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Population Pharmacokinetics of a Novel Oral Fosfomycin Prophylactic Scheme in the Plasma and Prostate of Patients Undergoing Endoscopic Surgery for Benign Prostatic Hyperplasia
Fosfomycin trometamol may be a valuable option for antimicrobial prophylaxis before urological surgery for benign prostatic hyperplasia. The objective is to develop a population pharmacokinetic model of a novel oral fosfomycin prophylactic scheme in the plasma and prostate of patients undergoing endoscopic surgery for benign prostatic hyperplasia.
Methods
One- and two-compartment plasma pharmacokinetic models were fitted to fosfomycin plasma data, and different plasma-prostate linked models were tested by means of non-linear mixed effects modelling. Monte Carlo simulation was used to obtain 1000-subject concentration-time profiles of fosfomycin in the prostate. Probabilities of target attainment ≥ 90% of an area under the plasma concentration-time curve/minimum inhibitory concentration (MIC) > 83.3 and of a 70%t > MIC in the prostate were considered as optimal. Cumulative fractions of response against both wild-type and extended-spectrum beta-lactamase-producing Escherichia coli were calculated.
Results
A total of 104 patients, each providing a pair of plasma and prostate concomitant samples were included in the study. A one-compartment pharmacokinetic model was used to describe plasma fosfomycin concentration. Fosfomycin plasma–prostate relationships were adequately described by a direct response model with a power function. Simulations showed that fosfomycin disposition in the prostate was closely related to that in plasma. Optimal probabilities of target attainments were ensured against Enterobacterales having an MIC up to 0.5–1 mg/L in the 12 h vulnerable period after completing the prophylactic scheme.
Conclusion
A prophylactic regimen of two doses of oral fosfomycin trometamol 3 g 12 h apart before undergoing prostatic surgery may grant effective concentrations in the prostatic tissue of patients for a 12 h vulnerable period.
Fosfomycin trometamol may be used for oral prophylaxis of surgical intervention for benign prostatic hyperplasia thanks to its penetration into the prostate and the urinary tract. A novel scheme consisting of two doses of fosfomycin 3 g 12 h apart before surgery was suggested to allow more flexibility for timing of surgical intervention.
A population pharmacokinetic model was developed by simultaneously fitting both plasma and prostate concentrations in 104 patients. Fosfomycin plasma–prostate relationships were adequately described by a direct response model with a power function.
The proposed prophylactic scheme achieved optimal probability of pharmacodynamic target attainment against Enterobacterales with a minimum inhibitory concentration up to 0.5–1 mg/L in the 12 h vulnerable period after completing the prophylactic scheme.
1 Introduction
Benign prostatic hyperplasia is a common clinical condition associated with ageing [1]. At a population level, its prevalence is estimated to be as high as 70% in patients aged 60–69 years and higher than 80% in those aged over 70 years [2]. Benign prostatic hyperplasia may cause different lower urinary tract symptoms such as incomplete emptying, nocturia, weak stream, and frequency, sometimes urinary incontinence and in the most severe cases may be complicated by urinary tract infections (UTIs) [3]. Patients for whom medical therapy failed or was not tolerated are candidates for surgical intervention. Transurethral resection of the prostate (TURP) has been the standard surgical procedure for decades. In most recent years, Holmium laser enucleation of the prostate (HoLEP) has been shown to be particularly advantageous for medical patients with complex case mix or for those with voluminous prostates [4‐6].
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TURP and HoLEP are clean-contaminated surgical procedures requiring antimicrobial prophylaxis. International guidelines recommend either trimethoprim/sulfamethoxazole or an oral fluoroquinolone before intervention, essentially to counteract contamination by Enterobacterales, mainly by Escherichia coli [7, 8]. Unfortunately, in the last two decades, the resistance rates of E. coli to these agents have continued to increase. In a study including urinary tract E. coli isolates collected among 18 European countries in 2018, resistance rates to trimethoprim/sulfamethoxazole and fluoroquinolones were as high as 32.7% and > 20%, respectively [9]. Worryingly, the prevalence of multidrug-resistance due to the production of extended-spectrum beta-lactamases (ESBL) conferring resistance to third-generation cephalosporins is also increasing globally [10].
