Population Pharmacokinetics and Dosing Optimization of Imipenem in Children with Hematological Malignancies

ABSTRACT Imipenem is widely used for the treatment of children with serious infections. Currently, studies on the pharmacokinetics of imipenem in children with hematological malignancies are lacking. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population. After children were treated with imipenem-cilastatin (IMP-CS), blood samples were collected from the children and the concentrations of imipenem were quantified using high-performance liquid chromatography with UV detection. Then, a population-level pharmacokinetic analysis was conducted using NONMEM software. Data were collected from 56 children (age range, 2.03 to 11.82 years) with hematological malignancies to conduct a population pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be the most suitable. The parameters of current weight, age, and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 41.4%, 56.1%, and 67.1% of the children reached the pharmacodynamic target (the percentage of the time during the total dosing interval that the free drug concentration remains above the MIC of 70%) against sensitive pathogens with an MIC of 0.5 mg/liter with imipenem at 15, 20, and 25 mg/kg of body weight every 6 h (q6h), respectively. However, only 11.1% of the children achieved the pharmacodynamic target against Pseudomonas aeruginosa isolates with an MIC of 2 mg/liter at a dose of 25 mg/kg q6h. The population pharmacokinetics of imipenem were assessed in children. The current dosage regimens of imipenem result in underdosing against resistant pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii. However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h. (The study discussed in this paper has been registered at ClinicalTrials.gov under identifier NCT03113344.)

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P110 Population pharmacokinetics and dosing optimisation of imipenem in children with haematological malignancie

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.148 ◽

2019 ◽

Vol 104 (6) ◽

pp. e63.3-e63

Author(s):

L Dong ◽

X-Y Zhai ◽

Y-L Yang ◽

L Wang ◽

Y Zhou ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Population Pharmacokinetics ◽

Elimination Rate ◽

Population Level ◽

Compartment Model ◽

Population Based ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Studies ◽

Dosage Regimens ◽

Age Range

BackgroundImipenem/cilastatin is widely used for the treatment of children with serious infections. Currently, there is lack of pharmacokinetic studies of imipenem in children with hematological malignancies. Given the significant impact of disease on pharmacokinetics and increased resistance, we aimed to conduct a population based pharmacokinetic study of imipenem and optimize the dosage regimens for this vulnerable population.MethodsAfter treated with IMP/CS, blood samples of children were collected and the concentration of imipenem were quantified using HPLC-UV. Then, population level pharmacokinetic analysis was conducted using NONMEM software.ResultsData from 56 children (age range: 2.03–11.82 years) with haematological malignancies were collected to conduct a population based pharmacokinetic analysis. In this study, a two-compartment model that followed first-order elimination was found to be best suitable. The parameters of current weight, age and creatinine elimination rate were significant covariates that influenced imipenem pharmacokinetics. As a result, 52.0%, 65.2% and 76.6% of children reached the pharmacodynamic target (70% fT>MIC) against sensitive pathogens with an MIC of 0.5 mg/L at 15, 20 and 25 mg/kg q6h of imipenem, respectively. However, only 17.2% of children achieved the pharmacodynamic target against Pseudomonas aeruginosa with an MIC of 2 mg/L at a dose of 25 mg/kg q6h.ConclusionPopulation pharmacokinetics of imipenem was assessed in children. The current dosage regimens of imipenem are underdose for resistant pathogens including Pseudomonas aeruginosa and Acinetobacter baumannii. However, for sensitive pathogens, imipenem has an acceptable pharmacodynamic target rate at a dosage of 25 mg/kg q6h.Disclosure(s)Nothing to disclose.

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Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Infants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02486-17 ◽

2018 ◽

Vol 62 (4) ◽

Cited By ~ 7

Author(s):

Zhong-Ren Shi ◽

Xing-Kai Chen ◽

Li-Yuan Tian ◽

Ya-Kun Wang ◽

Gu-Ying Zhang ◽

...

Keyword(s):

Population Pharmacokinetics ◽

High Performance ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Generation Cephalosporin ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Dosing Regimen ◽

Age Range

ABSTRACT Ceftazidime, a third-generation cephalosporin, can be used for the treatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data are limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and to define the appropriate dose to optimize ceftazidime treatment. Blood samples were collected from children treated with ceftazidime, and concentrations of the drug were quantified by high-performance liquid chromatography with UV detection (HPLC-UV). A population pharmacokinetic analysis was performed using NONMEM software ( version 7.2.0). Fifty-one infants ( age range, 0.1 to 2.0 years ) were included. Sparse pharmacokinetic samples ( n = 90 ) were available for analysis. A one-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that body weight and creatinine clearance (CL CR ) were significant covariates influencing ceftazidime clearance. Monte Carlo simulation demonstrated that the currently used dosing regimen of 50 mg / kg twice daily was associated with a high risk of underdosing in infants. In order to reach the target of 70% of the time that the free antimicrobial drug concentration exceeds the MIC ( fT >MIC ), 25 mg/kg every 8 h (q8h) and 50 mg/kg q8h were required for MICs of 4 and 8 mg/liter, respectively. The population pharmacokinetic characteristics of ceftazidime were evaluated in infants. An evidence-based dosing regimen was established based on simulation.

