The Bioavailability of Nasogastric VersusTablet-Form Oral Trovafloxacin in

Healthy SubjectsJohn Vincent, MD, PhD, Renli Teng, PhD,* Shawn M. Pelletier, BS, Susan A. Willavize, PhD,

Hylar L. Friedman, MD, Groton, Connecticut

BACKGROUND: Patients in the hospital, as well asthose in home care settings, often require nutri-tional supplementation with enteral feeding solu-tions. In addition, patients with serious infectionswho are clinically unstable often cannot maintainadequate intake by mouth and may require analternative to oral antibiotic administration. How-ever, delivery of crushed oral formulations ofdrugs via nasogastric tubes is often carried outwithout adequate bioavailability data, and thismethod of administration may not always beequivalent to oral drug delivery.

METHODS: In an open-label, randomized, four-period, four-treatment, cross-over study, 24healthy volunteers were given one dose of eachof the following treatments, with a 7-day wash-out between dosing periods: Treatment A: two100-mg trovafloxacin tablets given orally with240 mL water; Treatment B: two crushed 100-mgtrovafloxacin tablets suspended in water and ad-ministered through a nasogastric tube into thestomach; Treatment C: two crushed 100-mgtrovafloxacin tablets suspended in water and ad-ministered through a nasogastric tube into theduodenum; or Treatment D: two crushed 100-mgtrovafloxacin tablets suspended in water andgiven through a nasogastric tube into the stom-ach concomitantly with an enteral feeding solu-tion (240 mL full-strength Osmolite). RESULTS:Pharmacokinetic analyses showed that the bio-availability of trovafloxacin after administrationof crushed tablets into the stomach with or with-out concomitant enteral feeding was not signifi-cantly different from that of the orally adminis-tered whole tablets: the 90% confidence limits ofthe area under the concentration-time curve(AUC0–`) for Treatment B versus Treatment A(91.3%, 109.5%) and Treatment D versus Treat-ment A (91.6%, 109.9%) were well within the bio-equivalence criteria of 80% to 125%. Results ofanalysis of variance (ANOVA) indicated no signifi-cant sequence, period, or treatment-by-period

interaction effects. Administration of trovafloxa-cin into the duodenum (Treatment C) resulted inreduced systemic exposure to trovafloxacin, witha 31% decrease in AUC0–` and a 30% decreasein peak serum concentration (Cmax) compared tooral administration. Time to peak serum concen-tration (Tmax) was 1.7 hours after oral administra-tion of trovafloxacin and 1.1 hours after adminis-tration directly into the stomach or duodenumthrough a nasogastric tube in the absence ofconcomitant enteral feeding. All four treatmentswere well tolerated; no participant discontinuedthe study due to adverse events and no seriousadverse events were reported.

CONCLUSIONS: These results showed that adminis-tration of crushed trovafloxacin tablets through anasogastric tube into the stomach, with or with-out concomitant enteral feeding, achieves ab-sorption and tolerability comparable to those oforally admin istered trovafloxacin tablets. Am JSurg. 1998;176(Suppl 6A):23S–26S. © 1998 by Ex-cerpta Medica, Inc.

Patients in the hospital, as well as those in home caresettings, often require nutritional supplementationwith enteral feeding solutions.1 In addition, patients

with serious infections who are clinically unstable oftencannot maintain adequate intake by mouth and may re-quire an alternative route to oral antibiotic administra-tion.2,3 One option for these patients would be delivery ofan oral antibiotic via a nasogastric tube.2 However, deliv-ery of crushed oral formulations of drugs via nasogastrictubes is often carried out without adequate bioavailabilitydata,2 and this method of administration may not always beequivalent to oral drug delivery. For example, administra-tion of acetaminophen via nasogastric tube results in mark-edly decreased serum levels of the drug relative to thoseachieved with oral administration.4

Trovafloxacin is a novel synthetic fourth-generation fluoro-quinolone with a broad spectrum of activity against mostcommonly isolated bacterial pathogens. In vitro studies haveshown that trovafloxacin has greater activity than otherfluoroquinolones against gram-positive organisms (includingstaphylococci, pneumococci, streptococci, and entero-cocci),5–11 anaerobes (including Bacteroides fragilis),12–14 andthe atypical respiratory pathogens Mycoplasma pneumoniae,Legionella pneumophila, and Chlamydia pneumoniae.8,10,11

The activity of trovafloxacin is comparable to that of otherfluoroquinolones against gram-negative organisms.15

The antimicrobial spectrum of trovafloxacin, along with its

From Pfizer Central Research, Groton, Connecticut.* Current affiliation: Astra Merck, Wayne, Pennsylvania.Requests for reprints should be addressed to John Vincent,

MD, PhD, Pfizer Central Research, Eastern Point Road, Groton,Connecticut 06340.