This worrying scenario has led to a renewed interest in older agents such as fosfomycin. Fosfomycin trometamol is an oral formulation with a broad-spectrum activity against both Gram-positive and Gram-negative pathogens, including ESBL-producing Enterobacterales. Fosfomycin, by distributing well into deep tissues and by concentrating in the urinary tract, may be a suitable prophylactic agent for urological procedures involving the prostate.
Previous studies have shown that fosfomycin may effectively concentrate in the prostate with a mean prostate-to-plasma concentration ratio of 0.67 [11, 12]. The usual fosfomycin trometamol scheme adopted nowadays in the urological setting is based on a prophylactic/pre-emptive strategy with two doses of 3 g, namely one administered 3 h before the intervention and the second 24 h after [13‐16]. In this scenario, we recently proposed a novel fully prophylactic scheme based on two doses of 3 g administered 12 h apart before surgical intervention. This approach turned out to be effective in preventing infectious complications in urologic patients undergoing HoLEP or TURP in the following 12 h vulnerable period [17]. In fact, among the 96 patients prospectively included, the prevalence of proven UTIs at 14 days from intervention was as low as 1.0%, and none had proven bloodstream infections or UTI-related sepsis requiring emergency department admission at 14 days.
The aim of this study was to conduct a population pharmacokinetic study of fosfomycin in plasma and in prostate samples collected during that study to assess precisely the time of effective concentrations of the proposed prophylactic scheme in terms of probability of target attainment against E. coli during the 12h vulnerable period of surgical intervention and after the second dose.
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2 Methods
2.1 Study Design
This was a prospective single-center study that included patients undergoing TURP or HoLeP for benign prostatic hypertrophy in the period February 2022 to September 2023 at the Urology Department of the IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. The study was conducted according to the Declaration of Helsinki guidelines and approved by the local ethics committee (no. 882/2021/Oss/AOUBo on January 31, 2022). All participants provided informed written consent.
Briefly, all patients received two prophylactic doses of oral fosfomycin trometamol 3 g 12 h apart before undergoing HoLEP or TURP, namely at 8:00 PM of the day before and at 8:00 AM of the day of surgical procedure (3g t−12h + 3g t0h), as shown in Fig. 1. All patients received the trometamol oral formulation, due to its 2- to 4-fold higher oral bioavailability compared with fosfomycin calcium [18]. While undergoing HoLEP or TURP under general or spinal anesthesia within the 12 h from the second dose of fosfomycin, plasma and prostate samplings were performed concomitantly in each patient. Specifically, only two samples (a blood sample and a prostate bioptic sample) were drawn for each individual. Opportunistic sampling was not applied. The details of the design were extensively described in a previous study assessing the clinical efficacy of this novel prophylactic regimen [17]. Here, we detail the methods concerning the population pharmacokinetic study.
Fig. 1
Scheduled scheme of fosfomycin dosing in relation to blood and prostate sampling. HoLEP Holmium laser enucleation of the prostate, TURP transurethral resection of the prostate
Blood samples were immediately centrifuged at 5000 g/min for 3 min. Afterwards, plasma was separated and then stored at −80 °C until analysis. Prostate samples were dissected, placed in a homogenizer tube, and stored dry at −80°°C until subsequent analysis. The time that elapsed from completing the prophylactic scheme to blood/prostate sampling was recorded.
Fosfomycin concentrations were measured by means of two separated specific validated liquid chromatography tandem mass spectrometry methods: one for plasma samples [19] and the other for prostate samples [20] with electrospray ionization operating in the negative mode. In regard to detection of fosfomycin in plasma, intra- and inter-day coefficients of variation of the quality controls ranged from 8.1 to 9.2% and from 0.9 to 2.7%, respectively, and the lower limit of quantification was 1 mg/L [19]. In regard to detection of fosfomycin in the prostate tissue, intra- and inter-day coefficients of variation of the quality control levels ranged from 2.8 to 8.6% and from 4.1 to 9.9%, respectively, and the lower limit of quantification was 0.1 μg/g [20].
Each patient’s demographic (age, weight, height, and body mass index), clinical (comorbidities, type of surgery, prostate and prostate adenoma volumes at transrectal prostatic ultrasound), and laboratory data (serum creatinine, estimated glomerular filtration rate [eGFR], and serum prostate-specific antigen [PSA] level) were collected. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [21] was used to calculate eGFR.
