Estimation of the Steady-State Volume of Distribution for Digoxin: A Comparison of Model-Independent Methods with a Two-Compartment Model in Healthy Volunteers

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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Steady-State Pharmacokinetics of Cefoperazone and Sulbactam in Patients with Acute Appendicitis

Annals of Pharmacotherapy ◽

10.1177/106002809402800602 ◽

1994 ◽

Vol 28 (6) ◽

pp. 703-707

Author(s):

Larry H. Danziger ◽

Stephen C. Piscitelli ◽

Donna J. Occhipinti ◽

Daniel J. Resnick ◽

Keith A. Rodvold

Keyword(s):

Steady State ◽

Acute Appendicitis ◽

Dosage Reduction ◽

Area Under The Curve ◽

Compartment Model ◽

Hepatic Function ◽

Volume Of Distribution ◽

Two Compartment Model ◽

Elimination Half ◽

G Prior

OBJECTIVE: To determine the steady-state pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to patients with acute appendicitis. METHODS: Six patients with normal renal and hepatic function received cefoperazone 2 g with sulbactam 1 g prior to appendectomy and then every 12 hours. Serial blood samples were collected after each patient received at least three doses of cefoperazone/sulbactam. RESULTS: Cefoperazone and sulbactam could be best described by a two-compartment model. Mean ± SD values for cefoperazone steady-state volume of distribution (Vssd), elimination half-life (t1/2β), clearance (Cl), and area under the curve (AUC0-t) were 19.8 ± 8.0 L, 3.97 ± 1.06 h, 62.6 ± 16.3 mL/min, and 556.9 ± 122.0 mg·h/L, respectively. Sulbactam Vssd, t1/2β, Cl, and AUC0-t were 34.7 ± 13.9 L, 1.39 ± 0.4 h, 288.6 ± 68.2 mL/min, and 64.8 ± 24.5 mg·h/L, respectively. CONCLUSIONS: Compared with data from healthy volunteers, cefoperazone exhibited a decreased Cl and increased Vssd and t1/2β in patients with acute appendicitis. An increased Vssd also was observed for sulbactam. The disposition of cefoperazone/sulbactam is altered in this group of patients; however, these changes are not likely to warrant a dosage reduction.

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Estimation of the rate of appearance in the non-steady state with a two-compartment model

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.263.2.e400 ◽

1992 ◽

Vol 263 (2) ◽

pp. E400-E415 ◽

Cited By ~ 26

Author(s):

A. Mari

Keyword(s):

Steady State ◽

Time Course ◽

Specific Activity ◽

Glucose Production ◽

Compartment Model ◽

New Method ◽

Two Compartment Model ◽

Glucose Clamp Technique ◽

Glucose Output ◽

The Relationship

A simple tracer-based method for calculating the rate of appearance of endogenous substances in the non-steady state, free from the inconsistencies of Steele's equation, is still lacking. This paper presents a method based on a two-compartment model by which the rate of appearance can be calculated with only a modest increase in complexity over Steele's approach. An equation is developed where the rate of appearance is expressed as a sum of three terms: a steady-state term, a term for the first compartment, and a term for the second compartment. The formula employs three parameters and makes the relationship between rate of appearance and specific activity changes explicit. An equation is also provided for estimating the error of the method in each individual run. The algorithm can be implemented with a spreadsheet on a personal computer. Simulated and experimental data obtained by the hyperinsulinemic euglycemic glucose clamp technique were used as a test. The accuracy with which the time course of glucose production could be reconstructed was clearly better than that using Steele's equation. Marked negative values for endogenous glucose output were calculated with Steele's equation but not with the new method. The characteristics of generality, simplicity, and accuracy and the availability of an error estimate make this new method suitable for routine application to non-steady-state tracer analysis.

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1573. Population Pharmacokinetic Analyses for Cefepime in Adult and Pediatric Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1437 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S574-S575

Author(s):

Jiajun Liu ◽

Michael Neely ◽

Jeffrey Lipman ◽

Fekade B Sime ◽

Jason Roberts ◽

...

