pharmacokinetics and metabolism of single oral doses of trovafloxacin

Pharmacokinetics and Metabolism of SingleOral Doses of Trovafloxacin

John Vincent, MD, PhD, Renli Teng, PhD,* Deepak K. Dalvie, PhD, Hylar L. Friedman, MD,Groton, Connecticut

Trovafloxacin, a new fluoronaphthyridone deriva-tive related to fluoroquinolone antimicrobialdrugs, has demonstrated the following charac-teristics: significant gram-positive and gram-negative activity; significant activity againstanaerobes and atypical respiratory pathogens;approximately 11-hour elimination half-life, per-mitting once-daily administration; and good tis-sue penetration. Because <10% of an orally ad-ministered dose is recovered in urine asunchanged drug, the predominant route of trova-floxacin elimination appears to be nonrenal. Thetwo studies described in this review examinedthe metabolism and excretion of trovafloxacinand compared the time course and concentra-tions of trovafloxacin and its metabolites in bileto those in serum.

In the first study, four healthy male volunteersreceived a single, oral 200-mg dose of radiola-beled trovafloxacin. In the second study, threepatients with indwelling nasobiliary tubes re-ceived a single 200-mg dose of trovafloxacin.Samples of blood, urine, bile, and feces werecollected. Trovafloxacin in urine and serum wasanalyzed by high-performance liquid chromatog-raphy (HPLC) with ultraviolet (UV) detection andin bile by HPLC-mass spectroscopy (MS). Levelsof the N-acetyl metabolite in bile were deter-mined by HPLC/UV/MS. Metabolites in serum,urine, and feces were determined by reverse-phase HPLC/MS, and radioactivity in these sam-ples was assayed by liquid scintillation counting.

In the first study, 63.3% and 23.1% of total ra-dioactivity were recovered in feces and urine,respectively, with most of the radioactivity inurine in the form of the ester glucuronide metab-olite (12.8%) and unchanged trovafloxacin (5.9%).Unchanged drug, the N-acetyl metabolite, andthe N-sulfate of trovafloxacin accounted for43.2%, 9.2%, and 3.9%, respectively, of the ra-dioactivity in feces. In the second study, biliarytrovafloxacin concentrations were highest be-tween 1.5 and 10 hours postdose, and the maxi-

mum concentrations ranged from 18.9 to 37.9mg/mL. The mean bile:serum ratio of trovafloxa-cin was 14.9, and the biliary concentration ofparent drug was higher than that of its N-acetylmetabolite. In both studies, trovafloxacin waswell tolerated, with no discontinuations due toadverse events.

The pharmacokinetic profile of trovafloxacin inserum was consistent in healthy subjects and inindividuals who had undergone recent hepato-biliary surgery. Trovafloxacin is metabolized pri-marily by the liver, through phase II metabolism(glucuronidation 13.2%, N-acetylation 10.4%, andN-sulfoconjugation 4.1%); minimal oxidative me-tabolism was detected. Renal elimination ac-counted for <10% of the administered dose. Thehigh bile to serum ratio and higher trovafloxacinconcentrations relative to metabolite concentra-tions are consistent with nonrenal elimination.These pharmacokinetic and pharmacodynamicresults, together with a broad antimicrobialspectrum, long 11-hour elimination half-life, andlow drug-interaction potential, suggest thattrovafloxacin may be particularly appropriate foruse in the surgical setting. Am J Surg. 1998;176(Suppl 6A):8S–13S. © 1998 by Excerpta Medica,Inc.

Newer-generation fluoroquinolone antibiotics haveexcellent activity against gram-negative pathogensand are effective in the treatment of a wide range

of infections, including those of the respiratory tract, uri-nary tract, and skin and skin structure, as well as againstsexually transmitted diseases and for surgical prophylax-is.1–3 In contrast, older fluoroquinolones have relativelypoor activity against clinically important enterococci,streptococci, and anaerobic bacteria.4 The older drugs inthis class also have elimination half-lives that necessitateadministration at least twice a day and require dosageadjustments in patients with renal dysfunction.4,5

Trovafloxacin, a new fourth-generation fluoroquinolone,offers significant advantages over older members of thisclass. Trovafloxacin is highly active in vitro against a widerange of gram-positive bacteria (including penicillin-resis-tant strains) and anaerobes,6,7 while retaining the tradi-tional gram-negative activity of fluoroquinolones.8 Theapproximately 11-hour half-life (t1/2) permits once-daily(oral or intravenous) dosing for all indications.9,10 Al-though much is known about the serum pharmacokineticsof trovafloxacin9,11 and its penetration levels in tissues,12

inflammatory fluids,13 and cells,14 its metabolism and elim-ination in humans are less completely understood. The

From the Department of Clinical Research, Pfizer Central Re-search, Groton, Connecticut.

