RESEARCH/PRACTICE REPORTS
DOSE-RANGING PHARMACOKINETIC STUDY OF CIPROFLOXACIN AFrER 2()()', 3()()', AND 4OO-MG INTRAVENOUS DOSES David E. Nix,J. Michael Spivey, Allyn Norman, and Jerome J. Schentag
To assess the pharmacokineticsand toleranceof ciprofloxacinafter the administrationof single intravenousdoses of 200, 300, and 400 mg. DESIGN: Double-blind,three-period,randomized,crossover trial.
OBJRCTIVE:
Private, university-affiliated, hospital-based, clinical researchcenter. PATIENTS: Normal healthy male volunteers, 18-40 years of age. INTERVENTIONS: Subjects received 200-, 300-, and 4OO-mg single intravenousdoses of ciprofloxacin via 30-minute infusions in random sequence. MAIN OUTCOME MEASURES: Serum ciprofloxacinconcentrationswere determinedby HPLC after each dose and the results were used to derive phannacokinetic parameters.Tolerance was assessed by reported and observed adverse events, urine microscopic examinationsfor crystals, and examination of intravenous infusion sites. SETIlNG:
The mean area under the time curve (AUC) values displayed linearity with respect to the administereddose. No statisticaldifferenceswere observed in total body clearance, steadystate volume of distribution,or elimination half-life with respect to dose administered. The mean total body clearance, steady-state volume of distribution,or elimination half-life ranged from 36 to 41 L/h, 146 to 169 L, and 3.5 to 3.7 h for the 200-, 300-, and 400-mg doses, respectively. Adverse effects, including venous irritation(four subjects)and crystalluria(two subjects), were mild and did not require withdrawal of any subject from the study. CONCLUSIONS: Intravenous ciprofloxacinin doses ranging from 200 to 400 mg demonstrated linear pharmacokinetics. These single doses were well tolerated,although cases of transient venous irritationand crystalluriawere observed. RESULTS:
Ann Pharmacother 1992;26:8-10. DAVID E. NIX, Pharm.D., is the Assistant Director, Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, and a Clinical Assistant Professor of Pharmacy, Center for Clinical Pharmacy Research, State University of New York at Buffalo; J. MICHAEL SPIVEY, Pharm.D., is a Clinical Instructor, Department of Family Medicine, East Carolina Medical School, Greenville, NC; at the time of this work, he was a Fellow at The Clinical Pharmacokinetics Laboratory of Millard Fillmore Hospital; ALLYN NORMAN, D.O., is an Attending Physician, Department of Medicine, Millard Fillmore Hospital; JEROME J. SCHENTAG, Pharm.D., is the Director, Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, a Professor of Pharmaceutics and Pharmacy, and the Chairman, Center for Clinical Pharmacy Research, State University of New York at Buffalo. Reprints: David E. Nix, Pharm.D.; Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, 3 Gates CiT.,Buffalo, NY 14209.
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is active against a wide variety of gram-positive and gram-negative pathogens, including Pseudomonas aeruginosa and Staphylococcus aureus) Previous dose-ranging pharmacokinetic studies with intravenous ciprofloxacin have been limited to doses ~250 mg. l ' S The recent emergence of resistant isolates of P. aeruginosa, S. aureus, and other marginally susceptible pathogens has led to proposals to use higher doses of intravenous ciprofloxacin.v-'! The objectives of this study were to evaluate the linearity of the pharmacokinetics of ciprofloxacin after single intravenous doses ranging from 200 (0.60 mmol) to 400 mg (1.21 mmol) and to compare their toxicities in a randomized, double-blind, crossover fashion. CIPROFLOXACIN, A FLUOROQUINOLONE ANTIBIOTIC,
Methods The study was approved by the Millard Fillmore Hospital Human Research Committee, and writteninformed consentwas obtainedfrom each subject. Twelve male volunteers between the ages of 18 and 40 years were recruited. Subjectsweighedwithin 15percentof their ideal body weight as determinedby the MetropolitanLife InsuranceTable, 1983. They weredetermined to be healthy by history andphysical examination and by clinical laboratory profiles. Excluded from the study were patients witha clinically significant history of cardiovascular, respiratory, liver, renal,or gastrointestinal diseases; enlarged prostate; glaucoma; neurologicor psychiatricdisorders; significantdrug or alcohol abuse; history of allergy to ciprofloxacin or othercarboxyquinolones; or use of any medication within 24 hoursof the study. Subjectswere instructed to abstainfrom any caffeinated beverages, charcoal-broiled foods, smoking, alcoholic beverages, and nonsteroidal antiinflammatory drugs24 hoursbeforeandaftereachdose. The subjects werealso askedto fast from midnight the nightbeforeeach dosing period. Subjects received a standard lunchanddinnerat three