Flavoured water consumption alters pharmacokinetic parameters and increases exposure of erlotinib and gefitinib in a preclinical study using Wistar rats

Background Erlotinib (ERL) and Gefitinib (GEF) are considered first line therapy for the management of non-small cell lung carcinoma (NSCLC). Like other tyrosine kinase inhibitors (TKIs), ERL and GEF are mainly metabolized by the cytochrome P450 (CYP450) CYP3A4 isoform and are substrates for transporter proteins with marked inter-/intra-individual pharmacokinetic (PK) variability. Therefore, ERL and GEF are candidates for drug-drug and food-drug interactions with a consequent effect on drug exposure and/or drug-related toxicities. In recent years, the consumption of flavoured water (FW) has gained in popularity. Among multiple ingredients, fruit extracts, which might constitute bioactive flavonoids, can possess an inhibitory effect on the CYP450 enzymes or transporter proteins. Therefore, in this study we investigated the effects of different types of FW on the PK parameters of ERL and GEF in Wistar rats. Methods ERL and GEF PK parameters in different groups of rats after four weeks consumption of different flavours of FW, namely berry, peach, lime, and pineapple, were determined from plasma drug concentrations using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Results Data indicated that tested FWs altered the PK parameters of both ERL and GEF differently. Lime water had the highest impact on most of ERL and GEF PK parameters, with a significant increase in Cmax (95% for ERL, 58% for GEF), AUC0–48 (111% for ERL, 203% for GEF), and AUC0–∞ (200% for ERL, 203% for GEF), along with a significant decrease in the apparent oral clearance of both drugs (65% for ERL, 67% for GEF). The order by which FW affected the PK parameters for ERL and GEF was as follows: lime > pineapple > berry > peach. Conclusion The present study indicates that drinking FW could be of significance in rats receiving ERL or GEF. Our results indicate that the alteration in PKs was mostly recorded with lime, resulting in an enhanced bioavailability, and reduced apparent oral clearance of the drugs. Peach FW had a minimum effect on the PK parameters of ERL and no significant effect on GEF PKs. Accordingly, it might be of clinical importance to evaluate the PK parameters of ERL and GEF in human subjects who consume FW while receiving therapy.

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Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01701-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 12

Author(s):

Sampson Antwi ◽

Hongmei Yang ◽

Anthony Enimil ◽

Anima M. Sarfo ◽

Fizza S. Gillani ◽

...

Keyword(s):

Drug Dose ◽

Pharmacokinetic Parameters ◽

Oral Clearance ◽

First Line ◽

Time Curve ◽

Apparent Oral Clearance ◽

Tb Treatment ◽

Hiv Coinfection ◽

Drug Concentrations ◽

Immunodeficiency Virus

ABSTRACT Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC0–8), maximum concentration (C max), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores (P < 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC0–8 values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC0–8 for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)

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Artemisinin Pharmacokinetics and Efficacy in Uncomplicated-Malaria Patients Treated with Two Different Dosage Regimens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.4.1026-1031.2002 ◽

2002 ◽

Vol 46 (4) ◽

pp. 1026-1031 ◽

Cited By ~ 39

Author(s):

Toufigh Gordi ◽

Dinh Xuan Huong ◽

Trinh Ngoc Hai ◽

Nguyen Thi Nieu ◽

Michael Ashton

Keyword(s):

High Performance ◽

Parasite Clearance ◽

Oral Dosage ◽

Pharmacokinetic Parameters ◽

Oral Clearance ◽

Dosage Regimens ◽

Drug Concentrations ◽

Group A ◽

Group B ◽

Pass Metabolism

ABSTRACT The immediate efficacies of two oral dosage regimens of artemisinin were investigated in 77 male and female adult Vietnamese falciparum malaria patients randomly assigned to treatment with either 500 mg of artemisinin daily for 5 days (group A; n = 40) or artemisinin at a dose of 100 mg per day for 2 days, with the dose increased to 250 mg per day for 2 consecutive days and with a final dose of 500 mg on the fifth day (group B; n = 37). Parasitemia was monitored every 4 h. The average parasite clearance time was longer in group B than in group A (means ± standard deviations, 50 ± 23 and 34 ± 14 h, respectively; P < 0.01). Artemisinin concentrations in saliva samples obtained on days 1 and 5 were quantified by high-performance liquid chromatography. The average oral clearance, based on saliva drug concentrations in group B patients, was twofold higher than that in group A patients on day 1 (P < 0.01), with no differences in drug half-lives (P = 0.40), indicating a saturable first-pass metabolism. Female patients had higher oral clearance values on day 1. Artemisinin's pharmacokinetic parameters were similar on day 5 in both groups, although a significant increase in oral clearance from day 1 to day 5 was evident. Thus, artemisinin exhibited both dose- and time-dependent pharmacokinetics. The escalating dose studied did not result in higher artemisinin concentrations toward the end of the treatment period.