* Current affiliation: Astra Merck, Wayne, Pennsylvania.Requests for reprints should be addressed to Dr. John Vincent,

Pfizer Central Research, Eastern Point Road, Groton, Connecti-cut 06340.

8S © 1998 by Excerpta Medica, Inc. 0002-9610/98/$19.00All rights reserved. PII S0002-9610(98)00213-X

degree of renal elimination of older fluoroquinolonesvaries.2–4,15 For example, 30% to 50% of a dose of cipro-floxacin is excreted in the urine, whereas 73% to 90% of adose of ofloxacin is eliminated by the kidneys.2–4 However,relatively little trovafloxacin (,10%) is excreted in theurine,9,11 suggesting that the primary route of eliminationis nonrenal. Results in experimental animals support thisobservation.16

Older fluoroquinolones also vary in their potential forinteracting with other drugs.17,18 Minimal oxidative me-tabolism of trovafloxacin and the associated reduced po-tential for drug–drug interactions confers potential clinicalsignificance and advantages for surgical patients, who arelikely to receive additional medication, including anesthet-ics, analgesics, and muscle relaxants.

This article reviews the results of two studies of themetabolism and elimination of orally administered trova-floxacin19 and the time course and concentrations of trova-floxacin and its metabolites in bile to those in serum.

METHODSStudy Population

The metabolism of radiolabeled trovafloxacin was as-sessed in four healthy men (study 1), and hepatobiliaryelimination was evaluated in two men and one woman(study 2). Local institutional review board approval wasobtained prior to the initiation of each study and writteninformed consent was obtained from all enrollees. Partici-pants were within 30% of ideal weight for age, sex, height,and frame, as established in the 1983 Metropolitan LifeInsurance tables. The women tested negative for pregnancyand agreed to use an appropriate birth-control methodduring the trial. All participants tested negative for bothhepatitis B surface antigen and core antibody and hadtaken no investigational drugs for at least 4 weeks orrecreational or over-the-counter drugs within the previous2 weeks. None had any condition that could affect drugabsorption, were hypersensitive to quinolones, or had evi-dence or history of clinically significant allergic, hematologic,renal, pulmonary, endocrine, gastrointestinal, cardiovascu-lar, hepatic, psychiatric, or neurologic disease (includingall forms of epilepsy). The patients in study 2 had biliaryT-tubes or indwelling nasobiliary tubes associated withbiliary tract surgery for cholecystostomy secondary to cho-lecystitis (two patients) and cholelithiasis (one patient).The study was performed 4 to 5 days postoperatively topermit stabilization of biliary flow.

TreatmentVolunteers in study 1 received a suspension equivalent to

200 mg of trovafloxacin base that contained 118 mCi of[14C]trovafloxacin. Participants fasted for 8 hours beforedosing. In order to standardize experimental conditions,patients did not eat and refrained from drinking caffeinatedbeverages for 4 hours after dosing; they then consumed astandard meal.19 Patients in study 2 were given a single200-mg oral dose of trovafloxacin with 240 mL of water onan empty stomach at approximately 7:00 AM. They ab-stained from food and caffeine-containing beverages for atleast 8 hours before and for 4 hours after study drug ad-ministration. No restrictions were placed on drinkingwater.

Sample CollectionBlood samples were collected just before and 0.5, 1.5, 2,

3, 4, 6, 8, 12, 16, 24, 48, and 72 hours after dosing in bothstudies and also 96, 120, 144, 168, 192, 216, and 240 hoursafter dosing in study 1.19 Additional samples were obtained1, 5, and 12 hours after dosing in study 1 for quantitationand characterization of the compound and related metab-olites.19

Samples were collected in evacuated tubes, allowed toclot for 45 minutes at room temperature, and centrifuged toseparate the serum. Serum samples were immediately fro-zen and stored at 220°C.

Bile samples were collected before trovafloxacin admin-istration and from 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, 6 to8, 8 to 12, 12 to 16, 16 to 24, 24 to 36, 36 to 48, and 48to 72 hours postdose. Bile volumes were recorded andsamples were frozen at 220°C.