2.2 Model Development
A non-linear mixed-effects model with stochastic expectation minimization algorithm was used to develop a population pharmacokinetic model by means of Monolix v. 2023R1. To overcome some model instabilities that arose when fitting simultaneously plasma and prostate data in a two-compartment pharmacokinetic model, a joint plasma/tissue model was developed using an approach similar to that previously employed by other authors in similar circumstances [22].
Plasma concentrations were fitted by two pharmacokinetic base models, namely a one- and a two-compartment model parameterized for clearance (CL) and for volume of distribution (V), and with first-order elimination from the central compartment. Subsequently, the feasibility of linking prostate concentrations (Cpr) as a function of plasma concentrations (Cpl) was tested in each pharmacokinetic base model by means of three different direct-response models [22]: (1) a proportional model, namely \({\text{Cpr}}\left( t \right) = {\text{PR}} \times {\text{Cpl}}\left( t \right)\), where PR is the prostate/plasma penetration ratio; (2) a power model, namely \({\text{Cpr}}\left( t \right) = {\text{PR}} \times {\text{Cpl}}\left( t \right)^{{{\text{POW}}}}\), where PR is the prostate/plasma penetration ratio and POW is an exponential value; and (3) a saturable Emax model, namely \({\text{Cpr}}\left( t \right) = \frac{{{\text{Emax}} \times {\text{Cpl}}\left( t \right)}}{{{\text{Km}} + {\text{Cpl}}\left( t \right)}}\), where Emax is the maximum estimated prostate concentration and Km is the plasma concentration at which half of Emax is achieved.
Absorption constant (ka) had to be fixed to 0.92 h−1, namely the value found after oral administration of fosfomycin in healthy volunteers [23], given the impossibility of estimating it due to lack of blood sampling during the absorption phase. Exponential random effects were assumed to describe inter-individual variability. Correlations between random effects were tested in the variance–covariance matrix and implemented into the structural model accordingly. Residual noise was tested by means of constant, proportional, or combined error model.
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2.3 Model Evaluation
The selection of the final base model describing at best fosfomycin concentrations both in plasma and in prostate tissue was based primarily on having an objective function value (OFV) reduction ≥ 3.84 coupled with a consensual reduction of the Akaike information criterion (AIC). Other parameters taken into account were also the goodness of fit of the observed versus concentration-predicted plots, the distribution of the weighted residuals, the residual standard error of the population estimates (that should have been < 30%), and the fitness of the prediction-corrected visual predictive check, the plot of which describes the time course of the 10th, the 50th and the 90th percentiles of the observed plasma and prostate concentrations in relation to the corresponding 90% prediction intervals calculated by means of 1000 Monte Carlo simulations. The uncertainty of each of the population parameters was evaluated through a non-parametric bootstrap resampling technique by means of the “Rsmlx” package of R (R version 4.2.1). The 95% confidence interval of the pharmacokinetic parameter estimates were derived from bootstrap empirical posterior estimates and compared with the population estimates.
Subsequently, by using a power function, we tested the potential impact that several biologically plausible covariates, namely age, weight, height, body mass index, serum creatinine, eGFR, and some variables reflecting the severity of the underlying prostatic disease such as serum PSA, might have had on the fosfomycin CL and V estimated in the final base model. Covariate selection was made according to a forward/backward process. In the forward step, the inclusion of a covariate in the model was based on the result of Pearson’s correlation test between each covariate and the random effect of the estimated pharmacokinetic parameter. In the backward step, the Wald test was used to test whether any covariate could be removed from the full covariate model. Any covariate eventually leading to a simultaneous decrease of the OFV of ≥ 3.84 point, the AIC, and the inter-patient variability of the fixed-effect parameter would have been retained in the final model.
2.4 Model Simulation
Monte Carlo simulations of plasma and prostate concentration versus time profiles were generated from the final joint plasma/prostate population pharmacokinetics model by means of Simulix 2023R1. A total of 1000 Monte Carlo pair simulations were elaborated for each of the following prophylactic dosing schemes of oral fosfomycin administered before surgery: two 3 g doses 12 h apart (3 g t−12h + 3 g t0h), one 3 g and one 6 g dose 12 h apart (3 g t−12h + 6 g t0h) and one 3 g and one 6 g dose 8 h apart (3 g t−8h + 6 g t0h).
