Ceftriaxone Pharmacokinetics during Iatrogenic Hydroxyethyl Starch-induced Hypoalbuminemia

Background Although various drugs used by anesthesiologists highly bind to plasma proteins, the impact of iatrogenically induced hypoproteinemia on their pharmacologic effects has never been investigated. The authors determined the pharmacokinetics of ceftriaxone, a cephalosporin that binds strongly to albumin in postsurgical patients with hydroxyethyl starch-induced hypoalbuminemia. Methods Eleven hypoalbuminemic (serum albumin < 25 g/l) patients and age (+/- 5 yr)-, sex-, and body surface area (+/- 10%)-matched healthy volunteers received a 2-g ceftriaxone dose infused over a 15-min period. Fourteen venous blood samples were collected during the 24-h study period. Free ceftriaxone concentrations were determined by ultrafiltration. Antibiotic concentrations in plasma and ultrafiltrate were measured by ion-paired reversed-phase chromatography. The pharmacokinetic parameters derived from total and free antibiotic concentrations were determined using a noncompartmental method. Data are expressed as median and range. Results The pharmacokinetic parameters derived from total ceftriaxone concentrations were similar for the two groups, except for the median corrected volume of distribution at steady state, which was increased (P = 0.05) to 0.18 l/kg (range, 0. 11-0.29 l/kg) in patients, compared with 0.15 l/kg (range, 0.13-0.22 l/kg) in volunteers. The area under the free ceftriaxone concentration-time curve was twice as high in patients as in volunteers (median 192, range 114-301 vs. median 122, range 84-169 h. mg-1. l-1;P = 0.03). Moreover, the free ceftriaxone concentration remained more than 4 mg/l during more time in patients (median, 16. 7; range, 12.6-21.4 vs. median, 11.1; range, 6.0-19.0 h; P = 0.03). Conclusions Compared with healthy volunteers, patients with iatrogenic hypoalbuminemia have higher free ceftriaxone concentrations during the 24 h after antibiotic administration. This modification increases drug distribution into extravascular space and may enhance effectiveness.

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Pharmacokinetics and Arteriovenous Differences in Clevidipine Concentration following a Short- and a Long-term Intravenous Infusion in Healthy Volunteers

Anesthesiology ◽

10.1097/00000542-200004000-00016 ◽

2000 ◽

Vol 92 (4) ◽

pp. 993-1001 ◽

Cited By ~ 35

Author(s):

Hans Ericsson ◽

Ulf Bredberg ◽

Ulf Eriksson ◽

Åse Jolin-Mellgård ◽

Margareta Nordlander ◽

...

Keyword(s):

Blood Pressure ◽

Steady State ◽

Healthy Volunteers ◽

Venous Blood ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Blood Levels ◽

Blood Concentrations ◽

Arterial Blood ◽

The Mean

Background Clevidipine is an ultra-short-acting calcium antagonist developed for reduction and control of blood pressure during cardiac surgery. The objectives of the current study were to determine the pharmacokinetics of clevidipine after 20-min and 24-h intravenous infusions, and to determine the relation between the arterial and venous concentrations and the hemodynamic responses to clevidipine in healthy volunteers. Methods Four volunteers received clevidipine for 20 min, and eight subjects were administered clevidipine intravenously for 24 h at two different dose rates. Arterial and venous blood samples were drawn for pharmacokinetic evaluation, and blood pressure and heart rate were recorded. Results A triexponential disposition model described the pharmacokinetics of clevidipine. The mean arterial blood clearance of clevidipine was 0.069l/kg-1/min-1 and the mean volume of distribution at steady state was 0.19 l/kg. The duration of the infusion had negligible effect on the pharmacokinetic parameters, and the context-sensitive half-time for clevidipine, simulated from the mean pharmacokinetic parameters derived after 24 h infusion at the highest dose, was less than 1 min. The arterial blood levels reached steady state within 2 min of the start of infusion and were about twice as high as those in the venous blood at steady state. The peak response preceded the peak venous concentration and was slightly delayed from the peak arterial blood concentration. Conclusion Clevidipine is a high clearance drug with a small volume of distribution, resulting in extremely short half-lives in healthy subjects. The initial rapid increase in the arterial blood concentrations and the short equilibrium time between the blood and the biophase suggest that clevidipine can be rapidly titrated to the desired effect.