© 1998 by Excerpta Medica, Inc. 0002-9610/98/$19.00 23SAll rights reserved. PII S0002-9610(98)00216-5

prolonged half-life and extensive systemic distribution, havesuggested the potential use of this drug as a once-daily treat-ment for infections of the upper and lower respiratory tract,skin and soft tissues, abdomen, pelvis, and urinary tract.16–19

In certain circumstances, administration of the oral for-mulation of trovafloxacin through a nasogastric tube maybe the preferred route. In light of trovafloxacin’s highbioavailability, any alterations in absorption when given bynasogastric tube might have major consequences on sys-temic exposure. Furthermore, certain patients in these set-tings require nutritional supplementation with enteralfeeding solutions administered through a nasogastric tube,which also serves as the route for drug administration.These solutions contain cations such as magnesium, zinc,iron, and calcium. Because certain cations can interferewith the absorption of quinolones, including trovafloxa-cin,20 presumably via chelation of the antibiotic, the effectof concomitant administration of a supplemental enteralfeeding solution with trovafloxacin merits evaluation.

The purposes of this study, conducted in healthy volunteers,were to determine the bioavailability of a crushed tabletsuspension of trovafloxacin administered through a nasogas-tric tube into the stomach or duodenum relative to that of awhole tablet given orally and to evaluate the effect of asupplemental enteral feeding solution on absorption of thesuspension when coadministered into the stomach.

METHODSTwenty-four healthy volunteers (nine men, 15 women)

were enrolled in this open-label, randomized, four-period,four-treatment, cross-over study. The study was conductedwith local Institutional Review Board approval. For inclu-sion, participants had to be between the ages of 20 and 65and women of childbearing potential were required to useappropriate contraceptive methods and to have had a neg-ative pregnancy test immediately before entry into thestudy. All subjects were required to weigh within 20% oftheir ideal body weight, as established by the 1983 Metro-politan Life Insurance height and weight tables. Laboratoryparameters, as evaluated by clinical chemistry and hema-tologic profiles and urinalysis, were required to be within10% of normal ranges. Subjects were to have negativeresults for hepatitis B surface antigen, ethanol breath tests,and urine drug screen. Informed written consent was ob-tained from each subject.

Any prescription or over-the-counter drug therapy orillicit drug use was prohibited for at least 2 weeks beforeenrollment, and investigational drug use was prohibited forat least 4 weeks before study participation. Subjects withevidence or a history of any of the following conditionswere excluded: clinically significant allergic, hematologic,endocrine, renal, gastrointestinal, cardiovascular, hepatic,psychiatric, or neurologic disease; any condition possiblyaffecting drug absorption; or peptic ulceration.

Subjects were randomly assigned to receive each of thefollowing treatments in cross-over fashion on study days 1,8, 15 and 22, with a 7-day washout between each dosingperiod: Treatment A: two 100-mg trovafloxacin tabletsgiven orally with 240 mL water; Treatment B: two crushed100 mg trovafloxacin tablets suspended in water and ad-ministered through a nasogastric tube into the stomach;Treatment C: two crushed 100-mg trovafloxacin tablets

suspended in water and administered through a nasogastrictube into the duodenum; Treatment D: two crushed100-mg trovafloxacin tablets suspended in water and giventhrough a nasogastric tube into the stomach, together withan enteral feeding solution (240 mL full-strength Osmolite,Ross Products Division, Abbott Laboratories, Columbus,OH).

On days 1, 8, 15, and 22, subjects were confined to theclinical research facility for at least 12 hours before and24 hours after dosing and were instructed to abstain fromfood and caffeine-containing beverages for at least 8 hoursbefore and 4 hours after dosing.

Blood samples were collected at hour 0 (just before dos-ing) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and48 hours after dosing on days 1, 8, 15, and 22. Serumtrovafloxacin concentrations were performed by means of avalidated high performance liquid chromatography methodthat used ultraviolet detection.21 The primary pharmaco-kinetic parameters evaluated included peak serum concen-tration (Cmax), time to peak serum concentration (Tmax),area under the concentration-time curve (AUC0–`), andthe terminal-phase half-life (t1/2).

Safety assessments included monitoring of adverse events,evaluated as to seriousness, severity, duration, and possiblerelationship to study drug. Vital signs were also recorded.

