Ciprofloxacin population pharmacokinetics during long-term treatment of osteoarticular infections

Abstract

Background Ciprofloxacin is an antibiotic used in osteoarticular infections owing to its very good bone penetration. Very few pharmacokinetic data are available in this population. Objectives To investigate oral ciprofloxacin population pharmacokinetics in adult patients treated for osteoarticular infections and propose guidance for more effective dosing. Methods A retrospective population-pharmacokinetic analysis was performed on 92 consecutive hospitalized patients in the orthopaedic department. Ciprofloxacin plasma samples were obtained on one or two occasions during treatment. Plasma concentration was measured using ultra-performance liquid chromatography system coupled with tandem mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2019R2. Results A total of 397 plasma samples were obtained with 11.5% and 41.6% of patients being below the therapeutic target for Gram-negative and staphylococcal infections, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model with a first-order absorption. Ciprofloxacin apparent plasma clearances and volumes of distribution were dependent on patients’ fat-free mass according to the allometric rule. Elimination clearance was also positively related to renal function through the modification of diet in renal disease equation (MDRD) and rifampicin co-administration. When patients are co-treated with rifampicin, ciprofloxacin dosage should be increased by 50% to 60%. Conclusions This study showed that free-fat mass was a better size predictor than total body weight for ciprofloxacin clearance and volumes terms. Moreover, both MDRD and rifampicin status were significant predictors of individual ciprofloxacin clearance. Our study suggests that individual adjustment of ciprofloxacin dose in osteoarticular infections with less-susceptible bacteria might be indicated to reach required efficacy targets.

Pharmacokinetics of oral ciprofloxacin in adult patients: A scoping review

“…The parameter estimates for the basic model for Cl ranged from 5.4 74 to 48.5 L h −1 79 with a median of 13.6. For Vdc, the estimates varied from 22.72 74 to 143.0 L, 78 with a median of 66.3 L. Vdp ranged from 75.0 76 to 212.0 L, 79 with a median of 89.5 L, and Q ranged from 19.9 73 to 91.9 L h −1 71 with a median of 39.4 L h −1 .…”

“…The parameter estimates for the basic model for Cl ranged from 5.4 74 to 48.5 L h À179 with a median of 13.6. For Vdc, the estimates varied from 22.72 74 to 143.0 L, 78 with a median of 66.3 L. Vdp ranged from 75.0 76 to 212.0 L, 79 with a median of 89.5 L, and Q ranged from 19.9 73 to 91.9 L h À171 with a median of 39. Regarding the covariate models, the studies investigated numerous covariates that might be related to Cl, Vdc and Vdp values, but only 11 were found to be significant in the popPK models.…”

Pooled Population Pharmacokinetic Analysis for Exploring Ciprofloxacin Pharmacokinetic Variability in Intensive Care Patients

“…This may be indicated by the estimated posterior mean of CL, V 1 , and V 2 , which were all smaller for the patients of study 3 compared with the patients of study 1 and 2 (Table 3 ). In addition, as we previously mentioned, there is a deviation in the reported PK parameters in the published studies [ 6 , 8 – 12 , 14 , 15 ]. The parameters’ estimates of our model differ from previously published models to varying extents as well.…”

“…Published models of ciprofloxacin are to a large extent similar in terms of identified covariates [8,[11][12][13][14][15]. The most commonly found are body weight and renal function.…”

“…In theory, given sufficient data that includes all relevant model covariates, a well-developed model should be capable of accurately describing the entire patient population of the training data, i.e., the data used for the model development. However, considerable deviation can be observed in the reported population PK parameter estimates [ 6 , 8 – 12 , 14 , 15 ]. Such results do not only highlight the high PK variability of ciprofloxacin in the ICU patient population, but also suggest that an important part of the variability may still be unexplained in the ICU patient population.…”