Understanding adefovir pharmacokinetics as a component of a transporter phenotyping cocktail.

PURPOSE: Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CLR) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail. METHODS: Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination. RESULTS: A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h-1 vs. 5.18 h-1) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (Km) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (Vmax) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min. CONCLUSION: The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high Km value suggests that assessing renal OAT1 activity by CLR has no relevant misspecification error with the cocktail doses used.

Clinical and demographic factors affecting trough levels of isavuconazole in critically ill patients with or without COVID-19.

BACKGROUND: The broad-spectrum antifungal isavuconazole is administered to treat invasive aspergillosis and mucormycosis. OBJECTIVES: Isavuconazole plasma concentrations in critically ill ICU patients with or without COVID-19 and invasive fungal infection were determined, and factors for sub-therapeutic drug levels (<1 µg/mL) were evaluated. PATIENTS AND METHODS: Isavuconazole plasma levels were measured as part of therapeutic drug monitoring (TDM) in ICUs of a tertiary hospital. Concentrations determined 20-28 h after previous dosing were defined as trough (Cmin ) levels. A total of 160 Cmin levels from 62 patients with invasive fungal infections were analysed, 30 of which suffering from COVID-19. Patient characteristics included into univariable and multivariable analyses were gender, age, COVID-19 status, body mass index (BMI), sepsis-related organ failure (SOFA) score, renal replacement therapy (RRT) and extracorporeal membrane oxygenation (ECMO) requirement. RESULTS: The mean Cmin of isavuconazole in all patients was 1.64 µg/mL (interquartile range 0.83-2.24 µg/mL, total range 0.24-5.67 µg/mL). In total, 34.4% of the Cmin values (corresponding to 46.8% of patients) were below a threshold concentration of 1 µg/mL. Drug concentrations between patients with or without COVID-19 did not differ (p = .43). In contrast, levels were significantly lower in patients with female sex (p = .0007), age ≤ 65 years (p = .002), BMI > 25 (p = .006), SOFA score > 12 (p = .026), RRT (p = .017) and ECMO requirement (p = .001). CONCLUSIONS: Isavuconazole plasma levels can be negatively affected by patients' risk factors, supportive renal replacement and ECMO therapy. Future prospective studies analysing the relevance of isavuconazole drug levels in ICU patient outcome are urgently needed.

Pharmacokinetics of Nirmatrelvir and Ritonavir in COVID-19 Patients with End-Stage Renal Disease on Intermittent Hemodialysis.

Nirmatrelvir/ritonavir is an effective antiviral therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Use is not recommended in patients with end-stage renal disease (ESDR) due to a lack of data. We investigated the pharmacokinetics of nirmatrelvir/ritonavir (150 mg/100 mg twice a day) in four patients with ESRD undergoing hemodialysis. Nirmatrelvir peak concentrations ranged from 4,563 to 7,898 ng/mL and declined after hemodialysis. Concentrations were up to 4-fold higher but still within the range known from patients without ESRD, without accumulation of nirmatrelvir after the end of treatment.

Isavuconazole therapeutic drug monitoring in critically ill ICU patients: A monocentric retrospective analysis.