andninehours, respectively, relative to the starting timeof theciprofloxacin dosing. Each subjectreceivedsingleintravenous dosesof 200 (0.60mmol), 300 (0.91 mmol), and 400 mg (1.21 mmol) of ciprofloxacin, witha seven-daywashoutintervalbetweendosingperiods. The sequence of dosingperiods was randomized and double-blind. An appropriate volume of intravenous ciprofloxacin solution 200mgl20mL (lot#2417; Miles) was added to sterilebags, and a sufficient volumeof NaCI 0.9% was added to provide a total volume of 200 mL. Doses were prepared by an unblinded pharmacist Ciprofloxacin was delivered as a constant-rate infusion over 30 minutesby an infusion pumpintoa forearm vein.The subjects received each dose at the sametimeof day. An indwelling venous catheterwitha male
TheAnnalsofPharmacotherapy • 1992 January, Volume 26
a two-compartment intravenous infusion model and nonlinear regression analysis with l/y2 weighting, which best characterized the ciprofloxacin concentration-time profiles. Table 1 provides the mean pharmacokinetic parameters for the three dosage levels. The mean ciprofloxacin concentration-time curves for all three dosage levels are shown in Figure 1. The mean AVC values displayed linearity with respect to the administered dose. No statistically significant differss ences were seen in total body Cl, Vd , or Btl /2 with respect to the three dosage levels (p>0.05).
adaptor plug was inserted in the ann opposite the ciprofloxacin infusion site for blood sampling. The catheter was kept patent with a dilute heparin solution (10 units/ml.), which was extracted prior to blood sampling. Blood samples were collected before the start of the ciprofloxacin infusion, 15 and 30 minutes after the infusion was started, and at 0.25, 0.5, 1,2,3,4,6,8, 10, 12, 16, and 24 hours after ciprofloxacin administration was completed. Blood samples were collected in heparinized tubes and centrifuged within one hour of collection. Plasma was separated and frozen at -20°C. Plasma ciprofloxacin concentrations were determined by HPLC by Miles as described prevlously.uThe minimum detection limit was 0.0 I mg/L. The intra- and interday coefficients of variation ranged from four to nine percent. The mobile phase consisted of acetonitrile:methanol and trichloroacetic acid with pH adjusted to 3.0 with IN sodium hydroxide. Two- and three-compartment intravenous infusion models were used to fit the plasma ciprofloxacin concentration-time profiles by using nonlinear least-squares regression.» Selection of the appropriate model was determined by evaluation of Akaike's Information Criterioni- and inspection of the residuals. The area under the time curve (AVC) and the area under the first moment curve (AVMC) were integrated from the model and estimated phannacokinetic parameters. The total body clearance (CI) and steady-state volume of distribution (vt) were calculated using AVe, AUMC, and appropriate equations. The mean values for total body CI, vt, and elimination half-life (6t '/2) for the three dosage levels within subjects were compared using ANDV A appropriate for a three-way crossover design. An alpha level of 0.05 was used to defme a significant difference.
Discussion Plasma ciprofloxacin concentration-time curves were best characterized by a two-compartment intravenous infusion model, which is consistent with previously reported concentration-time data in normal volunteers.v' In addition, an apparent third elimination phase, which was seen but could not be fully described, has been reported.' A plausible explanation for this delayed elimination phase would be slow release from a tissue compartment, which is compatible with ciprofloxacin's extensive tissue distribution. This slow terminal elimination rate is unlikely to be clinically significant. Previous studies have reported a linear relationship between dose and AVC with ciprofloxacin at lower doses.3-6,8 ss The mean total body Cl, Vd , and Btl / 2 observed in this study were in agreement with previous studies in subjects with normal renal and hepatic function and did not differ with respect to increasing dosage levels. 2,4-6,8 The presence
Results All 12 subjects completed the study. The mean age was 24.5 ± 3 years (range 20-30) and mean weight was 78.0 ± 8.7 kg (range 64-91). Two subjects were noted to have possible ciprofloxacin crystals in their urine. These crystals were round with irregular edges and were
DOSE-RANGING PHARMACOKINETIC STUDY OF CIPROFLOXACIN AFrER 2()()', 3()()', AND 4OO-MG INTRAVENOUS DOSES David E. Nix,J. Michael Spivey, Allyn Norman, and Jerome J. Schentag
To assess the pharmacokineticsand toleranceof ciprofloxacinafter the administrationof single intravenousdoses of 200, 300, and 400 mg. DESIGN: Double-blind,three-period,randomized,crossover trial.