In study 1, urine was collected just before dosing and in24-hour blocks for at least 10 days after administration of[14C]trovafloxacin or until two consecutive urine and fecalsamples contained ,1% of the administered radioactivity.All urine voided in the first 24 hours and 30-mL aliquotsfrom specimens of all other blocks were stored at 220°Cuntil assayed for trovafloxacin.19 In study 2, all urine col-lected for 72 hours after trovafloxacin dosing was pooled as24-hour fractions; 20-mL aliquots from each collectionperiod were stored at 270°C.

Fecal samples were collected from study 1 during at least240 hours after dosing or until two consecutive urine andfecal samples contained ,1% of the administered radioac-tivity.19

Analysis of Trovafloxacin and MetabolitesSerum and urinary concentrations of trovafloxacin were

measured by a validated high-performance liquid chroma-tography (HPLC) assay with ultraviolet (UV) detection(dynamic range 0.1 to 20.0 mg/mL).20 Bile concentrationsof trovafloxacin and its N-acetyl metabolite were deter-mined by HPLC mass spectroscopy (MS); dynamic rangesof these assays were 0.025 to 25 mg/mL and 0.1 to 2.5mg/mL, respectively. HPLC/UV/MS was used to measureother metabolites in bile samples. In study 1, trovafloxacinmetabolites were measured in deproteinated serum, lyo-philized urine, and extracted feces by reverse-phase HPLC/MS.19

The total radioactivity in serum and urine was quanti-tated directly by liquid scintillation counting. Feces weresuspended in water, hoursomogenized, air-dried, and com-busted in an oxidizer, with the liberated 14CO2 trapped incarbosorb, placed in liquid scintillate, and counted. Theamount of radioactivity in the dose was expressed as 100%;radioactivity in the urine and feces at each sampling timewas expressed as the percentage of dose excreted in thosematrices. The amount of radioactivity in the serum, ex-pressed as milligram-equivalents/milliliter, was calculatedby means of the specific activity of the administered dose,and the minimum quantifiable level of radioactivity was setat twice the background level (0.3 mg-Eq/mL). Metabolitesin urine and fecal extracts were quantified by determiningthe percentage of radioactivity in individual peaks ob-tained by reverse-phase HPLC, and the percentages of

PHARMACOKINETICS AND METABOLISM OF TROVAFLOXACIN/VINCENT ET AL

THE AMERICAN JOURNAL OF SURGERY® VOLUME 176 (Suppl 6A) DECEMBER 1998 9S

metabolites in serum were determined by fractionatingserum samples and counting individual effluents.19

Pharmacokinetic AnalysisThe terminal-phase rate constant (Kel) was estimated

through least-squares regression analysis of trovafloxacinserum concentration-time data obtained over the terminallog-linear phase; Kel also was calculated through least-squares regression analysis of biliary excretion rate–mid-point time data over the terminal log-linear dispositionphase. Individual terminal-phase half-lives were calculatedas 0.693/Kel, with mean t1/2 defined as 0.693/mean Kel. Themaximum serum concentration (Cmax) and its time ofoccurrence (Tmax) for each dose were obtained directlyfrom experimental data. The area under the concentration–time curve (AUC) from zero to the last sampling time (t)with a quantifiable concentration (AUC0–t) was calcu-lated by the linear trapezoidal rule.

The area from t to infinity (AUCt–`) was estimated asCest(t)/Kel, in which Cest(t) is the estimated concentrationat time t based on the regression analysis for Kel. The totalAUC from zero to infinity (AUC0–`) was estimated as thesum of AUC0–t and AUCt–`, whereas the AUC0–24 fortrovafloxacin and its N-acetyl metabolite in bile were ob-tained as 0–24 Cb 3 DT, with Cb representing the con-centration of drug or metabolite at the collection interval(DT).

Safety EvaluationsCausality was judged and recorded for all observed or

volunteered adverse events occurring within 7 days of drugadministration. Vital signs were recorded at screening, justprior to, and 24 hours after trovafloxacin administration.

Statistical AnalysisPharmacokinetic data for each study participant were

summarized through data tabulations, descriptive statistics,and graphic presentations. The mean values and standarddeviations for Cmax and AUC0–24 were geometric. Noinferential statistical analyses were performed.

RESULTSSerum Pharmacokinetics

For participants in study 1, the Cmax for trovafloxacin was2.9 6 0.4 mg/mL, the Tmax 1.3 6 0.5 hours, the AUC0–`

32.2 6 8.6 mg z hours/mL, and the t1/2 13.6 hours (TableI). For patients in study 2, the Cmax was 2.0 6 0.4 mg/mL,Tmax 3.7 6 0.6 hours, AUC0–` 22.0 6 5.5 mg z hours/mL,and t1/2 8.5 hours (Table I).