BACKGROUND: The broad-spectrum triazole isavuconazole is used for the treatment of invasive aspergillosis and mucormycosis. Data regarding human plasma concentrations in clinical routine of the drug are rare. OBJECTIVES: Plasma concentrations of isavuconazole were determined in critically ill ICU patients while considering different patients' characteristics. METHODS: Retrospective analysis of isavuconazole plasma concentrations were obtained as part of routine therapeutic drug monitoring (TDM) of ICU patients with invasive aspergillosis or other fungal infections treated with isavuconazole. Plasma levels 0-4 h after last dosing were defined as peak levels (Cmax ), those 20-28 h after last dosing as trough levels (Cmin ). RESULTS: Overall, 223 isavuconazole levels of 41 patients were analysed, divided into 141 peak levels and 82 trough levels. The overall median Cmax was 2.36 µg/ml (mean 2.43 µg/ml, range 0.41-7.79 µg/ml) and the overall median Cmin was 1.74 µg/ml (mean 1.77 µg/ml, range 0.24-4.96 µg/ml). In total, 31.7% of the Cmin values of the total cohort were below the plasma target concentrations of 1 µg/ml, defined as EUCAST antifungal clinical breakpoint for Aspergillus fumigatus. Both peak and trough plasma levels of isavuconazole were significantly lower among patients with a body mass index (BMI) ≥25. In addition, a significant correlation was observed between isavuconazole trough levels and sepsis-related organ failure assessment (SOFA) score. CONCLUSIONS: This study shows that isavuconazole plasma concentrations vary in critical ill ICU patients. Significantly lower isavuconazole levels were associated with elevated BMI and higher SOFA score indicating a need of isavuconazole TDM in this specific patient population.

Recovery of cefazolin and clindamycin in in vitro pediatric CPB systems.

Cardiopulmonary bypass (CPB) is often necessary for congenital cardiac surgery, but CPB can alter drug pharmacokinetic parameters resulting in underdosing. Inadequate plasma levels of antibiotics could lead to postoperative infections with increased morbidity. The influence of pediatric CPB systems on cefazolin and clindamycin plasma levels is not known. We have measured plasma levels of cefazolin and clindamycin in in vitro pediatric CPB systems. We have tested three types of CPB systems. All systems were primed and spiked with clindamycin and cefazolin. Samples were taken at different time points to measure the recovery of cefazolin and clindamycin. Linear mixed model analyses were performed to assess if drug recovery was different between the type of CPB system and sampling time point. The experiments were conducted at a tertiary university hospital. 81 samples were analyzed. There was a significant difference in the recovery over time between CPB systems for cefazolin and clindamycin (P < .001). Cefazolin recovery after 180 minutes was 106% (95% CI: 91-123) for neonatal, 99% (95% CI: 85-115) for infant, and 77% (95% CI: 67-89) for pediatric systems. Clindamycin recovery after 180 minutes was 143% (95% CI: 116-177) for neonatal, 111% (95% CI: 89-137) for infant, and 120% (95% CI: 97-149) for pediatric systems. Clindamycin recovery after 180 minutes compared to the theoretical concentration was 0.4% for neonatal, 1.2% for infants, and 0.6% for pediatric systems. The recovery of cefazolin was high in the neonatal and infant CPB systems and moderate in the pediatric system. We found a large discrepancy between the theoretical and measured concentrations of clindamycin in all tested CPB systems.

In Vitro Recovery of Sufentanil, Midazolam, Propofol, and Methylprednisolone in Pediatric Cardiopulmonary Bypass Systems.

OBJECTIVES: To evaluate in vitro drug recovery in cardiopulmonary bypass (CPB) systems used for pediatric cardiac surgery. DESIGN: Observational in vitro study. SETTING: Single-center university hospital. PARTICIPANTS: In vitro CPB systems used for pediatric cardiac surgery. INTERVENTIONS: Three full neonatal, infant, and pediatric CPB systems were primed according to hospital protocol and kept running for 6 hours. Midazolam, propofol, sufentanil, and methylprednisolone were added to the venous side of the systems in doses commonly used for induction of general anesthesia. Blood samples were taken from the postoxygenator side of the circuit immediately after injection of the drugs and after 2, 5, 7, 10, 30, 60, 180, and 300 minutes. MEASUREMENTS AND MAIN RESULTS: Linear mixed model analyses were performed to assess the relationship between log-transformed drug concentration (dependent variable) and type of CPB system and sample time point (independent variables). The mean percentage of drug recovery after 60 and 180 minutes compared with T1 was 41.7% (95% confidence interval [CI] 35.9-47.4) and 23.0% (95% CI 9.2-36.8) for sufentanil, 87.3% (95% CI 64.9-109.7) and 82.0% (95% CI 64.6-99.4) for midazolam, 41.3% (95% CI 15.5-67.2) and 25.0% (95% CI 4.7-45.3) for propofol, and 119.3% (95% CI 101.89-136.78) and 162.0% (95% CI 114.09-209.91) for methylprednisolone, respectively. CONCLUSIONS: The present in vitro experiment with neonatal, infant, and pediatric CPB systems shows a variable recovery of routinely used drugs with significant differences between drugs, but not between system categories (with the exception of propofol). The decreased recovery of mainly sufentanil and propofol could lead to suboptimal dosing of patients during cardiac surgery with CPB.