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Pharmacokinetics and Monte Carlo Simulations of Doripenem in Patients with Febrile Neutropenia

Annals of Pharmacotherapy ◽

10.1345/aph.1r097 ◽

2012 ◽

Vol 46 (10) ◽

pp. 1281-1286 ◽

Cited By ~ 10

Author(s):

Gary E Stein ◽

Grace Kulhanek ◽

Curtis L Smith ◽

Joseph L Kuti ◽

David P Nicolau ◽

...

Keyword(s):

Monte Carlo ◽

Febrile Neutropenia ◽

Drug Exposure ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Gram Negative Bacteria ◽

Time Curve ◽

Gram Negative ◽

Probability Estimates ◽

Drug Concentrations

Background: Doripenem is a group 2 carbapenem with enhanced in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. There is a paucity of pharmacokinetic/pharmacodynamic data on doripenem in patients with febrile neutropenia. Objective: To conduct a pharmacokinetic evaluation of 2 doses of doripenem in patients with febrile neutropenia and provide probability estimates of attaining effective drug exposure against common gram-negative pathogens. Methods: We obtained multiple blood samples from 12 adults with febrile neutropenia who were receiving either 500 mg or 1000 mg of intravenous doripenem over 4 hours every B hours. Following at least 2 doses, serum concentrations were measured in each subject at 1, 4, 6, and 8 hours after initiation of a dose by a validated high-performance liquid chromatography assay. The derived pharmacokinetic parameters from these serum levels were used to perform a 5000-patient Monte Carlo simulation against bacteria with minimal inhibitory concentrations (MICs) of 0.008-64 mg/L to determine probability estimates of the time in which unbound drug concentrations remain above the MIC (fT>MIC). Results: The mean pharmacokinetic parameters in these patients were a volume of distribution of 43.9 L, an elimination rate constant of 0.37 h-1, a total clearance of 14.4 L/h, and an area under the concentration-time curve of 57.6 mg·h/L. An optimal probability of target attainment (40% fT>MIC) of 90% was obtained against bacteria with MICs ≤2 mg/L and ≤4 mg/L with 500-mg and 1000-mg doses, respectively. Adverse events associated with doripenem were not observed. Conclusions: The findings from this analysis of doripenem suggest that higher doses, as well as prolonged infusions, may be necessary to optimally treat selected gram-negative bacteria (eg, P. aeruginosa) in patients with febrile neutropenia.

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A Phase I and Pharmacokinetic Study of Pegylated Camptothecin as a 1-Hour Infusion Every 3 Weeks in Patients With Advanced Solid Malignancies

Journal of Clinical Oncology ◽

10.1200/jco.2003.03.143 ◽

2003 ◽

Vol 21 (1) ◽

pp. 148-157 ◽

Cited By ~ 102

Author(s):

Eric K. Rowinsky ◽

Jinee Rizzo ◽

Leonel Ochoa ◽

Chris H. Takimoto ◽

Bahram Forouzesh ◽

...

Keyword(s):