Probabilities of target attainment (PTA%) were calculated in the 12–24 h vulnerable period following the second fosfomycin dose for both of the two pharmacokinetic/pharmacodynamic (PK/PD) targets found to be related to efficacy against Enterobacterales, namely an area under the plasma concentration-time curve (AUC)/minimum inhibitory concentration (MIC) > 83.3 [24] and a 70% T > MIC [25‐27]. PTAs > 90% were considered to be optimal.
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Cumulative fractions of response (CFR%) for both the PK/PD targets were also calculated against the EUCAST MIC distribution for both wild-type (n = 2351) and ESBL-producing (n = 775) E. coli [28].
3 Results
A total of 104 patients were prospectively enrolled in this study. Median (minimum; maximum) age, body weight, body mass index, and eGFR were 70 (49; 84) years, 78 (60; 107) kg, 26.3 (20.6; 41.5) kg/m2, and 78.5 (34; 102) mL/min/1.73 m2, respectively. Median (minimum; maximum) prostate volume and PSA levels before intervention were 75 (20; 220) mL and 3.10 (0.02; 66) ng/mL, respectively. The urological surgical procedure was HoLEP in 81.7 % (85/104) of cases and TURP in the remaining 18.3 % (19/104). The median (minimum; maximum) plasma and prostate fosfomycin concentrations were 11.1 (2.1; 26.6) mg/L and 11.6 (1.2; 603) μg/g, respectively, at a median (minimum; maximum) sampling time of 3.86 (0.42–10.7) h (Fig. S1 electronic supplementary material [ESM]). The median (minimum; maximum) observed prostate-to-plasma ratio is 1.04 (0.23; 5.85).
The definitive plasma/prostate population pharmacokinetic model was a one-compartment plasma model with a power plasma/prostate correlation function. The comparative performances of the different tested base models in terms of relative OFV, AIC, and adequacy of VPC are summarized in Table S1 in the ESM. Univariate analysis testing the potential impact of each covariate on apparent CL and V applied to the final selected base model is depicted in Table S2 in the ESM. Body weight was the only covariate to significantly impact on fosfomycin V (ΔOFV = 5.49, ΔAIC = 3.49, 32.3% decrease of the inter-individual variability of V) and was included in the final covariate model. A direct comparison of the selected base model versus the updated model, including apparent V parameterized by body weight as covariate is reported in Table S3 in the ESM. The population pharmacokinetic parameters of the final covariate model were estimated with good precision (Table 1). Median (minimum; maximum) individual apparent V and CL were 288.9 (173.8; 723.1) L and 15.7 (5.12; 72.6) L/h, respectively. The visual predictive check plot demonstrated acceptable predictive performance of the data set, given that the 10th, 50th, and 90th percentiles of the observed data were inside the simulated prediction intervals (Fig. S5 in the ESM). Model diagnostic plots are summarized in Figs. S2–S5 in the ESM.
Table 1
Population pharmacokinetic parameter estimates of the final model
Parameter
Model estimates
Bootstrap results
Value
RSE (%)
Median
Minimum; maximum
Fixed effects
ka (h−1)
0.92
–
0.92
–
V (L)
60.86
44.1
76.25
33.84; 207.01
β_V_weight
0.02
26.9
0.17
0.004; 0.03
CL (L/h)
14.68
14.4
13.32
9.72; 16.34
PR
0.26
7.09
0.36
0.25; 0.38
POW
1.57
1.80
1.47
1.39; 1.59
Standard deviation of the random effects
ω_ka
1.09
–
1.09
–
ω_V
0.38
17.8
0.53
0.08; 0.71
ω_CL
0.76
12.4
0.56
0.26; 0.94
ω_PR
0.42
11.8
0.31
0.12; 0.56
ω_POW
0.095
15.4
0.12
0.08; 0.13
Error model parameters
a_plasma
1.35
20.5
1.02
0.57; 2.51
a_prostate
1.01
34.0
0.89
0.64; 1.61
CL clearance, ka first-order rate of oral absorption, POW power term, PR prostate/blood penetration ratio at a plasma concentration of 1 mg/L, RSE relative standard error, V distribution volume. The letter “a” for error model identifies the estimated parameter for the constant error model
Where V is the distribution volume relative to plasma, BW is patient body weight, Cp is fosfomycin prostate concentration, and Cc is fosfomycin plasma concentration. The concentration–time profiles of predicted individual concentrations for plasma and prostate of the first 20 patients are reported in Figs. S6 and S7 in the ESM, respectively.