Influence of Sustained Low-Efficiency Dialysis Treatment on Isavuconazole Plasma Levels in Critically Ill Patients.

Isavuconazole plasma concentrations were measured before and after sustained low-efficiency dialysis (SLED) treatment in 22 critically ill adult patients with probable invasive aspergillosis and underlying hematological malignancies. Isavuconazole levels were significantly lower after SLED treatment (5.73 versus 3.36 µg/ml; P < 0.001). However, even after SLED treatment, isavuconazole concentrations exceeded the in vivo MICs for several relevant Aspergillus species.

Quantification of Hydrochlorothiazide and Ramipril/Ramiprilate in Blood Serum and Cerebrospinal Fluid: A Pharmacokinetic Assessment of Central Nervous System Adverse Effects.

BACKGROUND: A drug must reach the central nervous system (CNS) in order to directly cause CNS adverse effects (AEs). Our current study addressed the pharmacokinetic (PK) background of the assumption that CNS concentrations of hydrochlorothiazide (HCT) and ramiprilate may directly cause CNS AEs such as headache and drowsiness. METHODS: In neurological patients, paired serum and cerebrospinal fluid (CSF) samples were withdrawn simultaneously. Some of them were treated with HCT (n = 15, daily chronic doses 7.5-25 mg) or ramipril (n = 9, 2.5-10 mg). Total concentrations of HCT and ramiprilate were quantified in these samples. To this end, sensitive liquid chromatography/tandem mass spectrometry methods were developed. RESULTS: CSF reached 4.1% (interquartile ranges 2.5-5%) of total serum concentrations for HCT and 2.3% (1.7-5.7%) for ramiprilate, corresponding to about 11.3% and 5.5% of respective unbound serum concentrations. CONCLUSION: The PK/Pharmacodynamic characteristics of HCT and ramiprilate in the CNS are unknown. However, since the CSF levels of these agents, both free and bound, were much lower than the corresponding concentrations in serum, it is unlikely that the observed CNS AEs are mediated primarily via direct effects in the brain.

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples.

BACKGROUND: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. METHODS: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. RESULTS: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. CONCLUSION: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.

Environmental pollution with antimicrobial agents from bulk drug manufacturing industries in Hyderabad, South India, is associated with dissemination of extended-spectrum beta-lactamase and carbapenemase-producing pathogens.

PURPOSE: High antibiotic and antifungal concentrations in wastewater from anti-infective drug production may exert selection pressure for multidrug-resistant (MDR) pathogens. We investigated the environmental presence of active pharmaceutical ingredients and their association with MDR Gram-negative bacteria in Hyderabad, South India, a major production area for the global bulk drug market. METHODS: From Nov 19 to 28, 2016, water samples were collected from the direct environment of bulk drug manufacturing facilities, the vicinity of two sewage treatment plants, the Musi River, and habitats in Hyderabad and nearby villages. Samples were analyzed for 25 anti-infective pharmaceuticals with liquid chromatography-tandem mass spectrometry and for MDR Gram-negative bacteria using chromogenic culture media. In addition, specimens were screened with PCR for bla VIM, bla KPC, bla NDM, bla IMP-1, and bla OXA-48 resistance genes. RESULTS: All environmental specimens from 28 different sampling sites were contaminated with antimicrobials. High concentrations of moxifloxacin, voriconazole, and fluconazole (up to 694.1, 2500, and 236,950 µg/L, respectively) as well as increased concentrations of eight other antibiotics were found in sewers in the Patancheru-Bollaram industrial area. Corresponding microbiological analyses revealed an extensive presence of extended-spectrum beta-lactamase and carbapenemase-producing Enterobacteriaceae and non-fermenters (carrying mainly bla OXA-48, bla NDM, and bla KPC) in more than 95% of the samples. CONCLUSIONS: Insufficient wastewater management by bulk drug manufacturing facilities leads to unprecedented contamination of water resources with antimicrobial pharmaceuticals, which seems to be associated with the selection and dissemination of carbapenemase-producing pathogens. The development and global spread of antimicrobial resistance present a major challenge for pharmaceutical producers and regulatory agencies.