Dose Level ◽

Topoisomerase I ◽

Small Cell Lung Carcinoma ◽

Plasma Concentrations ◽

Maximum Tolerated Dose ◽

Unknown Primary ◽

Pharmacokinetic Parameters ◽

Cell Lung Carcinoma ◽

Phase Ii Studies ◽

Solid Malignancies

Purpose: To assess the feasibility of administering camptothecin (CPT), the prototypic topoisomerase I inhibitor, as polyethylene glycol (PEG)-CPT, a macromolecule consisting of CPT conjugated to chemically modified PEG. The study also sought to determine the maximum-tolerated dose (MTD) of PEG-CPT, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. Patients and Methods: Patients with advanced solid malignancies were treated with escalating doses of PEG-CPT as a 1-hour intravenous (IV) infusion every 3 weeks. A modified continual reassessment method was used for dose-level assignment to determine the MTD, which was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. Results: Thirty-seven patients were treated with 144 courses of PEG-CPT at seven dose levels ranging from 600 to 8,750 mg/m2. Severe myelosuppression was consistently experienced by heavily pretreated (HP) and minimally pretreated (MP) patients at the highest dose level evaluated, 8,750 mg/m2, whereas both HP and MP patients tolerated repetitive treatment at 7,000 mg/m2. Cystitis, nausea, vomiting, and diarrhea were also observed but were rarely severe. A partial response was noted in a patient with platinum- and etoposide-resistant small-cell lung carcinoma, and minor responses were noted in one patient each with adenocarcinoma of unknown primary type and osteosarcoma. The pharmacokinetics of free CPT were dose proportional. Free CPT accumulated slowly in plasma, with maximal plasma concentrations achieved at 23 ± 12.3 hours; the harmonic mean half-life (t1/2) of free CPT was long (t1/2, 77.46 ± 36.77 hours). Conclusion: Clinically relevant doses of CPT can be delivered by administering PEG-CPT. The recommended dose for phase II studies in both MP and HP patients is 7,000 mg/m2 as 1-hour IV every 3 weeks. The characteristics of the myelosuppressive effects of PEG-CPT, the paucity of severe nonhematologic toxicities with repetitive treatment, the preliminary antitumor activity noted, and the slow clearance of CPT enabling simulation of desirable pharmacokinetic parameters with a convenient single-dosing regimen warrant further disease-directed evaluations.

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Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa049 ◽

2020 ◽

Vol 75 (6) ◽

pp. 1546-1553 ◽

Cited By ~ 7

Author(s):

Luzelena Caro ◽

David P Nicolau ◽

Jan J De Waele ◽

Joseph L Kuti ◽

Kajal B Larson ◽

...

Keyword(s):

Drug Exposure ◽

Phase 1 ◽

Study Drug ◽

Pharmacokinetic Parameters ◽

Respiratory Pathogens ◽

Open Label ◽

Dosing Interval ◽

Multicentre Phase ◽

Drug Concentrations ◽

Pharmacodynamic Profile

Abstract Objectives Ceftolozane/tazobactam is approved for hospital-acquired/ventilator-associated bacterial pneumonia at double the dose (i.e. 2 g/1 g) recommended for other indications. We evaluated the bronchopulmonary pharmacokinetic/pharmacodynamic profile of this 3 g ceftolozane/tazobactam regimen in ventilated pneumonia patients. Methods This was an open-label, multicentre, Phase 1 trial (clinicaltrials.gov: NCT02387372). Mechanically ventilated patients with proven/suspected pneumonia received four to six doses of 3 g of ceftolozane/tazobactam (adjusted for renal function) q8h. Serial plasma samples were collected after the first and last doses. One bronchoalveolar lavage sample per patient was collected at 1, 2, 4, 6 or 8 h after the last dose and epithelial lining fluid (ELF) drug concentrations were determined. Pharmacokinetic parameters were estimated by non-compartmental analysis and pharmacodynamic analyses were conducted to graphically evaluate achievement of target exposures (plasma and ELF ceftolozane concentrations >4 mg/L and tazobactam concentrations >1 mg/L; target in plasma: ≥30% and ≥20% of the dosing interval, respectively). Results Twenty-six patients received four to six doses of study drug; 22 were included in the ELF analyses. Ceftolozane and tazobactam Tmax (6 and 2 h, respectively) were delayed in ELF compared with plasma (1 h). Lung penetration, expressed as the ratio of mean drug exposure (AUC) in ELF to plasma, was 50% (ceftolozane) and 62% (tazobactam). Mean ceftolozane and tazobactam ELF concentrations remained >4 mg/L and >1 mg/L, respectively, for 100% of the dosing interval. There were no deaths or adverse event-related study discontinuations. Conclusions In ventilated pneumonia patients, 3 g of ceftolozane/tazobactam q8h yielded ELF exposures considered adequate to cover ceftolozane/tazobactam-susceptible respiratory pathogens.

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Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria

Malaria Journal ◽

10.1186/s12936-020-03553-6 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Thomas A. Anyorigiya ◽

Sandra Castel ◽

Katya Mauff ◽

Frank Atuguba ◽

Bernhards Ogutu ◽

...