Keyword(s):

Rate Constant ◽

Pediatric Patients ◽

Validation Cohort ◽

External Validation ◽

Compartment Model ◽

Volume Of Distribution ◽

Information Criteria ◽

Population Pharmacokinetic ◽

Final Model ◽

Two Compartment Model

Abstract Background Cefepime (CEF) is commonly used for adult and pediatric infections. Several studies have examined CEF’s pharmacokinetics (PK) in various populations; however, a unifying PK model for adult and pediatric subjects does not yet exist. We developed a combined population model for adult and pediatric patients and validated the model. Methods The initial model includes adult and pediatric patients with a rich cefepime sampling design. All adults received 2 g CEF while pediatric subjects received a mean of 49 (SD 5) mg/kg. One- and two-compartment models were considered as base models and were fit using a non-parametric adaptive grid algorithm within the Pmetrics package 1.5.2 (Los Angeles, CA) for R 3.5.1. Compartmental model selection was based on Akaike information criteria (AIC). Covariate relationships with PK parameters were visually inspected and mathematically assessed. Predictive performance was evaluated using bias and imprecision of the population and individual prediction models. External validation was conducted using a separate adult cohort. Results A total of 45 subjects (n = 9 adults; n = 36 pediatrics) were included in the initial PK model build and 12 subjects in the external validation cohort. Overall, the data were best described using a two-compartment model with volume of distribution (V) normalized to total body weight (TBW/70 kg) and an allometric scaled elimination rate constant (Ke) for pediatric subjects (AIC = 4,138.36). Final model observed vs. predicted plots demonstrated good fit (population R2 = 0.87, individual R2 = 0.97, Figure 1a and b). For the final model, the population median parameter values (95% credibility interval) were V0 (total volume of distribution), 11.7 L (10.2–14.6); Ke for adult, 0.66 hour−1 (0.38–0.78), Ke for pediatrics, 0.82 hour−1 (0.64–0.85), KCP (rate constant from central to peripheral compartment), 1.4 hour−1 (1.3–1.8), KPC (rate constant from peripheral to central compartment), 1.6 hour−1 (1.2–1.8). The validation cohort has 12 subjects, and the final model fit the data well (individual R2 = 0.75). Conclusion In this diverse group of adult and pediatrics, a two-compartment model described CEF PK well and was externally validated with a unique cohort. This model can serve as a population prior for real-time PK software algorithms. Disclosures All authors: No reported disclosures.

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Population Pharmacokinetics of Liposomal Amphotericin B and Caspofungin in Allogeneic Hematopoietic Stem Cell Recipients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00265-11 ◽

2011 ◽

Vol 56 (1) ◽

pp. 536-543 ◽

Cited By ~ 25

Author(s):

Gudrun Würthwein ◽

Charlotte Young ◽

Claudia Lanvers-Kaminsky ◽

Georg Hempel ◽

Mirjam N. Trame ◽

...

Keyword(s):

