Current Issue : January-March Volume : 2022 Issue Number : 1 Articles : 5 Articles
The aims of this study were to characterize the antifungal activity of amphotericin B against Candida auris in a static in vitro system and to evaluate different dosing schedules and MIC scenarios by means of semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation. A two-compartment model consisting of a drug-susceptible and a drug-resistant subpopulation successfully characterized the time-kill data and a modified Emax sigmoidal model best described the effect of the drug. The model incorporated growth rate constants for both subpopulations, a death rate constant and a transfer constant between both compartments. Additionally, the model included a parameter to account for the delay in growth in the absence or presence of the drug. Amphotericin B displayed a concentration-dependent fungicidal activity. The developed PK/PD model was able to characterize properly the antifungal activity of amphotericin B against C. auris. Finally, simulation analysis revealed that none of the simulated standard dosing scenarios of 0.6, 1 and 1.5 mg/kg/day over a week treatment showed successful activity against C. auris infection. Simulations also pointed out that an MIC of 1 mg/L would be linked to treatment failure for C. auris invasive infections and therefore, the resistance rate to amphotericin B may be higher than previously reported....
The aim of this study was to apply molecular epidemiology, antimicrobial surveillance, and PK/PD analysis to guide the antimicrobial treatment of gonococci infections in a region of the north of Spain. Antibiotic susceptibility testing was performed on all isolates (2017 to 2019, n = 202). A subset of 35 isolates intermediate or resistant to at least two antimicrobials were selected to search for resistance genes and genotyping through WGS. By Monte Carlo simulation, we estimated the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the antimicrobials used to treat gonorrhea, both indicative of the probability of treatment success. In total, 2.0%, 6.4%, 5.4%, and 48.2% of the isolates were resistant to ceftriaxone, cefixime, azithromycin, and ciprofloxacin, respectively. Twenty sequence types were identified. Detected mutations were related to antibiotic resistance. PK/PD analysis showed high probability of treatment success of the cephalosporins. In conclusion, multiple populations of N. gonorrhoeae were identified. We can confirm that ceftriaxone (even at the lowest dose: 250 mg) and oral cefixime are good candidates to treat gonorrhea. For patients allergic to cephalosporins, ciprofloxacin should be only used if the MIC is known and ≤0.125 mg/L; this antimicrobial is not recommended for empirical treatment....
Palbociclib is an oral CDK4/6 inhibitor indicated in HR+/HER2- advanced or metastatic breast cancer in combination with hormonotherapy. Its main toxicity is neutropenia. The aim of our study was to describe the kinetics of circulating neutrophils from real-life palbociclib-treated patients. A population pharmacokinetic (popPK) model was first constructed to describe palbociclib pharmacokinetic (PK). Individual PK parameters obtained were then used in the pharmacokinetic/ pharmacodynamic (PK/PD) model to depict the relation between palbociclib concentrations and absolute neutrophil counts (ANC). The models were built with a population of 143 patients. Palbociclib samples were routinely collected during therapeutic drug monitoring, whereas ANC were retrospectively retrieved from the patient files. The optimal popPK model was a mono-compartmental model with a first-order absorption constant of 0.187 h−1 and an apparent clearance Cl/F of 57.09 L (32.8% of inter individuality variability (IIV)). The apparent volume of distribution (1580 L) and the lag-time (Tlag: 0.658 h) were fixed to values from the literature. An increase in creatinine clearance and a decrease in alkaline phosphatase led to an increase in palbociclib Cl/F. To describe ANC kinetics during treatment, Friberg’s PK/PD model, with linear drug effect, was used. Parameters estimated were Base (2.92 G/L; 29.6% IIV), Slope (0.0011 L/μg; 28.8% IIV), Mean Transit Time (MTT; 5.29 days; 17.9% IIV) and γ (0.102). The only significant covariate was age on the initial ANC (Base), with lower ANC in younger patients. PK/PD model-based simulations show that the higher the estimated CressSS (trough concentration at steady state), the higher the risk of developing neutropenia. In order to present a risk lower than 20% to developing a grade 4 neutropenia, the patient should show an estimated CressSS lower than 100 μg/L....
Parkinson’s disease (PD) is a progressive, neurodegenerative disorder primarily affecting dopaminergic neuronal systems, with impaired motor function as a consequence. The most effective treatment for PD remains the administration of oral levodopa (LD). Long-term LD treatment is frequently associated with motor fluctuations and dyskinesias, which exert a serious impact on a patient’s quality of life. The aim of our study was to determine the pharmacokinetics of LD: used as monotherapy or in combination with ropinirole, in patients with advanced PD. Furthermore, an effect of ropinirole on the pharmacokinetics of 3-OMD (a major LD metabolite) was assessed. We also investigated the correlation between the pharmacokinetic parameters of LD and 3-OMD and the occurrence of motor complications. Twenty-seven patients with idiopathic PD participated in the study. Thirteen patients received both LD and ropinirole, and fourteen administered LD monotherapy. Among 27 patients, twelve experienced fluctuations and/or dyskinesias, whereas fifteen were free of motor complications. Inter- and intra-individual variation in the LD and 3-OMD concentrations were observed. There were no significant differences in the LD and 3-OMD concentrations between the patients treated with a combined therapy of LD and ropinirole, and LD monotherapy. There were no significant differences in the LD concentrations in patients with and without motor complications; however, plasma 3-OMD levels were significantly higher in patients with motor complications. A linear one-compartment pharmacokinetic model with the first-order absorption was adopted for LD and 3-OMD. Only mean exit (residence) time for 3-OMD was significantly shorter in patients treated with ropinirole. Lag time, V/F, CL/F and tmax of LD had significantly lower values in patients with motor complications. On the other hand, AUC were significantly higher in these patients, both for LD and 3-OMD. 3-OMD Cmax was significantly higher in patients with motor complications as well. Our results showed that ropinirole does not influence LD or 3-OMD concentrations. Higher 3-OMD levels play a role in inducing motor complications during long-term levodopa therapy....
This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of tegoprazan and to predict the drug–drug interaction (DDI) potential between tegoprazan and cytochrome P450 (CYP) 3A4 perpetrators. The PBPK model of tegoprazan was developed using SimCYP Simulator® and verified by comparing the model-predicted pharmacokinetics (PKs) of tegoprazan with the observed data from phase 1 clinical studies, including DDI studies. DDIs between tegoprazan and three CYP3A4 perpetrators were predicted by simulating the difference in tegoprazan exposure with and without perpetrators, after multiple dosing for a clinically used dose range. The final PBPK model adequately predicted the biphasic distribution profiles of tegoprazan and DDI between tegoprazan and clarithromycin. All ratios of the predicted-to-observed PK parameters were between 0.5 and 2.0. In DDI simulation, systemic exposure to tegoprazan was expected to increase about threefold when co-administered with the maximum recommended dose of clarithromycin or ketoconazole. Meanwhile, tegoprazan exposure was expected to decrease to ~30% when rifampicin was co-administered. Based on the simulation by the PBPK model, it is suggested that the DDI potential be considered when tegoprazan is used with CYP3A4 perpetrator, as the acid suppression effect of tegoprazan is known to be associated with systemic exposure....
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