Comparison of Pantoprazole Concentrations in Simultaneous Cerebrospinal Fluid and Serum Samples.

BACKGROUND: Pantoprazole is a proton pump inhibitor drug mainly used for treating peptic diseases. Adverse effects of pantoprazole in the occasional central nervous system (CNS) include headache, vertigo and sleep disturbances. Data in rats suggest that proton pumps are expressed in the inner ear and in the epithelium of the choroid plexus, which would be a potential target to mediate such proton pump inhibitor effects. METHODS: To assess the distribution of pantoprazole into the human CNS despite its low lipophilicity (log p = 0.5), we quantified pantoprazole concentrations by liquid chromatography/tandem mass spectrometry in serum and cerebrospinal fluid retain samples withdrawn simultaneously. Twenty-six sample pairs were obtained from 23 neurological patients with therapeutic administration of pantoprazole prior to sampling. RESULTS: Median (interquartile range) serum concentration of total pantoprazole was 142 ng/ml (30.8-622). Cerebrospinal fluid concentration of total pantoprazole was 2.79 ng/ml (1.59-7.3) and reached 2.0% (1.0-4.5%) of simultaneous serum concentrations. CONCLUSION: This value corresponds to the unbound fraction of pantoprazole in serum reported previously and indicates that pantoprazole CNS concentrations are high enough to exert some effects on possible CNS targets.

Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration.

This study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 µg/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 µg/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00877370.).

Targeted and untargeted screening for impurities in losartan tablets marketed in Germany by means of liquid chromatography/high resolution mass spectrometry.

Technical advances in the field of quality analysis allow an increasingly deeper look into the impurity profile of drugs. The ability to detect unexpected impurities in addition to known impurities ensures the supply of high-quality drugs and can prevent recalls due to the detection of harmful unexpected impurities, as has happened recently with the N-nitrosamine and azido impurities in losartan (LOS) drug products. In the present study, the LC-MS/HRMS approach described by Backer et al. was applied to an even more complex system, being the investigation of 35 LOS drug products and combination preparations purchased in 2018 and 2022 in German pharmacies. The film-coated tablets were analysed by means of four LC-MS/HRMS method variants. For the separation a Zorbax RR StableBond C18 column (3.0 ×100 mm, particle size of 3.5 µm, pore size of 80 Å), a gradient elution and for mass spectrometric detection a qTOF mass spectrometer with electrospray ionization in positive and negative mode was used. An information-dependent acquisition method was applied for the acquisition of high-resolution mass spectrometry data. The combination of an untargeted and a targeted screening approach revealed the finding of eight impurities in total. Beside the five LOS related compounds, LOS impurity F, J, K, L, M, and related compound D from amlodipine besilate, LOS azide and an unknown derivative thereof were detected. Identification and structure elucidation, respectively, were successfully performed using in silico fragmentation. Differences in the impurity profiles of drug products from 2018 and 2022 could be observed. This study shows that broad screening approaches like this are applicable to the analysis of drug products and can be an important enhancement of the quality assurance of medicinal products.

Application of advanced high resolution mass spectrometric techniques for the analysis of losartan potassium regarding known and unknown impurities.