Model-based simulated concentration–time profiles in plasma and in prostate after administering the prophylactic scheme of 3 g t−12h + 3 g t0h is shown in Fig. 2. The proportions of simulated cases having prostate-to-plasma fosfomycin penetration ratios <1, 1–2, and >2 were 48.3, 37.5, and 14.2%, respectively (Fig. 3).
Fig. 2
Simulated concentration–time profile of fosfomycin from the population pharmacokinetic model following two doses of 3 g t−12h + 3 g t0h. Red, drug concentration in plasma. Yellow, drug concentration in prostate. Solid lines represent median concentrations
The PTAs of the two PK/PD targets, namely AUC/MIC>83.3 and 70%t > MIC, achievable with the three tested dosing schemes of oral fosfomycin are reported in Fig. 4. In regard to the former target, optimal PTAs in the 12 h vulnerable period after completing the prophylactic scheme were granted by the dosing scheme of 3 g t−12h + 3 g t0h against pathogens having an MIC up to 0.5 mg/L and by the other two dosing schemes, namely 3 g t−12h + 6 g t0h and 3 g t−8h + 6 g t0h, against pathogens having an MIC up to 1 mg/L. In regard to the target of 70%t > MIC, the dosing scheme of 3 g t−12h + 3 g t0h granted optimal PTAs for the entire 12 h vulnerable period against pathogens with an MIC up to 1 mg/L and for 2–5 h period against pathogens with an MIC up to 4 mg/L. By using the other two dosing schemes, optimal PTAs were granted for most of the 12 h period against pathogens with an MIC up to 4 mg/L.
Fig. 4
Probability of target attainment (PTA%) of achieving an area under the plasma concentration-time curve (AUC)/minimum inhibitory concentration (MIC) >83.3 (A) and a 70%t > MIC (B–D) in the prostate in relation to the three dosing schemes of oral fosfomycin of 3 g t−12h + 3 g t0h, 3 g t−12h + 6 g t0h and 3 g t−8h + 6 g t0h. The histograms in A are the EUCAST MIC distribution frequencies of Escherichia coli (white columns, n = 2351 strains) and of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (black columns, n = 775 strains). The dotted lines identify desirable PTA (≥ 90%)
The overall cumulative fraction of response against the EUCAST MIC distribution of wild-type and ESBL-producing E.coli were around 72–78% with the dosing scheme of 3 g t−12h + 3 g t0h and increased up to 85–87% with the other two dosing schemes (Table 2)
Table 2
Cumulative fraction of response (CFR, %) of different dosing schemes of oral fosfomycin in attaining the two pharmacokinetic (PK)/pharmacodynamic (PD) target of efficacy of area under the plasma concentration-time curve (AUC)/minimum inhibitory concentration (MIC) >83.3 and 70%t > MIC for prophylaxis against Escherichia coli and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli in the prostate
Dosing scheme
Target PK/PD
Pathogens
Wild-type E. coli (n = 2351)
ESBL-producing E. coli (n = 775)
3 g t−12h + 3 g t0h
AUC/MIC>83.3
73.88
71.98
3 g t−12h + 6 g t0h
85.86
86.75
3 g t-8h + 6 g t0h
86.69
87.78
3 g t−12h + 3 g t0h
70%t > MIC
78.44
78.24
3 g t−12h + 6 g t0h
85.57
85.56
3 g t-8h + 6 g t0h
86.36
86.35
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4 Discussion
This study first prospectively investigated the population pharmacokinetics of fosfomycin in the prostatic tissue of patients undergoing surgical intervention for benign prostatic hyperplasia after receiving a novel prophylactic scheme based on two 3 g doses of oral fosfomycin trometamol 12 h apart before. Overall, the findings showed that fosfomycin disposition in the prostate was closely related to that in plasma and that the proposed dosing scheme could be effective in ensuring optimal PTAs for a vulnerable period of 12 h against Enterobacterales with an MIC up to 1 mg/L, namely the MIC50 of fosfomycin against E. coli.