Statistical AnalysisNatural log-transformed AUC0–` and Cmax and untrans-

formed Tmax and elimination rate constant (Kel) valueswere analyzed by an analysis of variance (ANOVA) modelthat contained sequence, subject within sequence, period,treatment, and treatment-by-period interaction effects. A5% level of significance was used to test for these effects.For AUC0–` and Cmax, the antilog (exponent) of thedifferences and confidence limits were calculated to esti-mate the ratio between treatment effects (ie, relative bio-availability) and the 90% confidence interval of the ratio.For Tmax and Kel, the 90% confidence interval of the maindifference between treatments was calculated. The resultsfrom the group receiving orally administered, intact trova-floxacin were compared with the results from each of thegroups that received crushed trovafloxacin through a na-sogastric tube. No formal statistical analyses were per-formed on the safety data.

RESULTSBaseline Characteristics of Patients

Twenty-four healthy individuals participated in thestudy; none were excluded from the pharmacokinetic orsafety analyses. Participants ranged in age from 20 to 66years (mean age, 37.7 years). Twenty-three were white andone was black. Although 11 participants had at least oneconcomitant disease or syndrome noted in their medicalhistory at study entry, none of these diseases or syndromeswas anticipated to have an effect on study outcome. Allhad normal physical examination findings at baseline.

PharmacokineticsThe mean respective AUC0–` estimates of trovafloxa-

cin after Treatments A, B, and D were 23.9, 23.9, and24.0 mg z hour/mL (Table I). The 90% confidence limitsof the AUC0–` rates for Treatments B versus A (91.3%,

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109.5%) and Treatments D versus A (91.6%, 109.9%)were well within the bioequivalence criteria of 80% to125% (Table II). The mean respective Cmax values forTreatments A, B, and D were 2.0, 2.2, and 1.9 mg/mL. Tmaxvalues after oral and nasogastric administration into thestomach with concomitant enteral feeding were similar(1.7 and 2.0 hours, respectively), whereas nasogastric ad-ministration into the stomach without concomitant en-teral feeding resulted in a Tmax value of 1.1 hours. Themean t1/2 values for Treatments A, B, and D were 9.2, 9.4,and 9.9 hours, respectively. Repeated measures ANOVAindicated no significant sequence, period, or treatment-by-period interaction.

Administration of crushed trovafloxacin tablets into theduodenum (Treatment C) was associated with a 31% de-crease in the AUC0–` relative to oral administration (16.6vs. 23.9 mg z hour/mL). The Cmax value following Treat-ment C was decreased by 30% (1.4 vs. 2.0 mg z hour/mL),and the corresponding Tmax value was 1.1 hours. The t1/2value for Treatment C (9.0 hours) was not significantlydifferent from that of Treatment A (9.2 hours).

SafetyThe number of participants reporting adverse events and

the incidence of adverse events were similar across the four

treatment groups. Most adverse events were associatedwith the central and peripheral nervous systems (eg, head-ache, dizziness). With the exception of one report of severeheadache during Treatment A, all adverse events duringTreatments A, B, and D were mild to moderate in inten-sity. No serious adverse events were reported in any group,and no participant discontinued the study due to an ad-verse event. No clinically significant median changes frombaseline were observed in any vital sign parameter through-out the study. For a thorough review of the safety andtolerability of trovafloxacin, please see the article by Wil-liams and Hopkins.22

DISCUSSIONThis pharmacokinetic study conducted in healthy sub-

jects showed that crushed trovafloxacin tablets giventhrough a nasogastric tube into the stomach, with or with-out concomitant enteral feeding solution, achieved a sys-temic drug exposure equivalent to that of trovafloxacintablets administered orally. Nasogastric administration ofcrushed trovafloxacin tablets into the duodenum, however,resulted in substantially decreased systemic exposure to thedrug versus oral administration: a 31% decrease inAUC0–` and a 30% decrease in Cmax.