Recalls of medicinal products can cause supply bottlenecks. This is often due to the findings of unexpected impurities that pose a health risk to patients. A recent example is losartan potassium which was contaminated with azido-impurities. The choice of the analytical method determines which substances can be detected and thus controlled. In this study a combination of an untargeted screening approach for impurities and a targeted evaluation of high-resolution mass spectrometry data was applied to search for impurities not described so far, leaving out a precise quantification. Six losartan potassium samples were studied regarding known and unknown impurities and hence highlight the applicability and capability of the approach. For separation a Zorbax RR StableBond C18 column (3.0 ×100 mm, particle size of 3.5 µm, pore size of 80 Å), a gradient elution and an electrospray ionization in positive and negative mode for mass spectrometric detection was used. An information-dependent acquisition method was applied for the measurement of losartan potassium samples. The untargeted data evaluation using general unknown comparative screening revealed the presence of N-methyl-2-pyrrolidone (NMP) and another impurity from synthesis. The identity of NMP was corroborated by a spiking experiment and the amount was estimated by means of standard addition. A targeted data evaluation by generating extracted ion chromatograms resulted in finding of four additional impurities. Combined approaches like this are needed to detect and respond to changes in the quality of drugs precociously.

A high performance liquid chromatography-tandem mass spectrometry assay for therapeutic drug monitoring of 10 drug compounds commonly used for antimicrobial therapy in plasma and serum of critically ill patients: Method optimization, validation, cross-validation and clinical application.

BACKGROUND AND AIMS: Intensive care antibiotic treatment faces challenges due to substantial pharmacokinetic differences in critically ill patients. Individualized antibiotic dosing guided by therapeutic drug monitoring (TDM) is considered to minimize the risk of treatment failure and toxicity. This study aimed to develop a valid method for simultaneous LC-MS/MS quantification of 10 drugs frequently used in intensive care antibiotic therapy for which TDM-guided dosing is recommended: piperacillin, meropenem, flucloxacillin, cefuroxime, vancomycin, colistin A and B, linezolid, ciprofloxacin and tazobactam. METHODS AND RESULTS: Thorough optimization of sample preparation and chromatography resulted in a fast and simple method based on protein precipitation of 50 µL plasma or serum and gradient elution using an Acquity UPLC HSS-T3 column. Electrospray ionization-triple quadrupole mass spectrometry in dynamic multiple reaction monitoring was used for quantification, covering the therapeutic range of each drug compound. Validation following EMA and FDA recommendations, including inter-platform validation and inter-laboratory comparison, demonstrated high accuracy, precision and robustness of the new method. The assay was successfully used to monitor plasma antibiotic levels of critically ill patients (n = 35). CONCLUSION: The established multiplex method covers major drug classes with documented dosing challenges, provides a reliable basis for the implementation of high-throughput TDM, and its application confirmed the clinical impact of TDM in a real-world setting.

The therapeutic effect of tigecycline, unlike that of Ceftazidime, is not influenced by whether the Klebsiella pneumoniae strain produces extended-spectrum ß-lactamases in experimental pneumonia in rats.

The efficacies of tigecycline and ceftazidime against fatal pneumonia in rats caused by an extended-spectrum ß-lactamase (ESBL)-positive Klebsiella pneumoniae strain or its wild-type (WT) progenitor were compared. Ceftazidime at 12.5 or 50 mg/kg of body weight twice daily (b.i.d.) was effective (50% or 100% rat survival) in pneumonia caused by the WT isolate but unsuccessful (100% rat mortality) in pneumonia caused by the ESBL-positive variant. In contrast, tigecycline at 6.25, 12.5, or 25 mg/kg b.i.d. showed dosage-dependent efficacy up to 100% rat survival irrespective of the ESBL character of the infecting organism.

Identification of low-level impurities in drug prototypes of carbocisteine by means of liquid chromatography-high-resolution mass spectrometry and general unknown comparative screening.