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Absence of Effect of Rufloxacin on Theophylline Pharmacokinetics in Steady State

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.9.2359 ◽

1998 ◽

Vol 42 (9) ◽

pp. 2359-2364 ◽

Cited By ~ 6

Author(s):

Martina Kinzig-Schippers ◽

Uwe Fuhr ◽

Marina Cesana ◽

Carola Müller ◽

A. Horst Staib ◽

...

Keyword(s):

Steady State ◽

Adverse Events ◽

Compartment Model ◽

Volume Of Distribution ◽

Reversed Phase ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Elimination Phase ◽

Once Daily ◽

Model Independent

ABSTRACT Several quinolone antibacterial agents are known to inhibit the metabolism of theophylline, with the potential to cause adverse events due to raised theophylline concentrations during coadministration. A randomized crossover study was therefore conducted with 12 healthy male volunteers (ages, 23 to 34 years; body weight, 64 to 101 kg) to evaluate a possible interaction between rufloxacin and theophylline. Both drugs were administered at steady state. Following the administration of an oral loading dose of 400 mg on day 1, rufloxacin was given orally at 200 mg once daily on days 2 to 7 during one period only. During both periods, 146 mg of theophylline was administered orally twice daily for 3 days (which were days 4 to 6 of the rufloxacin coadministration period) and intravenously once the next morning to test for an interaction. Theophylline and rufloxacin concentrations were measured by reversed-phase high-pressure liquid chromatography, the pharmacokinetics of theophylline at steady state following administration of the last dose were calculated by compartment-model-independent methods. To compare the treatments, analysis of variance-based point estimates and 90% confidence intervals (given in parentheses) were calculated for the mean ratios of the pharmacokinetic parameters from the test (rufloxacin coadministration) over those from the reference (theophylline without rufloxacin) period. These were as follows: maximum concentration at steady state, 1.01 (0.96 to 1.07); area under the concentration-time curve from 0 to 12 h, 0.98 (0.94 to 1.02); half-life, 0.99 (0.95 to 1.03); total clearance at steady state, 1.02 (0.99 to 1.06); and volume of distribution in the elimination phase, 1.01 (0.97 to 1.05). In conclusion, rufloxacin did not affect theophylline pharmacokinetics at steady state. Therefore, therapeutic coadministration of rufloxacin and theophylline is not expected to cause an increased incidence of theophylline-related adverse events.

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Pharmacokinetics and Tolerability of Daptomycin at Doses up to 12 Milligrams per Kilogram of Body Weight Once Daily in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00247-06 ◽

2006 ◽

Vol 50 (10) ◽

pp. 3245-3249 ◽

Cited By ~ 228

Author(s):

Mark Benvenuto ◽

David P. Benziger ◽

Sara Yankelev ◽

Gloria Vigliani

Keyword(s):

Body Weight ◽

Healthy Volunteers ◽

Bloodstream Infections ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Once Daily ◽

Complicated Skin ◽

Multiple Dose Pharmacokinetics ◽

Dose Proportional

ABSTRACT Daptomycin, a novel lipopeptide, is bactericidal against a broad range of gram-positive strains, including methicillin- (MRSA) and vancomycin-resistant Staphylococcus aureus. Daptomycin is approved at 4 mg/kg of body weight given intravenously once daily for the treatment of complicated skin and skin structure infections and at 6 mg/kg for the treatment of S. aureus bloodstream infections (bacteremia), including right-sided endocarditis caused by methicillin-susceptible S. aureus and MRSA. The present study was designed to evaluate the multiple-dose pharmacokinetics and safety of daptomycin at doses of 6 to 12 mg/kg in healthy volunteers. Three cohorts of 12 subjects each were given daptomycin (10 mg/kg) or placebo once daily for 14 days, daptomycin (12 mg/kg) or placebo once daily for 14 days, or daptomycin (6 or 8 mg/kg) once daily for 4 days. Daptomycin produced dose-proportional increases in the area under the plasma concentration-time curve and in trough daptomycin levels and nearly dose-proportional increases in peak daptomycin concentrations. Other pharmacokinetic parameters measured on day 1 and at steady state were independent of the dose, including the half-life (approximately 8 h), weight-normalized plasma clearance (9 to 10 ml/h/kg), and volume of distribution (approximately 100 ml/kg). Plasma protein binding was 90% to 93% and was independent of the daptomycin concentration. Daptomycin did not produce electrocardiographic abnormalities or electrophysiological evidence of muscle or nerve toxicity. Daptomycin was well tolerated in subjects dosed with up to 12 mg/kg intravenously for 14 days. Doses of daptomycin higher than 6 mg/kg once daily may be considered in further studies to evaluate the safety and efficacy of daptomycin in difficult-to-treat infections.