Metabolism and EliminationWithin 50 h after dosing, most radioactivity was recov-

ered unmetabolized in feces (Figure 1); by 240 hours, fecalrecovery of the total radioactivity was 63.3 6 2.2%(mean 6 standard deviation). Most of the remaining dosewas recovered in urine during this time, and by 240 hours,urinary recovery of parent compound plus metabolites av-eraged 23.1 6 3.7% of the trovafloxacin dose.19

Of the radioactivity recovered in urine, 12.8% was in theform of the ester glucuronide metabolite of trovafloxacinand 5.9% was unchanged drug (Table II). In feces, trova-

floxacin accounted for 43.2% of the total radioactivityrecovered, whereas N-acetyl-trovafloxacin and the sulfatemetabolite accounted for 9.2% and 3.9%, respectively. Themain compounds in serum were unmetabolized trovafloxa-cin (51.6%) and its glucuronide metabolite (21.7%).19

Trovafloxacin concentrations in bile (Table III) were10-fold higher than those achieved in serum. The meanCmax was 27.8 6 9.6 mg/mL, mean Tmax 6.2 6 4.3 hours,mean AUC0–24 327.7 6 142.9 mg z hours/mL, and meant1/2 10.7 hours. The pharmacokinetic parameters for theN-acetyl metabolite of trovafloxacin in bile are also sum-marized in Table III. The mean Cmax for this metabolitewas 3.8 6 3.4 mg/mL, mean Tmax 12.5 6 8.4 hours, meanAUC0–24 35.3 6 29.8 mg z hours/mL, and mean t1/28.3 hours. The glucuronide and sulfate metabolites oftrovafloxacin were also present in bile.

Oral administration of a single trovafloxacin dose waswell tolerated in both studies. Only one individual in study1 experienced an adverse event (back pain); in study 2,three adverse events (one moderate headache, two in-stances of mild gastrointestinal pain) occurred. None ofthese events were considered treatment related, and noserious adverse events or serious laboratory abnormalitieswere reported in either study. No patients discontinued thestudies due to adverse events. For a thorough review of thesafety and tolerability of trovafloxacin, see Williams andHopkins in this supplement.21

DISCUSSIONThe results reviewed here support several conclusions.

First, because the pharmacokinetic profile for this newfourth-generation fluoroquinolone was not substantially al-tered in patients having undergone recent hepatobiliarysurgery, trovafloxacin should be suitable for the treatmentof indicated infections in this population. Second, trova-floxacin undergoes phase II conjugation in the liver and iseliminated primarily in feces. Third, only a small amount ofa trovafloxacin dose is eliminated renally.

Metabolism and Drug-Interaction PotentialAs indicated in this review, trovafloxacin undergoes pri-

marily phase II hepatic metabolism (glucuronidation, N-acetylation, and N-sulfoconjugation); oxidative metabo-lism is minimal (Figure 2).19 It is important to note that

TABLE ISerum Pharmacokinetic Profile of Trovafloxacin in Healthy

Volunteers and Surgical Patients

MeasureHealthy

VolunteersSurgicalPatients

Cmax (mg/mL) 2.9 2.0(0.4) (0.4)

Tmax (hours) 1.3 3.7(0.5) (0.6)

AUC0–` (mg z hours/mL) 32.2 22.0(8.6) (5.5)

t1/2 (hours) 13.6 8.5Kel (hours21) 0.051 0.081

(0.02) (0.015)

Mean with SD in parentheses.


10S THE AMERICAN JOURNAL OF SURGERY® VOLUME 176 (Suppl 6A) DECEMBER 1998

most of a trovafloxacin dose reaches the bile as unchangeddrug. The maximum concentrations of trovafloxacin in bileranged from 18.9 to 37.9 mg/mL and the mean bile:serumratio of trovafloxacin was 14.9. The maximum biliary con-centration of the parent drug was more than seven timesgreater than that of its microbiologically inactive N-acetylmetabolite.