The effect of food on drug bioavailability is always of

TABLE IIStatistical Analysis of Pharmacokinetic Parameters of Trovafloxacin

ParameterTreatment

Comparisons*AdjustedMeans

Ratio orDifference

90% ConfidenceLimits

AUC0–` (mg z h/mL) B vs A 23.9 vs 23.9 100.0% (91.3%, 109.5%)C vs A 16.6 vs 23.9 69.2% (62.9%, 76.2%)D vs A 24.0 vs 23.9 100.3% (91.6%, 109.9%)

Cmax (mg/mL) B vs A 2.2 vs 2.0 111.0% (96.2%, 128.1%)C vs A 1.4 vs 2.0 69.6% (60.3%, 80.3%)D vs A 1.9 vs 2.0 95.5% (82.8%, 110.2%)

Tmax (h) B vs A 1.1 vs 1.7 20.6 (21.1, 20.1)C vs A 1.1 vs 1.7 20.6 (21.1, 20.1)D vs A 2.0 vs 1.7 0.3 (20.2, 0.8)

Kel B vs A 0.0735 vs 0.0755 20.0020 (20.0073, 0.0032)C vs A 0.0768 vs 0.0755 0.0013 (20.0042, 0.0068)D vs A 0.0701 vs 0.0755 20.0054 (20.0106, 20.0002)

* See Table I for explication of Treatments A–D. Arithmetic means and differences for Tmax and Kel; Geometric means and ratios forAUC0–` and Cmax.

TABLE IPharmacokinetic Parameters (Mean 6 SD) of Trovafloxacin Administered Orally or Nasogastrically

Parameter

Treatment*

A B C D

AUC0–t (mg z h/mL)† 22.1 6 7.2 21.8 6 7.0 13.4 6 5.7 22.0 6 5.8AUC0–` (mg z h/mL)† 23.9 6 7.2 23.9 6 6.9 16.6 6 5.8 24.0 6 5.6Cmax (mg/mL)† 2.0 6 0.5 2.2 6 0.9 1.4 6 0.7 1.9 6 0.4Tmax (h)‡ 1.7 6 0.9 1.1 6 0.9 1.1 6 1.0 2.0 6 1.5Kel (h21)‡ 0.0755 6 0.0188 0.0735 6 0.0182 0.0788 6 0.0158 0.0701 6 0.0189T1/2 (h)‡§ 9.2 9.4 8.8 9.9

* Treatment A: two whole 100-mg trovafloxacin tablets administered orally with 240 mL water; Treatment B: two crushed 100-mgtrovafloxacin tablets suspended in water and administered via nasogastric tube into the stomach; Treatment C: two crushed 100-mgtrovafloxacin tablets suspended in water and administered via nasogastric tube into the duodenum; Treatment D: two crushed 100-mgtrovafloxacin tablets suspended in water and administered via nasogastric tube into the stomach concomitantly with an enteral feedingsolution containing cations (240 mL full-strength Osmolite). † Mean values and standard deviations are geometric. ‡ Mean values andstandard deviations are arithmetic. § Estimated as 0.693/mean Kel.

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concern with orally administered medications, because thepresence of food in the gastrointestinal tract is known toalter the absorption of many drugs, potentially undermin-ing therapeutic efficacy.23 Previous studies have establishedthat the presence of food is unlikely to alter significantlythe pharmacokinetics of orally administered trovafloxacintablets.23 However, because enteral feeding solutions con-tain cations that may reduce trovafloxacin absorption, asobserved with antacid suspensions,20 it was necessary todetermine whether concomitant administration with acommonly used enteral feeding solution (Osmolite) wouldalter bioavailability. Lack of interaction between the feed-ing solution and trovafloxacin in this study was reassuring.

The present observations for trovafloxacin are consistentwith those reported previously for other fluoroquinolones.Delivery of ciprofloxacin via a nasogastric tube did notchange its bioavailability relative to oral administration.2

Whereas convenient once-daily parenteral antibiotic ther-apy with trovafloxacin can be achieved by administrationof its prodrug, alatrofloxacin,24 the ability to deliver trova-floxacin via a nasogastric tube provides an alternative withpotential for lowering costs associated with treatment inpatients with such devices in place.

Regardless of the method of administration, trovafloxacinwas well tolerated, with dizziness and headache the mostcommonly reported adverse events in each treatmentgroup. No subjects discontinued the study due to adverseevents, and no serious adverse events were reported. Withthe exception of one severe headache, no severe adverseevents were reported with oral or nasogastric administra-tion into the stomach.

CONCLUSIONThese results indicate that administration of trovafloxa-

cin via a nasogastric tube into the stomach is well toleratedand results in absorption similar to that of orally adminis-tered trovafloxacin, an attribute that should prove useful inclinical settings. Moreover, together with evidence of thebioequivalence of oral and intravenous formulations oftrovafloxacin,24 the current findings demonstrate that pa-tients can be switched from either of these dosage forms tothe other. Finally, this study has indicated that physicianscan prescribe administration of trovafloxacin via the naso-gastric route with concomitant enteral feeding withoutcompromising the bioavailability of the antibiotic.

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