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When Bioequivalence in Healthy Volunteers May not Translate to Bioequivalence in Patients: Differential Effects of Increased Gastric pH on the Pharmacokinetics of Levothyroxine Capsules and Tablets

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j36p5m ◽

2015 ◽

Vol 18 (5) ◽

pp. 844 ◽

Cited By ~ 10

Author(s):

Corinne Seng Yue ◽

Salvatore Benvenga ◽

Claudia Scarsi ◽

Luca Loprete ◽

Murray Ducharme

Keyword(s):

Healthy Volunteers ◽

Clinical Studies ◽

In Vitro Study ◽

Gastric Ph ◽

Pharmacokinetic Parameters ◽

Post Dose ◽

Time Curve ◽

Ph Conditions ◽

The Impact

Purpose: Clinical studies have suggested that proton pump inhibitors may decrease levothyroxine absorption and an in vitro study suggested that the effect of pH on dissolution may differ with formulation. To determine the impact of formulation on the pharmacokinetics of levothyroxine in altered gastric pH conditions, this study compared the pharmacokinetics of levothyroxine capsules and tablets, two formulations deemed bioequivalent in healthy volunteers under fasting conditions, when taken with or without esomeprazole. Methods: Two clinical studies were conducted in healthy volunteers given single dose levothyroxine (600 mg) with a 45-day washout period. In Study 1 (parallel-design/two-way crossover), 16 subjects received either levothyroxine capsules or tablets, each group with or without prior administration of intravenous esomeprazole (maximum dose of 80 mg). In Study 2 (two-way crossover), 16 subjects received both capsules or tablets after intravenous esomeprazole. Blood samples were collected pre-dose and up to 24 hours post-dose. Baseline-adjusted pharmacokinetic parameters were calculated: Cmax (maximal concentration), Tmax (time to Cmax), AUC0-t (area under the concentration-time curve from 0 to the last detectable concentration), AUC0-6 and AUC0-12 (areas under the curve from 0 to 6 and 12 hours, respectively). Analyses of variance were conducted to compare ln-transformed Cmax and AUC. Non-parametric Tmax analyses were done. Results: In Study 1, esomeprazole caused a greater decrease in overall levothyroxine exposure of tablets vs. capsules (13% vs 6% for Cmax, 18% vs. 14% for AUC0-6, 17% vs. 5% for AUC0-12 and 10% vs. 8% for AUC0-t). In Study 2 esomeprazole administration resulted in a 16% smaller levothyroxine exposure with tablets vs. capsules. No statistically significant differences in Tmax were found. Conclusions: Although both formulations are considered “bioequivalent” in healthy volunteers, they may not necessarily be bioequivalent in patients with impaired gastric pH conditions. Levothyroxine capsules may therefore be more appropriate for patients with decreased gastric acidity. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Impact of the C2/C6 Ratio of High-molecular-weight Hydroxyethyl Starch on Pharmacokinetics and Blood Coagulation in Pigs

Anesthesiology ◽

10.1097/01.anes.0000278879.76613.1c ◽

2007 ◽

Vol 107 (3) ◽

pp. 442-451 ◽

Cited By ~ 4

Author(s):

Sebastian Schramm ◽

Caroline Thyes ◽

Philippe Frascarolo ◽

Thierry Buclin ◽

Marco Burki ◽

...

Keyword(s):

Molecular Weight ◽

Blood Coagulation ◽

High Molecular Weight ◽

Hydroxyethyl Starch ◽

Compartment Model ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Two Compartment Model ◽

The Impact

Background High-molecular-weight, low-substituted hydroxyethyl starch (HES) may not affect blood coagulation more than low-molecular-weight, low-substituted HES. The authors assessed in vivo the effect of a lowered C2/C6 ratio on pharmacokinetic characteristics and the impact on blood coagulation of high-molecular-weight, low-substituted HES. Methods A prospective, randomized, parallel study in 30 pigs compared HES 650/0.42/2.8 with HES 650/0.42/5.6. Before, during, and after infusion of 30 ml/kg body weight HES, blood samples were collected over 630 min to measure HES concentrations and plasmatic coagulation and to assess blood coagulation in whole blood by Thrombelastography (TEG; Haemoscope Corporation, Niles, IL). Pharmacokinetic parameters were estimated using a two-compartment model. Results The elimination constant was 0.009 +/- 0.001 min(-1) for HES 650/0.42/2.8 and 0.007 +/- 0.001 min(-1) for HES 650/0.42/5.6 (P < 0.001); the area under the plasma concentration-time curve was 1,374 +/- 340 min x g/l for HES 650/0.42/2.8 and 1,697 +/- 411 min x g/l for HES 650/0.42/5.6 (P = 0.026). The measured plasma HES concentrations were not different between HES 650/0.42/2.8 and HES 650/0.42/5.6. Both HES solutions equally affected blood coagulation: Thrombelastographic coagulation index decreased similarly at the end of infusion of HES 650/0.42/2.8 and at the end of infusion of HES 650/0.42/5.6 (P = 0.293). Also, activated partial thromboplastin and prothrombin times increased similarly for HES 650/0.42/2.8 and HES 650/0.42/5.6 (P = 0.831). Conclusion Reducing the C2/C6 ratio in high-molecular, low-substituted HES solutions results in a slightly faster HES elimination. However, the blood coagulation compromising effect was unaffected.

