accumulation at steady state, based on the AUCratio and plasma trough concentrations, on day 3 and day 7 of maribavir administration.

Compared to placebo and based on the assessment of clinical safety laboratory parameters, electrocardiograms, physical examinations, and vital signs, maribavir was safe and well tolerated. There were no reported serious adverse events. Taste disturbance was the most commonly reported adverse event. Fifteen of 16 subjects (94%) reported taste disturbance. Other studies have also reported a high percentage of taste disturbance (i.e., >80%) (16, 28). Taste disturbance may be due to secretion of maribavir into the salivary glands after systemic absorption (28).

In summary, oral maribavir (400 mg twice daily for 10 days) administration showed a lack of bioequivalence for CYP 2C19 and CYP 2D6. These results suggest that maribavir decreased or inhibited CYP 2C19 and CYP 2D6 activities. Future studies with larger sample sizes are needed to provide conclusive evidence of the effect of maribavir on the activities of CYP 2C19 and CYP 2D6. Consequently, the clinical significance of the effect of maribavir on the activities of CYP 2C19 and CYP 2D6 remains to be determined. Repeated oral dosing with maribavir did not affect CYP 1A2, CYP 2C9, CYP 3A, NAT-2, or XO activity. The maribavir pharmacokinetics determined in this study are in agreement with those previously reported in the literature. In healthy subjects, maribavir was well tolerated, with taste disturbance reported as the most common adverse event.


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ACKNOWLEDGMENTS
 
This work was supported by a grant from ViroPharma Incorporated, Exton, PA.


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FOOTNOTES
 
* Corresponding author. Present address: ORI Drug Development Center, Ordway Research Institute, Inc., 150 New Scotland Ave., Albany, NY 12208. Phone: (518) 641-6410. Fax: (518) 641-6304. E-mail: sbertino{at}ix.netcom.com. Back

{dagger} Present address: Amgen Inc., Thousand Oaks, CA 91320. Back

{ddagger} Present address: ORI Drug Development Center, Ordway Research Institute, Inc., Albany, NY 12208. Back


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Antimicrobial Agents and Chemotherapy, April 2006, p. 1130-1135, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1130-1135.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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