Keyword(s):

Falciparum Malaria ◽

Active Metabolite ◽

Drug Exposure ◽

Age Groups ◽

Uncomplicated Falciparum Malaria ◽

Fixed Dose ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Close Monitoring ◽

Drug Concentrations

Abstract Background Accurate measurement of anti-malarial drug concentrations in therapeutic efficacy studies is essential to distinguish between inadequate drug exposure and anti-malarial drug resistance, and to inform optimal anti-malarial dosing in key target population groups. Methods A sensitive and selective LC–MS/MS method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine, and used to describe their pharmacokinetic parameters in Ghanaian patients with uncomplicated falciparum malaria treated with the fixed-dose combination, artesunate-amodiaquine. Results The day-28 genotype-adjusted adequate clinical and parasitological response rate in 308 patients studied was > 97% by both intention-to-treat and per-protocol analysis. After excluding 64 patients with quantifiable amodiaquine concentrations pre-treatment and 17 with too few quantifiable concentrations, the pharmacokinetic analysis included 227 patients (9 infants, 127 aged 1–4 years, 91 aged ≥ 5 years). Increased median day-3 amodiaquine concentrations were associated with a lower risk of treatment failure [HR 0.87 (95% CI 0.78–0.98), p = 0.021]. Amodiaquine exposure (median AUC0-∞) was significantly higher in infants (4201 ng h/mL) and children aged 1–5 years (1994 ng h/mL) compared to older children and adults (875 ng h/mL, p = 0.001), even though infants received a lower mg/kg amodiaquine dose (median 25.3 versus 33.8 mg/kg in older patients). Desethylamodiaquine AUC0-∞ was not significantly associated with age. No significant safety concerns were identified. Conclusions Efficacy of artesunate-amodiaquine at currently recommended dosage regimens was high across all age groups. Reassuringly, amodiaquine and desethylamodiaquine exposure was not reduced in underweight-for-age young children or those with high parasitaemia, two of the most vulnerable target populations. A larger pharmacokinetic study with close monitoring of safety, including full blood counts and liver function tests, is needed to confirm the higher amodiaquine exposure in infants, understand any safety implications and assess whether dose optimization in this vulnerable, understudied population is needed.

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Attomole-per Cell Atomic Mass Spectrometry Measurement of Platinum and Gold Drugs in Cultured Lung Cancer Cells

Molecules ◽

10.3390/molecules26247627 ◽

2021 ◽

Vol 26 (24) ◽

pp. 7627

Author(s):

Wioletta Jakubczak ◽

Maja Haczyk-Więcek ◽

Katarzyna Pawlak

Keyword(s):

Metal Ions ◽

Inductively Coupled Plasma ◽

Small Cell Lung Carcinoma ◽

Cross Flow ◽

Transition Metal Ions ◽

Normal Lung ◽

Lower Efficiency ◽

Cell Lung Carcinoma ◽

Drug Concentrations ◽

Inhibitory Drug

In this study, we developed a strategy to determine atto- and femtomolar amounts of metal ions in lysates and mineralizates of cells (human non-small-cell lung carcinoma (NSCLC, A549) and normal lung (MRC-5)) exposed to cytotoxic metallo-drugs: cisplatin and auranofin at concentrations close to the half-maximal inhibitory drug concentrations (IC50). The developed strategy combines data obtained using biological and chemical approaches. Cell density was determined using two independent cell staining assays using trypan blue, calcein AM/propidium iodide. Metal concentrations in lysed and mineralized cells were established employing a mass spectrometer with inductively coupled plasma (ICP-MS) and equipped with a cross-flow nebulizer working in aspiration mode. It allowed for detecting of less than 1 fg of metal per cell. To decrease the required amount of sample material (from 1.5 mL to ~100 µL) without loss of sensitivity, the sample was introduced as a narrow band into a constant stream of liquid (flow-injection analysis). It was noticed that the selectivity of cisplatin accumulation by cells depends on the incubation time. This complex is accumulated by cells at a lower efficiency than auranofin and is found primarily in the lysate representing the cytosol. In contrast, auranofin interacts with water-insoluble compounds. Despite their different mechanism of action, both metallo-drugs increased the accumulation of transition metal ions responsible for oxidative stress.

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Impact of Nonlinear Interactions of Pharmacokinetics and MICs on Sputum Bacillary Kill Rates as a Marker of Sterilizing Effect in Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03931-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 38-45 ◽

Cited By ~ 82

Author(s):

Emmanuel Chigutsa ◽

Jotam G. Pasipanodya ◽

Marianne E. Visser ◽

Paul D. van Helden ◽

Peter J. Smith ◽

...