High-resolution tandem quadrupole time-of-flight mass analysers enable new automated workflows for untargeted data evaluation of complex samples like drug products. An example of such procedure is the so-called general unknown comparative screening (GUCS), which is used for software-assisted, automated identification of components that are only present in a sample and not in a reference. The GUCS approach has been employed for the first time to detect both degradation products and reaction products in drug products. Two different carbocisteine containing syrup prototypes - one with sucrose and the other with artificial sweeteners - were selected as examples after nine months of storage at 40 °C and 75% relative humidity. The samples were analysed chromatographically using a Coresep SB mixed-mode column and high-resolution MS and MS/MS data were recorded in information dependant acquisition mode on a Sciex X500R quadrupole time-of-flight mass spectrometer. Data analysis was considerably facilitated using the corresponding placebo formulation as reference samples. With the GUCS approach two hitherto unknown degradation products of carbocisteine, i.e. the carbocisteine lactam of the sulfoxides and the disulfide between l-cysteine and thioglycolic acid, were detected at low concentrations in both of the syrup formulations. The presumed structures were confirmed by in silico analysis of the fragment spectra and high-resolution LC-MS experiments with reference substances. Two additional impurities were found in the sucrose-containing sample and identified as the N-glycosides of carbocisteine and its lactam, respectively, using binary mixtures with a 13C-labelled monosaccharide.

Population pharmacokinetics of piperacillin at two dose levels: influence of nonlinear pharmacokinetics on the pharmacodynamic profile.

Piperacillin in combination with tazobactam is one of the most commonly used intravenous antibiotics. There is evidence for a possible saturable elimination of piperacillin. Therefore, the saturable elimination and its impact on the choice of optimal dosage regimens were quantified. In a randomized crossover study, 10 healthy volunteers received 1,500 mg and 3,000 mg of piperacillin as 5-min intravenous infusion. Population pharmacokinetics based on plasma and urine data were determined utilizing NONMEM and S-ADAPT. Probabilities of target attainment (PTAs) were compared for different models and dosage regimens, based on the target time of the non-protein-bound concentration above the MIC of at least 50% of the dosing interval. Total clearance of piperacillin was 18% (geometric mean ratio, 90% confidence interval, 11 to 24%) lower (P < 0.01), and renal clearance was 24% (9 to 37%) lower (P = 0.02) at the high compared to the low dose. The final model included first-order nonrenal elimination and parallel first-order and mixed-order renal elimination. Nonrenal clearance was 5.44 liter/h (coefficient of variation, 18%), first-order renal clearance was 4.42 liter/h (47%), and the maximum elimination rate of mixed-order renal elimination was 219 mg/h (84%), with a Michaelis-Menten constant of 36.1 mg/liter (112%). Compared to models with saturable elimination, a linear model predicted up to 10% lower population PTAs for high-dose short-term infusions (6 g every 8 h) and up to 4% higher population PTAs for low-dose continuous infusions (6 g/day). While renal elimination of piperacillin was saturable at therapeutic concentrations, the extent of saturation of nonrenal clearance was small. The influence of saturable elimination on PTAs for clinically relevant dosage regimens was relatively small.

Caffeine, Paraxanthine, Theophylline, and Theobromine Content in Human Milk.

This study aimed to assess the content of caffeine and its metabolites-paraxanthine, theophylline, and theobromine-in breast milk according to selected factors. Samples of human milk were collected from 100 women living in the east-northeast region of Poland. Information on the consumption of beverages and foods containing caffeine was collected using a 3 day food record. The determination of caffeine and its metabolite content was performed using liquid chromatography-mass spectrometry (LC-MS/MS). This study research showed that more caffeine was found in the milk of women living in cities, with secondary education, aged 34-43, and also in milk from the 3rd and 4th lactation periods (p ≤ 0.05). Factors such as place of residence, level of education, age, and stage of lactation influenced the nutritional choices of breastfeeding women, which had an impact on the level of caffeine and its metabolites in breast milk. A positive correlation was found between the consumption of caffeine with food and drinks and its level in human milk.