Dose-Ranging Pharmacokinetic Study of Ciprofloxacin after 200-, 300-, and 400-mg Intravenous Doses

Nix, David E.; Spivey, Justin M; Norman, Allyn; Schentag, Jerome J.

doi:10.1177/106002809202600101

Cited by 31 publications

(16 citation statements)

References 13 publications

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“…Thus, under the assumption that the steady-state values of the area under the concentration-time curve, and therefore the steadystate ciprofloxacin concentrations in young cystic fibrosis patients, should be similar to those obtained in adult patients after the recommended dosing regimen, a formula can be derived giving the total daily dose (TDD) as a function of weight (WT): TDD ϭ (8.8 ϩ 0.391 ⅐ WT) ⅐ dose adult /CL adult for intravenous administration and TDD ϭ (8.8 ϩ 0.391 ⅐ WT) ⅐ dose adult ⅐ F 1 adult /CL adult ⅐ F 1 for oral dosing. The CL in adult volunteers was assumed to be 36.4 liters/h, as reported recently (4,6). The results are listed in Table 5.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients

Schaefer

Staß

Wedgwood

et al. 1996

Antimicrob Agents Chemother

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The pharmacokinetic characteristics of ciprofloxacin were studied in 10 children with cystic fibrosis, aged from 6 to 16 years, who had completed the standard regimen of intravenous ceftazidime and amikacin. The aim of the investigation was to derive dosing guidelines for young cystic fibrosis patients to be treated with ciprofloxacin. Each child received ciprofloxacin given as two 30-min infusions (10 mg/kg of body weight each) 12 h apart; this was followed by the administration of oral ciprofloxacin (15 mg/kg every 12 h). Blood samples were taken after both infusions and after the first oral dose. A total of 232 ciprofloxacin concentrations (203 concentrations in plasma and 29 concentrations in urine) were analyzed by use of NONMEM and a twocompartment body model with seven parameters: total body clearance (CL), volume of the central compartment (V 2 ), volume of the peripheral compartment (V 3 ), intercompartmental clearance, renal clearance, absorption rate constant, and bioavailability. The influences of weight (range, 18 to 42 kg) and age (range, 6 to 16 years) were investigated. CL (in liters per hour) was found to be linearly correlated with weight (typical value of CL ‫؍‬ 8.8 ؉ 0.396 ⅐ WT, where WT is weight; (interindividual coefficient of variation, 7.8%). V 2 and V 3 were directly proportional to weight, with slopes of 0.7 and 1.3 liters/kg, respectively. Interindividual variabilities were calculated to be 22.6 and 14.9% for V 2 and V 3 , respectively. No dependency of the other pharmacokinetic parameters on age or weight was seen. Because of the high correlations between age and weight, only one covariable was necessary. Weight had the strongest effect. Bioavailability (population mean) was estimated to be 61.8%, and renal clearance (population mean) was estimated to be 11.4 liters/h. The residual (intraindividual) variability was 31.9%. The protein binding was about 34%, which is similar to the results obtained for adults. In order to define the appropriate dosage regimen for children suffering from cystic fibrosis, a formula was derived so that steady-state concentrations, similar to those obtained in adults after the administration of dosages of 400 mg three times daily intravenously and 750 mg twice daily orally, could be reached. The calculated total daily dose increased with increasing body weight. Given as milligrams per kilogram of body weight, the calculated dosage regimens suggest that for younger children (weight range, 14 to 28 kg), 28 to 20 mg/kg orally twice daily should be given, and for older children (weight range, 28 to 42 kg), 20 to 15 mg/kg orally twice daily should be given. For intravenous administration, dosages of 15 to 10 mg/kg twice daily are sufficient.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients

Schaefer

Staß

Wedgwood

et al. 1996

Antimicrob Agents Chemother

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“…In fact, these patients achieved and tolerated steady-state AUCO24 values of 9 to 229 ,ug h/ml (Table 1). A healthy subject, with a ciprofloxacin clearance of 30 liters/h receiving 1,200 mg/day, would achieve a steady-state AUC-24 of 40 ,ug-h/ml (7,26).…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients