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Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

ACTA MEDICA IRANICA ◽

10.18502/acta.v60i1.8323 ◽

2022 ◽

Author(s):

Seyedeh Sana Khezrnia ◽

Bita Shahrami ◽

Mohammad Reza Rouini ◽

Atabak Najafi ◽

Hamid Reza Sharifnia ◽

...

Keyword(s):

Brain Injury ◽

Critically Ill ◽

Critically Ill Patients ◽

Normal Population ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Uv Detector ◽

Therapeutic Goals ◽

The Impact

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.

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Safety, toleration, and pharmacokinetics of intravenous azithromycin.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.11.2577 ◽

1996 ◽

Vol 40 (11) ◽

pp. 2577-2581 ◽

Cited By ~ 48

Author(s):

D R Luke ◽

G Foulds ◽

S F Cohen ◽

B Levy

Keyword(s):

Half Life ◽

Active Drug ◽

Slow Release ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Concentration Time ◽

Elimination Half ◽

The Mean ◽

Male Subjects

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

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Assessing the impact of a mushroom-derived food ingredient on vitamin D levels in healthy volunteers

Journal of the International Society of Sports Nutrition ◽

10.1186/s12970-020-00387-0 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Jorge Marques Pinto ◽

Viviane Merzbach ◽

Ashley G. B. Willmott ◽

Jose Antonio ◽

Justin Roberts

Keyword(s):

Vitamin D ◽

Healthy Volunteers ◽

Venous Blood ◽

Vitamin D Insufficiency ◽

Food Sources ◽

Natural Food ◽

Vitamin D Status ◽

Food Ingredient ◽

Vitamin D Levels ◽

The Impact

Abstract Background Prevalence of vitamin D insufficiency/deficiency has been noted in athletic populations, although less is known about recreationally active individuals. Biofortification of natural food sources (e.g. UV radiated mushrooms) may support vitamin D status and is therefore of current scientific and commercial interest. The aim of this study was to assess the impact of a mushroom-derived food ingredient on vitamin D status in recreationally active, healthy volunteers. Methods Twenty-eight participants were randomly assigned to either: 25 μg (1000 IU) encapsulated natural mushroom-derived vitamin D2; matched-dose encapsulated vitamin D3 or placebo (PL) for 12 weeks. Venous blood samples were collected at baseline, week 6 and 12 for analysis of serum 25(OH)D2 and 25(OH)D3 using liquid chromatography mass spectrometry. Habitual dietary intake and activity were monitored across the intervention. Results Vitamin D status (25(OH)DTOTAL) was significantly increased with vitamin D3 supplementation from 46.1 ± 5.3 nmol·L− 1 to 88.0 ± 8.6 nmol·L− 1 (p < 0.0001) across the intervention, coupled with an expected rise in 25(OH)D3 concentrations from 38.8 ± 5.2 nmol·L− 1 to 82.0 ± 7.9 nmol·L− 1 (p < 0.0001). In contrast, D2 supplementation increased 25(OH)D2 by + 347% (7.0 ± 1.1 nmol·L− 1 to 31.4 ± 2.1 nmol·L− 1, p < 0.0001), but resulted in a − 42% reduction in 25(OH)D3 by week 6 (p = 0.001). A net + 14% increase in 25(OH)DTOTAL was established with D2 supplementation by week 12 (p > 0.05), which was not statistically different to D3. Vitamin D status was maintained with PL, following an initial − 15% reduction by week 6 (p ≤ 0.046 compared to both supplement groups). Conclusions The use of a UV radiated mushroom food ingredient was effective in maintaining 25(OH)DTOTAL in healthy, recreationally active volunteers. This may offer an adjunct strategy in supporting vitamin D intake. However, consistent with the literature, the use of vitamin D3 supplementation likely offers benefits when acute elevation in vitamin D status is warranted.