The selected joint population pharmacokinetic model adequately fitted both the plasma and the prostate concentrations. Although a two-compartment model has previously been shown to be appropriate for fosfomycin [29], our study, which had fewer sampling points, found that a one-compartment model provided an adequate fit. Overall, the population pharmacokinetic parameter estimates were consistent with those identified in previous works. Specifically, the median fosfomycin plasma apparent V estimate (288 L) was consistent with the values reported in other studies conducted with fosfomycin trometamol in healthy volunteers (118–172 L or 2.42 L/kg) and in 26 patients undergoing TURP (169 L) [18, 30‐33]. Even if our median estimate is approximately twofold higher, this difference may be related to the fact that a more heterogenous case-mix is observed in the clinics with respect to the relative small sample size of healthy men included in the aforementioned studies. The population apparent CL (14.68 L/h) was in agreement with the range of values reported either by non-compartmental analysis in healthy volunteers (8.3–21.4 L/h) [18, 30‐32] or by a population pharmacokinetic study in patients undergoing TURP (15.02 L/h) [33]. The fact that renal function was not significantly associated with drug CL may be explained by considering that the vast majority (98% [102/104]) of the patients had preserved renal function (eGFR >50 mL/min), thus impairing the possibility of associating this covariate to any fixed-effect parameter.
The median value of the prostate-to-plasma penetration ratio observed in our study (1.06) is consistent with the mean values observed in two other studies carried out among patients undergoing TURP for prostatic adenoma after receiving a single oral dose of fosfomycin 3 g administered 3–12 h before surgery, namely 0.72–0.8 [31, 34] and 0.67 [11], respectively. Although not yet confirmed by any report, this value is consistent with the expected prostate interstitial fluid-to-plasma concentration ratio that may be close to one for small molecules such as fosfomycin, since plasma and interstitial fluid are in fast exchange. Our data confirm that fosfomycin may penetrate well within the prostatic tissue (considering the prostate-to-plasma penetration ratio of 1.06) and could also penetrate into the intra-cellular space (considering its mean V of 288 L). However, it is worth noting that the fosfomycin prostate-to-plasma penetration ratio is quite variable, being the CV% on observed data of 69.9%. Possible simulated values up to 8 may be an artifact due to the specific power model function applied.
Overall, this finding, coupled with that of having the plasma and the prostate concentration–time profiles simulated by our model present a similar behavior, may allow us to affirm that fosfomycin disposition in the prostate may be quite close to that observed in plasma. In this latter regard, it is worth mentioning that our model predicted fosfomycin accumulation in the prostate after the second prophylactic dose, similar to that previously observed in similar circumstances in healthy volunteers [31]. This may be helpful for achieving higher and relatively stable exposure during the 12 h vulnerable period in which the patient could undergo the surgical procedure.
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The novel prophylactic scheme based on two 3 g oral doses 12 h apart before TURP or HoLEP was proposed with the intent of offering the urologist more flexibility when planning the timing of surgical intervention for each patient within an 8–12 h vulnerable period after completing that scheme. In this regard, we previously showed that this prophylactic regimen was very effective because—in the 14 days after the intervention—only one of the 96 patients experienced a proven UTI and none had proven bloodstream infections or UTI-related sepsis [17]. The high success rate obtained with this approach may be explained by the findings of our PK/PD analysis. This prophylactic scheme was shown to ensure optimal PTAs in terms of AUC/MIC >83.3 for a vulnerable period of 24 h against pathogens with an MIC up to 0.5 mg/L and in terms of 70%t > MIC for a vulnerable period of 12 h against pathogens with an MIC up to 1 mg/L. According to the CFRs calculated by our model, this would mean granting adequate coverage against around three quarters of both wild-type and ESBL-producing E. coli, namely the most frequently involved pathogen in post-urological complications.