OBJRCTIVE:
Private, university-affiliated, hospital-based, clinical researchcenter. PATIENTS: Normal healthy male volunteers, 18-40 years of age. INTERVENTIONS: Subjects received 200-, 300-, and 4OO-mg single intravenousdoses of ciprofloxacin via 30-minute infusions in random sequence. MAIN OUTCOME MEASURES: Serum ciprofloxacinconcentrationswere determinedby HPLC after each dose and the results were used to derive phannacokinetic parameters.Tolerance was assessed by reported and observed adverse events, urine microscopic examinationsfor crystals, and examination of intravenous infusion sites. SETIlNG:
The mean area under the time curve (AUC) values displayed linearity with respect to the administereddose. No statisticaldifferenceswere observed in total body clearance, steadystate volume of distribution,or elimination half-life with respect to dose administered. The mean total body clearance, steady-state volume of distribution,or elimination half-life ranged from 36 to 41 L/h, 146 to 169 L, and 3.5 to 3.7 h for the 200-, 300-, and 400-mg doses, respectively. Adverse effects, including venous irritation(four subjects)and crystalluria(two subjects), were mild and did not require withdrawal of any subject from the study. CONCLUSIONS: Intravenous ciprofloxacinin doses ranging from 200 to 400 mg demonstrated linear pharmacokinetics. These single doses were well tolerated,although cases of transient venous irritationand crystalluriawere observed. RESULTS:
Ann Pharmacother 1992;26:8-10. DAVID E. NIX, Pharm.D., is the Assistant Director, Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, and a Clinical Assistant Professor of Pharmacy, Center for Clinical Pharmacy Research, State University of New York at Buffalo; J. MICHAEL SPIVEY, Pharm.D., is a Clinical Instructor, Department of Family Medicine, East Carolina Medical School, Greenville, NC; at the time of this work, he was a Fellow at The Clinical Pharmacokinetics Laboratory of Millard Fillmore Hospital; ALLYN NORMAN, D.O., is an Attending Physician, Department of Medicine, Millard Fillmore Hospital; JEROME J. SCHENTAG, Pharm.D., is the Director, Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, a Professor of Pharmaceutics and Pharmacy, and the Chairman, Center for Clinical Pharmacy Research, State University of New York at Buffalo. Reprints: David E. Nix, Pharm.D.; Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, 3 Gates CiT.,Buffalo, NY 14209.
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is active against a wide variety of gram-positive and gram-negative pathogens, including Pseudomonas aeruginosa and Staphylococcus aureus) Previous dose-ranging pharmacokinetic studies with intravenous ciprofloxacin have been limited to doses ~250 mg. l ' S The recent emergence of resistant isolates of P. aeruginosa, S. aureus, and other marginally susceptible pathogens has led to proposals to use higher doses of intravenous ciprofloxacin.v-'! The objectives of this study were to evaluate the linearity of the pharmacokinetics of ciprofloxacin after single intravenous doses ranging from 200 (0.60 mmol) to 400 mg (1.21 mmol) and to compare their toxicities in a randomized, double-blind, crossover fashion. CIPROFLOXACIN, A FLUOROQUINOLONE ANTIBIOTIC,
Methods The study was approved by the Millard Fillmore Hospital Human Research Committee, and writteninformed consentwas obtainedfrom each subject. Twelve male volunteers between the ages of 18 and 40 years were recruited. Subjectsweighedwithin 15percentof their ideal body weight as determinedby the MetropolitanLife InsuranceTable, 1983. They weredetermined to be healthy by history andphysical examination and by clinical laboratory profiles. Excluded from the study were patients witha clinically significant history of cardiovascular, respiratory, liver, renal,or gastrointestinal diseases; enlarged prostate; glaucoma; neurologicor psychiatricdisorders; significantdrug or alcohol abuse; history of allergy to ciprofloxacin or othercarboxyquinolones; or use of any medication within 24 hoursof the study. Subjectswere instructed to abstainfrom any caffeinated beverages, charcoal-broiled foods, smoking, alcoholic beverages, and nonsteroidal antiinflammatory drugs24 hoursbeforeandaftereachdose. The subjects werealso askedto fast from midnight the nightbeforeeach dosing period. Subjects received a standard lunchanddinnerat three