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Vancomycin Dosing in Obese Patients: Special Considerations and Novel Dosing Strategies

Annals of Pharmacotherapy ◽

10.1177/1060028017750084 ◽

2017 ◽

Vol 52 (6) ◽

pp. 580-590 ◽

Cited By ~ 5

Author(s):

Cheryl Durand ◽

Mary Bylo ◽

Brian Howard ◽

Paul Belliveau

Keyword(s):

Data Extraction ◽

Population Data ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Obese Patients ◽

Study Selection ◽

Dosing Strategies ◽

Primary Focus ◽

Monitoring Protocols ◽

The Impact

Objective: To review the literature regarding vancomycin pharmacokinetics in obese patients and strategies used to improve dosing in this population. Data Sources: PubMed, EMBASE (1974 to November 2017), and Google Scholar searches were conducted using the search terms vancomycin, obese, obesity, pharmacokinetics, strategy, and dosing. Additional articles were selected from reference lists of selected studies. Study Selection and Data Extraction: Included articles were those published in English with a primary focus on vancomycin pharmacokinetic parameters in obese patients and practical vancomycin dosing strategies, clinical experiences, or challenges of dosing vancomycin in this population. Data Synthesis: Volume of distribution and clearance are the pharmacokinetic parameters that most often affect vancomycin dosing in obese patients; both are increased in this population. Challenges with dosing in obese patients include inconsistent and inadequate dosing, observations that the obese population may not be homogeneous, and reports of an increased likelihood of supratherapeutic trough concentrations. Investigators have revised and developed dosing and monitoring protocols to address these challenges. These approaches improved target trough attainment to varying degrees. Conclusions: Some of the vancomycin dosing approaches provided promising results in obese patients, but there were notable differences in methods used to develop these approaches, and sample sizes were small. Although some approaches can be considered for validation in individual institutions, further research is warranted. This may include validating approaches in larger populations with narrower obesity severity ranges, investigating target attainment in indication-specific target ranges, and evaluating the impact of different dosing weights and methods of creatinine clearance calculation.

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Low Caspofungin Exposure in Patients in Intensive Care Units

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01582-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 18

Author(s):

Kim C. M. van der Elst ◽

Anette Veringa ◽

Jan G. Zijlstra ◽

Albertus Beishuizen ◽

Rob Klont ◽

...

Keyword(s):

Intensive Care ◽

Critically Ill ◽

Critically Ill Patients ◽

Drug Exposure ◽

Standard Dose ◽

Drug Distribution ◽

Volume Of Distribution ◽

Primary Objective ◽

Time Curve ◽

Icu Patients

ABSTRACT In critically ill patients, drug exposure may be influenced by altered drug distribution and clearance. Earlier studies showed that the variability in caspofungin exposure was high in intensive care unit (ICU) patients. The primary objective of this study was to determine if the standard dose of caspofungin resulted in adequate exposure in critically ill patients. A multicenter prospective study in ICU patients with (suspected) invasive candidiasis was conducted in the Netherlands from November 2013 to October 2015. Patients received standard caspofungin treatment, and the exposure was determined on day 3 of treatment. An area under the concentration-time curve from 0 to 24 h (AUC0–24) of 98 mg · h/liter was considered adequate exposure. In case of low exposure (i.e., <79 mg · h/liter, a ≥20% lower AUC0–24), the caspofungin dose was increased and the exposure reevaluated. Twenty patients were included in the study, of whom 5 had a positive blood culture. The median caspofungin AUC0–24 at day 3 was 78 mg · h/liter (interquartile range [IQR], 69 to 97 mg · h/liter). A low AUC0–24 (<79 mg · h/liter) was seen in 10 patients. The AUC0–24 was significantly and positively correlated with the caspofungin dose in mg/kg/day (P = 0.011). The median AUC0–24 with a caspofungin dose of 1 mg/kg was estimated using a pharmacokinetic model and was 114.9 mg · h/liter (IQR, 103.2 to 143.5 mg · h/liter). In conclusion, the caspofungin exposure in ICU patients in this study was low compared with that in healthy volunteers and other (non)critically ill patients, most likely due to a larger volume of distribution. A weight-based dose regimen is probably more suitable for patients with substantially altered drug distribution. (This study has been registered at ClinicalTrials.gov under registration no. NCT01994096.)

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