Stem Cell ◽

Amphotericin B ◽

Hematopoietic Stem Cell ◽

Liposomal Amphotericin ◽

Compartment Model ◽

Volume Of Distribution ◽

Concentration Data ◽

Hematopoietic Stem ◽

Two Compartment Model ◽

Proportional Error Model

ABSTRACTLiposomal amphotericin B (LAMB) and caspofungin (CAS) are important antifungal agents in allogeneic hematopoietic stem cell transplant (aHSCT) recipients. Little is known, however, about the pharmacokinetics (PK) of both agents and their combination in this population. The PK of LAMB and CAS and the potential for PK interactions between both agents were investigated within a risk-stratified, randomized phase II clinical trial in 53 adult aHSCT recipients with granulocytopenia and refractory fever. Patients received either LAMB (n= 17; 3 mg/kg once a day [QD]), CAS (n= 19; 50 mg QD; day 1, 70 mg), or the combination of both (CAS-LAMB;n= 17) for a median duration of 10 to 13 days (range, 4 to 28 days) until defervescence and granulocyte recovery. PK sampling was performed on days 1 and 4. Drug concentrations in plasma (LAMB, 405 samples; CAS, 458 samples) were quantified by high-pressure liquid chromatography and were analyzed using population pharmacokinetic modeling. CAS concentration data best fitted a two-compartment model with a proportional error model and interindividual variability (IIV) for clearance (CL) and central volume of distribution (V1) (CL, 0.462 liter/h ± 25%;V1, 8.33 liters ± 29%; intercompartmental clearance [Q], 1.25 liters/h; peripheral volume of distribution [V2], 3.59 liters). Concentration data for LAMB best fitted a two-compartment model with a proportional error model and IIV for all parameters (CL, 1.22 liters/h ± 64%;V1, 19.2 liters ± 38%;Q, 2.18 liters/h ± 47%;V2, 52.8 liters ± 84%). Internal model validation showed predictability and robustness of both models. None of the covariates tested (LAMB or CAS comedication, gender, body weight, age, body surface area, serum bilirubin, and creatinine clearance) further improved the models. In summary, the disposition of LAMB and CAS was best described by two-compartment models. Drug exposures in aHSCT patients were comparable to those in other populations, and no PK interactions were observed between the two compounds.

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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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Phosphorus Fluxes in Limnetic Cladocerans: Coupling of Allometry and Compartmental Analysis

Canadian Journal of Fisheries and Aquatic Sciences ◽

10.1139/f94-105 ◽

1994 ◽

Vol 51 (5) ◽

pp. 1055-1064 ◽

Cited By ~ 11

Author(s):

Yuan Hua Wen ◽

Alain Vézina ◽

Robert Henry Peters

Keyword(s):

Body Weight ◽

Steady State ◽

Body Size ◽

Time Course ◽

Compartmental Analysis ◽

Compartment Model ◽

Size Dependent ◽

Two Compartment Model ◽

Metabolic Activities ◽

Total P

A size-dependent two-compartment model was developed for estimation of 32P turnover and fluxes by limnetic cladocerans in steady state. After feeding on radioactively labelled food, uniformly labelled animals were fed unlabelled cells and the time course of release of tracer followed. Rates of turnover and size-specific fluxes were subsequently fitted to a two-compartment model. The model predicted that steady-state turnover and size-specific fluxes for 32P excretion declined with body weight and that the exponent of weight did not significantly differ from −0.25, suggesting the relationships between total P turnover or flux rates and body size in cladocerans follow the same allometry observed for other organisms and other metabolic activities. However, rate constants for intercompartmental exchanges declined faster than weight−0.25, indicating that their turnover and flux declined much faster with increasing body size than would be expected from general allometry. Size-specific ingestion and assimilation rates of 32P by cladocerans decreased with increasing body size with a slope of the allometric function similar to −0.25.

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Impact of Albumin and Omeprazole on Steady-State Population Pharmacokinetics of Voriconazole and Development of a Voriconazole Dosing Optimization Model in Thai Patients with Hematologic Diseases

Antibiotics ◽

10.3390/antibiotics9090574 ◽

2020 ◽

Vol 9 (9) ◽

pp. 574

Author(s):

Buddharat Khan-asa ◽

Baralee Punyawudho ◽

Noppaket Singkham ◽

Piyawat Chaivichacharn ◽

Ekapun Karoopongse ◽

...