It has been suggested that the potential for drug–druginteractions with a fluoroquinolone may be predicted bythe degree to which the antibiotic is metabolized throughoxidative mechanisms.15,17 Currently available findings fortrovafloxacin and other fluoroquinolones corroborate thisobservation. For example, ciprofloxacin significantly re-duces theophylline clearance, most likely as a result ofinhibition of the hepatic oxidative enzyme CYP1A2.22,23

In contrast, trovafloxacin differs from other fluoroquino-lones in that it undergoes minimal hepatic oxidation anddoes not alter the steady-state pharmacokinetics of theoph-ylline.23,24

While in the hospital, patients receive an average of 10

concomitant drugs, and surgical candidates may receivemany drugs perioperatively as part of their anesthetic reg-imen; this substantially increases the likelihood for druginteractions.25 The potential for interactions with otherperioperative medications adds fuel to the controversy sur-rounding use of prophylactic antibiotics in the surgicalsetting.26 Antibiotics such as trovafloxacin, with appropri-ately broad antibacterial spectra and low potential fordrug–drug interactions, may provide the safest and mosteffective surgical prophylaxis.

Route of EliminationThe results reviewed here indicate that trovafloxacin is

eliminated primarily in feces.19 The pharmacokinetic pro-file of trovafloxacin is thus unlikely to be altered in patientswith renal insufficiency.10 This characteristic distinguishestrovafloxacin from older fluoroquinolones. An evaluationof ciprofloxacin pharmacokinetics in patients with renalimpairment noted that both the Cmax and AUC of theparent drug and its primary metabolite were significantly

Figure 1. Mean percent radioactivity recovered from urine and feces of healthy male volunteers after a single oral dose of [14C]-trovafloxacin.

TABLE IIPooled Data for Trovafloxacin and Metabolites in Serum,

Feces, and Urine

Metabolite Serum (%)* Feces (%)† Urine (%)‡

Ester glucuronide 21.7 6 3.5 ND 12.8 6 1.5Ester glucuronide

of CP-161,320 2.7 6 0.8 ND 0.4 6 0.3Trovafloxacin 51.6 6 10.0 43.2 6 6.3 5.9 6 1.5Sulfate ND 3.9 6 2.0 0.2 6 0.1Diacid ND 0.9 6 0.5 0.2 6 0.1Hydroxycarboxylic acid ND NC 0.3 6 0.1N-Acetyl (CP-161,320) 2.5 6 1.0 9.2 6 5.2 1.2 6 0.5Pyrroline trace trace trace

ND 5 not detected; NC 5 not calculated. * 1, 5, and 12 hours postdose.† 0–120 hours postdose. ‡ 0–72 hours postdose.

TABLE IIIPharmacokinetic Parameters for Trovafloxacin and Its

N-Acetyl Metabolite in Bile

Parameter Trovafloxacin N-Acetyl Metabolite

Cmax (mg/mL) 27.8 3.8(9.6) (3.4)

Tmax (hours) 6.2 12.5(4.3) (8.4)

AUC0–24 (mg z hours/mL) 327.7 35.3(142.9) (29.8)

t1/2 (hours) 10.7 8.3Kel (hours21) 0.065 0.083

(0.012) (0.052)

Mean with SD in parentheses.



increased in patients with reduced creatinine clearance.27

Significant increases in the AUC and t1/2 of ciprofloxacinreported in patients with renal insufficiency prompted therecommendation for dose reduction in the presence of acreatinine clearance ,20 mL/min.28 Renal dysfunctionalso affects the pharmacokinetics of ofloxacin and levo-floxacin.29,30 In contrast, no dosage adjustment is requiredfor trovafloxacin in patients with impaired renal functionor acute hepatic changes (eg, elevated hepatic transami-nase activity in acute infection).31,32 Dosage adjustment isrequired, however, in patients with mild-to-moderate cir-rhosis (Child-Pugh Class A and B); patients with severecirrhosis (Child-Pugh Class C) have not been studied.That elimination of trovafloxacin is not altered to a clin-ically significant degree in patients with renal dysfunctionis particularly important in the surgical setting, since acuterenal failure can occur perioperatively, particularly in theelderly.33,34

In summary, trovafloxacin is excreted unchanged, primar-ily in the feces, with urinary excretion accountingfor ,10% of a single dose. Greater biliary concentrationsof trovafloxacin compared with the N-acetyl metabolite areconsistent with limited hepatic metabolism of trovafloxa-cin or efficient clearance of the metabolite. As renal elim-ination is low, there is no need for dose adjustment inpatients with renal dysfunction. Trovafloxacin is metabo-lized by phase II conjugation in the liver; the minimaloxidative metabolism is expected to reduce the potentialfor drug–drug interactions. In both studies, trovafloxacinwas well tolerated with no discontinuations due to adverseevents.

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Figure 2. Proposed metabolic pathway of trovafloxacin in healthy male volunteers. U 5 urine; F 5 feces; S 5 serum.


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pharmacokinetics and metabolism of single oral doses of trovafloxacin

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