andninehours, respectively, relative to the starting timeof theciprofloxacin dosing. Each subjectreceivedsingleintravenous dosesof 200 (0.60mmol), 300 (0.91 mmol), and 400 mg (1.21 mmol) of ciprofloxacin, witha seven-daywashoutintervalbetweendosingperiods. The sequence of dosingperiods was randomized and double-blind. An appropriate volume of intravenous ciprofloxacin solution 200mgl20mL (lot#2417; Miles) was added to sterilebags, and a sufficient volumeof NaCI 0.9% was added to provide a total volume of 200 mL. Doses were prepared by an unblinded pharmacist Ciprofloxacin was delivered as a constant-rate infusion over 30 minutesby an infusion pumpintoa forearm vein.The subjects received each dose at the sametimeof day. An indwelling venous catheterwitha male
TheAnnalsofPharmacotherapy • 1992 January, Volume 26
a two-compartment intravenous infusion model and nonlinear regression analysis with l/y2 weighting, which best characterized the ciprofloxacin concentration-time profiles. Table 1 provides the mean pharmacokinetic parameters for the three dosage levels. The mean ciprofloxacin concentration-time curves for all three dosage levels are shown in Figure 1. The mean AVC values displayed linearity with respect to the administered dose. No statistically significant differss ences were seen in total body Cl, Vd , or Btl /2 with respect to the three dosage levels (p>0.05).
adaptor plug was inserted in the ann opposite the ciprofloxacin infusion site for blood sampling. The catheter was kept patent with a dilute heparin solution (10 units/ml.), which was extracted prior to blood sampling. Blood samples were collected before the start of the ciprofloxacin infusion, 15 and 30 minutes after the infusion was started, and at 0.25, 0.5, 1,2,3,4,6,8, 10, 12, 16, and 24 hours after ciprofloxacin administration was completed. Blood samples were collected in heparinized tubes and centrifuged within one hour of collection. Plasma was separated and frozen at -20°C. Plasma ciprofloxacin concentrations were determined by HPLC by Miles as described prevlously.uThe minimum detection limit was 0.0 I mg/L. The intra- and interday coefficients of variation ranged from four to nine percent. The mobile phase consisted of acetonitrile:methanol and trichloroacetic acid with pH adjusted to 3.0 with IN sodium hydroxide. Two- and three-compartment intravenous infusion models were used to fit the plasma ciprofloxacin concentration-time profiles by using nonlinear least-squares regression.» Selection of the appropriate model was determined by evaluation of Akaike's Information Criterioni- and inspection of the residuals. The area under the time curve (AVC) and the area under the first moment curve (AVMC) were integrated from the model and estimated phannacokinetic parameters. The total body clearance (CI) and steady-state volume of distribution (vt) were calculated using AVe, AUMC, and appropriate equations. The mean values for total body CI, vt, and elimination half-life (6t '/2) for the three dosage levels within subjects were compared using ANDV A appropriate for a three-way crossover design. An alpha level of 0.05 was used to defme a significant difference.
Discussion Plasma ciprofloxacin concentration-time curves were best characterized by a two-compartment intravenous infusion model, which is consistent with previously reported concentration-time data in normal volunteers.v' In addition, an apparent third elimination phase, which was seen but could not be fully described, has been reported.' A plausible explanation for this delayed elimination phase would be slow release from a tissue compartment, which is compatible with ciprofloxacin's extensive tissue distribution. This slow terminal elimination rate is unlikely to be clinically significant. Previous studies have reported a linear relationship between dose and AVC with ciprofloxacin at lower doses.3-6,8 ss The mean total body Cl, Vd , and Btl / 2 observed in this study were in agreement with previous studies in subjects with normal renal and hepatic function and did not differ with respect to increasing dosage levels. 2,4-6,8 The presence
Results All 12 subjects completed the study. The mean age was 24.5 ± 3 years (range 20-30) and mean weight was 78.0 ± 8.7 kg (range 64-91). Two subjects were noted to have possible ciprofloxacin crystals in their urine. These crystals were round with irregular edges and were