Keyword(s):

Steady State ◽

Compartment Model ◽

Apparent Volume ◽

Volume Of Distribution ◽

Albumin Level ◽

Hematologic Diseases ◽

Mixed Effects Modeling ◽

Dosing Regimens ◽

The One ◽

Dosing Optimization

This study aimed to identify factors that significantly influence the pharmacokinetics of voriconazole in Thai adults with hematologic diseases, and to determine optimal voriconazole dosing regimens. Blood samples were collected at steady state in 65 patients (237 concentrations) who were taking voriconazole to prevent or treat invasive aspergillosis. The data were analyzed using a nonlinear mixed-effects modeling approach. Monte Carlo simulation was applied to optimize dosage regimens. Data were fitted with the one-compartment model with first-order absorption and elimination. The apparent oral clearance (CL/F) was 3.43 L/h, the apparent volume of distribution (V/F) was 47.6 L, and the absorption rate constant (Ka) was fixed at 1.1 h−1. Albumin and omeprazole ≥ 40 mg/day were found to significantly influence CL/F. The simulation produced the following recommended maintenance doses of voriconazole: 50, 100, and 200 mg every 12 h for albumin levels of 1.5–3, 3.01–4, and 4.01–4.5 g/dL, respectively, in patients who receive omeprazole ≤ 20 mg/day. Patients who receive omeprazole ≥ 40 mg/day and who have serum albumin level 1.5–3 and 3.01–4.5 g/dL should receive voriconazole 50 and 100 mg, every 12 h, respectively. Albumin level and omeprazole dosage should be carefully considered when determining the appropriate dosage of voriconazole in Thai patients.

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Population Pharmacokinetics of Finafloxacin in Healthy Volunteers and Patients with Complicated Urinary Tract Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02328-17 ◽

2018 ◽

Vol 62 (4) ◽

Author(s):

Max Taubert ◽

Mark Lückermann ◽

Andreas Vente ◽

Axel Dalhoff ◽

Uwe Fuhr

Keyword(s):

Urinary Tract ◽

Healthy Volunteers ◽

Urinary Tract Infections ◽

Pharmacokinetic Model ◽

Oral Absorption ◽

Compartment Model ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Data Set ◽

Tract Infections

ABSTRACTFinafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTIs), while the pharmacokinetics was characterized by highly variable concentration-versus-time profiles, suggesting the need for an elaborated pharmacokinetic model. Data from three clinical trials were evaluated: 127 healthy volunteers were dosed orally (n= 77) or intravenously (n= 50), and 139 patients with cUTI received finafloxacin intravenously. Plasma (2,824 samples from volunteers and 414 samples from patients) and urine (496 samples from volunteers and 135 samples patients) concentrations were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). NONMEM was used to build a population pharmacokinetic model, and pharmacokinetic/pharmacodynamic relationships were investigated via simulations and logistic regression. A two-compartment model with first-order elimination described the data best (central volume of distribution [Vc] and peripheral volume of distribution [Vp] of 47 liters [20%] and 43 liters [67%], respectively, and elimination clearance and intercompartmental clearance of 21 liters/h [54%] and 2.8 liters/h [57%], respectively [median bootstrap estimates {coefficients of variation}]).Vcincreased with body surface area, and clearance was reduced in patients (−29%). Oral absorption was described best by parallel first- and zero-order processes (bioavailability of 75%). No pharmacodynamic surrogate parameter of clinical/microbiological outcome could be identified, which depended exclusively on the MIC of the causative pathogens. Despite the interindividual variability, the present data set does not support covariate-based dose adjustments. Based on the favorable safety and efficacy data, the clinical relevance of the observed variability appears to be limited. (This study has been registered at ClinicalTrials.gov under identifier NCT01928433.)

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Population pharmacokinetics of daptomycin in patients with bone and joint infection: minimal effect of rifampicin co-administration and confirmation of a sex difference

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab006 ◽

2021 ◽

Author(s):

Romain Garreau ◽

Romain Bricca ◽

Marie-Claude Gagnieu ◽

Sandrine Roux ◽

Anne Conrad ◽

...

Keyword(s):

Joint Infection ◽

Compartment Model ◽

Volume Of Distribution ◽

Individual Variability ◽

Therapeutic Drug ◽

Marginal Effect ◽

Bone And Joint Infection ◽

Two Compartment Model ◽

Central Volume ◽

Trough Concentrations

Abstract Background Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. Objectives To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. Methods A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. Results A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. Conclusions A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.

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