We were very conservative in choosing the two different PK/PD targets of efficacy correlated with fosfomycin efficacy against Enterobacterales. This approach was dictated by the lack of agreement existing on this in the literature, with some studies suggesting target AUC/MIC of > 83.3 [24] and others 70%t > MIC [25‐27, 35, 36]. Indeed, in the only other population pharmacokinetic study of fosfomycin concentrations in the prostate, the authors choose 100%t > MIC as the PK/PD target and assessed the PTAs both in the transition and in the peripheral zone of the prostate [33]. Interestingly, it was shown that the likelihood of PK/PD target attainment varied in relation to the investigated part of the prostate gland [33]. After a single dose of oral fosfomycin 3 g, PTAs of 100%t > MIC against pathogens with an MIC up to 4 mg/L were achieved in 100% of the simulated cases for up to 9.2 h after administration in the transition zone and in only 70% of the simulated cases for 1–4 h after administration in the peripheral zone.
We acknowledge some limitations of our study. The study was monocentric. We cannot rule out that a proportional model may adequately fit plasma and prostate fosfomycin concentrations in a larger dataset, as the difference in the model performance was low. We recognize that stratifying simulations in relation to different regions of prostate gland sampling, namely the peripheral or the transition zone, could have increased the precision of the model. Moreover, simulated concentration–time profiles outside the 0–12 h window after the second dose may be biased by the absence of sampling points in the population and should be regarded with caution. On the other hand, the prospective design, the good sample size, and the robustness of the developed model may be considered strengths.
5 Conclusion
Our population pharmacokinetic study showed that a prophylactic regimen of two doses of oral fosfomycin trometamol 3 g 12 h apart may grant adequate protection in the prostate tissue of patients undergoing surgical intervention for benign prostatic hyperplasia for a vulnerable period up to 12 h against Enterobacterales with an MIC up to 0.5–1 mg/L. This means that around three-quarters of both wild-type and ESBL-producing E. coli potentially causing post-TURP or HoLeP complications would be adequately covered during that period. Large prospective clinical studies would hopefully confirm the effectiveness of such an approach.
Declarations
Conflict of interest
Pier Giorgio Cojutti has received a grant from Angelini and Shionogi, outside of the submitted work. Pierluigi Viale has served as a consultant for Advanz Pharma, Angelini, bioMérieux, Gilead, Merck Sharp & Dohme, InfectoPharm, Pfizer, Shionogi, Thermo-Fisher, Venatorx, and Viatris and served on the speaker’s bureau for Advanz Pharma, Angelini, Gilead, Merck Sharp & Dohme, InfectoPharm, Menarini, Pfizer, Shionogi, and Viatris outside the submitted work. Federico Pea has served as a consultant for Advanz Pharma, Angelini, Gilead, Merck Sharp & Dohme, Pfizer, and Viatris outside the submitted work and participated on speaker’s bureaus for Angelini, Gilead, Menarini, Merck Sharp & Dohme, InfectoPharm, Pfizer, Shionogi, and Viatris outside of the submitted work. Federico Pea is an editorial board member of Clinical Pharmacokinetics and was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. The other authors have no conflicts of interest to declare.
Ethics approval
The study was conducted according to the Declaration of Helsinki guidelines and approved by the local ethics committee (no. 882/2021/Oss/AOUBo on 31 January 2022).
Consent to participate
All participants provided informed written consent.
Consent for publication
All participants agreed to the publication policy as per study protocol.
Availability of data and material
The data presented in this study are available upon request from the corresponding author.
Code availability
The population pharmacokinetic codes are available in the electronic supplementary material.
Authors’ contributions
All authors contributed to the concept and interpretation of the study. PGC performed the study and curated and analyzed the data. PGC and FP wrote the original manuscript. FP, PV, and EB designed the research and supervised the study. PB, VR, LB, and RS reviewed and commented on the manuscript. All authors read and agreed to the published version of the manuscript.
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Population Pharmacokinetics of a Novel Oral Fosfomycin Prophylactic Scheme in the Plasma and Prostate of Patients Undergoing Endoscopic Surgery for Benign Prostatic Hyperplasia
Verfasst von
Pier Giorgio Cojutti
Pasquale Maria Berrino
Valeria Rotaru
Lorenzo Bianchi
Riccardo Schiavina
Eugenio Brunocilla
Pierluigi Viale
Federico Pea
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