Keyword(s):

Drug Exposure ◽

Sputum Sample ◽

Bactericidal Effect ◽

Multivariate Adaptive Regression Splines ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Content Type ◽

Drug Concentrations ◽

Adaptive Regression ◽

Rate Of Decline

ABSTRACTThe relationships between antituberculosis drug exposure and treatment effects on humans receiving multidrug therapy are complex and nonlinear. In patients on treatment, an analysis of the rate of decline in the sputum bacillary burden reveals two slopes. The first is the α-slope, which is thought to reflect bactericidal effect, followed by a β-slope, which is thought to reflect sterilizing activity. We sought to characterize the effects of standard first-line treatment on sterilizing activity. Fifty-four patients receiving combination therapy for pulmonary tuberculosis in a clinical trial had drug concentrations measured andMycobacterium tuberculosisisolates available for MIC identification. Sputum sample cultures were performed at baseline and weekly for 8 weeks. A time-to-event model based on the days to positivity in the liquid cultures was used to estimate the β-slope. The pharmacokinetic parameters of rifampin, isoniazid, ethambutol, and pyrazinamide were determined for each patient. Multivariate adaptive regression splines analyses, which simultaneously perform linear and nonlinear analyses, were used to identify the relationships between the predictors and the β-slope. The potential predictors examined included HIV status, lung cavitation, 24-h area under the concentration-time curve (AUC), peak drug concentration (Cmax), AUC/MIC ratio,Cmax/MIC ratio, and the time that that concentration persisted above MIC. A rifampinCmaxof >8.2 mg/liter and a pyrazinamide AUC/MIC of >11.3 were key predictors of the β-slope and interacted positively to increase the β-slope. In patients with a rifampin AUC of <35.4 mg · h/liter, an increase in the pyrazinamide AUC/MIC and/or ethambutolCmax/MIC increased the β-slope, while increasing isoniazidCmaxdecreased it, suggesting isoniazid antagonism. Antibiotic concentrations and MICs interact in a nonlinear fashion as the main drivers of a sterilizing effect. The results suggest that faster speeds of sterilizing effect might be achieved by omitting isoniazid and by increasing rifampin, pyrazinamide, and ethambutol exposures. However, isoniazid and ethambutol exposures may only be of importance when rifampin exposure is low. These findings need confirmation in larger studies. (This study has been registered atcontrolled-trials.comunder registration no. ISRCTN80852505.)

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Comparative Plasma Pharmacokinetics of Ceftriaxone and Ertapenem in Normoalbuminemia, Hypoalbuminemia, and Albumin Replacement in a Sheep Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02584-19 ◽

2020 ◽

Vol 64 (7) ◽

Author(s):

Jayesh A. Dhanani ◽

Benjamin Ahern ◽

Liad Lupinsky ◽

Karen Jackson ◽

Steven C. Wallis ◽

...

Keyword(s):

Drug Exposure ◽

Area Under The Curve ◽

Apparent Volume ◽

Volume Of Distribution ◽

The Other ◽

Terminal Phase ◽

Pharmacokinetic Parameters ◽

Sheep Model ◽

Drug Concentrations ◽

Ultrahigh Performance Liquid Chromatography

ABSTRACT Optimal concentrations of unbound antimicrobials are essential for a maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare the effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model. The study design was a prospective, three-phase intervention observational study. The subjects were healthy Merino sheep. Eight sheep were subjected to three experimental phases: normoalbuminemia, hypoalbuminemia using plasmapheresis, and albumin replacement using a 25% albumin solution. In each phase, ceftriaxone at 40 mg/kg of body weight and ertapenem at 15 mg/kg were given intravenously. Blood samples were collected at predefined intervals and analyzed using an ultrahigh-performance liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters such as the area under the curve from 0 to 24 h (AUC0–24), plasma clearance (CL), and apparent volume of distribution in the terminal phase (V) were estimated and compared between the phases. The protein and albumin concentrations were significantly different between phases. Hypoalbuminemia resulted in a significantly lower AUC0–24 and higher CL of total and unbound concentrations of ceftriaxone than in the other phases, whereas albumin replacement led to higher AUC0–24 and lower CL than in the other phases for both drugs. The V values for total drug concentrations for both drugs were significantly lower with albumin replacement. For highly protein-bound drugs such as ceftriaxone and ertapenem, both hypoalbuminemia and albumin replacement may affect unbound drug exposure.

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