Forrest

Nix

Ballow

et al. 1993

Antimicrob Agents Chemother

1,029

750

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Seventy-four acutely ill patients were treated with intravenous ciprofloxacin at dosages ranging between 200 mg every 12 h and 400 mg every 8 h. A population pharmacokinetic-pharmacodynamic analysis relating drug exposure (and other factors) to infectious outcome was performed. Plasma samples were obtained and assayed for ciprofloxacin by high-performance liquid chromatography. Samples from patients were frequently cultured so that the day of bacterial eradication could be determined. The pharmacokinetic data were fitted by iterative two-stage analysis, assuming a linear two-compartment model. Logistic regression was used to model ciprofloxacin exposure (and other potential covariates) versus the probabilities of achieving clinical and microbiologic cures. The same variables were also modelled versus the time to bacterial eradication by proportional hazards regression. The independent variables considered were dose, site of infection, infecting organism and the MIC for it, percent time above the MIC, peak, peak/MIC ratio, trough, trough/MIC ratio, 24-h area under the concentration-time curve (AUC), AUC/MIC ratio (AUIC), presence of other active antibacterial agents, and patient characteristics. The most important predictor for all three measures of ciprofloxacin pharmacodynamics was the AUIC. A 24-h AUIC of 125 SIT-' h (inverse serum inhibitory titer integrated over time) was found to be a significant breakpoint for probabilities of both clinical and microbiologic cures. At an AUIC below 125 (19 patients), the percent probabilities of clinical and microbiologic cures were 42 and 26%, respectively. At an AUIC above 125 (45 patients), the probabilities were 80%o (P < 0.005) and 82% (P < 0.001), respectively. There were two significant breakpoints in the time-to-bacterialeradication data. At an AUIC below 125 (21 patients), the median time to eradication exceeded 32 days; at an AUIC of 125 to 250 (15 patients), time to eradication was 6.6 days; and at AUIC above 250 (28 patients), the median time to eradication was 1.9 days (groups differed; P < 0.005). These findings, when combined with pharmacokinetic data reported in the companion article, provide the rationale and tools needed for targeting the dosage of intravenous ciprofloxacin to individual patients' pharmacokinetics and their bacterial pathogens' susceptibilities. An a priori dosing algorithm (based on MIC, patient creatinine clearance and weight, and the clinician-specified AUIC target) was developed. This approach was shown, retrospectively, to be more precise than current guidelines, and it can be used to achieve more rapid bacteriologic and clinical responses to ciprofloxacin, as a consequence of targeting the AUIC.

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“…In dose-ranging studies, C max and AUC increased in a linear, dose-proportional fashion. 43,58,69,74 As indicated by their large volumes of distribution, most fluoroquinolones penetrate rapidly and efficiently through the body, achieving tissue and fluid concentrations that are generally higher than those in plasma. 47,53,55,60,66 Most fluoroquinolones have low protein binding, ranging from 2-40%.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Comparison of the Fluoroquinolones Based on Pharmacokinetic and Pharmacodynamic Parameters

2000

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Assessment of pharmacodynamic activity from standard in vitro minimum inhibitory concentrations (MICs) alone is insufficient to predict in vivo potency. Achievable serum and tissue concentrations as well as pharmacokinetic characteristics must be considered. When pharmacokinetic and pharmacodynamic values are combined, the area under the inhibitory curve (AUIC) and peak concentration: MIC ratio predict clinical cure for fluoroquinolones. Clinical data and animal models indicate that a peak:MIC of 10:1 and above and an AUIC of 125 and above are predictive of a clinical cure for this class of antimicrobials against gram‐negative organisms. The values may be used to compare and contrast fluoroquinolones to determine which would be best for treating a specific microorganism. Pharmacodynamic data also can be used to design regimens that minimize the risk of suboptimal drug levels. Ensuring the optimal fluoroquinolone dosage based on pharmacodynamic principles would diminish the emergence of resistant organisms and prevent treatment failures.

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Dose-Ranging Pharmacokinetic Study of Ciprofloxacin after 200-, 300-, and 400-mg Intravenous Doses

Abstract: Intravenous ciprofloxacin in doses ranging from 200 to 400 mg demonstrated linear pharmacokinetics. These single doses were well tolerated, although cases of transient venous irritation and crystalluria were observed.

Cited by 31 publications

References 13 publications

Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients

Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients

Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients

Comparison of the Fluoroquinolones Based on Pharmacokinetic and Pharmacodynamic Parameters

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