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Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Neonates and Young Infants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02336-18 ◽

2018 ◽

Vol 63 (2) ◽

pp. e02336-18 ◽

Cited By ~ 4

Author(s):

Bo-Hao Tang ◽

Yue-E Wu ◽

Chen Kou ◽

Yu-Jie Qi ◽

Hui Qi ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Dosage Regimen ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Term Neonates ◽

Premature Neonates ◽

Young Infants ◽

Dosage Regimens ◽

Early Onset Sepsis ◽

Age Range

ABSTRACT Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice. The pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate the population pharmacokinetics of amoxicillin through a large sample size covering the entire age range of neonates and young infants and to establish evidence-based dosage regimens based on developmental pharmacokinetics-pharmacodynamics. This is a prospective, multicenter, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high-performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM. A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range, 28.4 to 46.3 weeks) were available for analysis. A two-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age, and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25 mg/kg twice daily [BID]) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (percent time above MIC), using a MIC breakpoint of 1 mg/liter. For late-onset sepsis, 86.1% of premature neonates treated with 25 mg/kg three times a day (TID) and 79.0% of term neonates receiving 25 mg/kg four times a day (QID) reached the pharmacodynamic target, using a MIC breakpoint of 2 mg/liter. The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics.

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Exploiting the Natural Diversity of RhlA Acyltransferases for the Synthesis of the Rhamnolipid Precursor 3-(3-Hydroxyalkanoyloxy)Alkanoic Acid

Applied and Environmental Microbiology ◽

10.1128/aem.02317-19 ◽

2020 ◽

Vol 86 (6) ◽

Cited By ~ 9

Author(s):

Andrea Germer ◽

Till Tiso ◽

Conrad Müller ◽

Beate Behrens ◽

Christian Vosse ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

High Performance ◽

Serratia Plymuthica ◽

Dickeya Dadantii ◽

Transfer Event ◽

Alkanoic Acid ◽

Content Type ◽

Genes Encoding ◽

Natural Diversity ◽

Burkholderia Ambifaria

ABSTRACT While rhamnolipids of the Pseudomonas aeruginosa type are commercially available, the natural diversity of rhamnolipids and their origin have barely been investigated. Here, we collected known and identified new rhlA genes encoding the acyltransferase responsible for the synthesis of the lipophilic rhamnolipid precursor 3-(3-hydroxyalkanoyloxy)alkanoic acid (HAA). Generally, all homologs were found in Betaproteobacteria and Gammaproteobacteria. A likely horizontal gene transfer event into Actinobacteria is the only identified exception. The phylogeny of the RhlA homologs from Pseudomonas and Burkholderia species is consistent with the organism phylogeny, and genes involved in rhamnolipid synthesis are located in operons. In contrast, RhlA homologs from the Enterobacterales do not follow the organisms’ phylogeny but form their own branch. Furthermore, in many Enterobacterales and Halomonas from the Oceanospirillales, an isolated rhlA homolog can be found in the genome. The RhlAs from Pseudomonas aeruginosa PA01, Pseudomonas fluorescens LMG 05825, Pantoea ananatis LMG 20103, Burkholderia plantarii PG1, Burkholderia ambifaria LMG 19182, Halomonas sp. strain R57-5, Dickeya dadantii Ech586, and Serratia plymuthica PRI-2C were expressed in Escherichia coli and tested for HAA production. Indeed, except for the Serratia RhlA, HAAs were produced with the engineered strains. A detailed analysis of the produced HAA congeners by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) highlights the congener specificity of the RhlA proteins. The congener length varies from 4 to 18 carbon atoms, with the main congeners consisting of different combinations of saturated or monounsaturated C10, C12, and C14 fatty acids. The results are discussed in the context of the phylogeny of this unusual enzymatic activity. IMPORTANCE The RhlA specificity explains the observed differences in 3-(3-hydroxyalkanoyloxy)alkanoic acid (HAA) congeners. Whole-cell catalysts can now be designed for the synthesis of different congener mixtures of HAAs and rhamnolipids, thereby contributing to the envisaged synthesis of designer HAAs.

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Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01011-16 ◽

2016 ◽

Vol 61 (1) ◽

Cited By ~ 15

Author(s):

Rajbharan Yadav ◽

Jürgen B. Bulitta ◽

Roger L. Nation ◽

Cornelia B. Landersdorfer

Keyword(s):

Pseudomonas Aeruginosa ◽

Multidrug Resistant ◽

Viable Count ◽

Resistant Isolate ◽

Pharmacodynamic Modeling ◽

Combination Regimen ◽

Bacterial Killing ◽

Content Type ◽

Dosage Regimens ◽

Combination Regimens

ABSTRACT Optimizing antibiotic combinations is promising to combat multidrug-resistant Pseudomonas aeruginosa. This study aimed to systematically evaluate synergistic bacterial killing and prevention of resistance by carbapenem and aminoglycoside combinations and to rationally optimize combination dosage regimens via a mechanism-based mathematical model (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. aeruginosa isolates. Viable-count profiles of total and resistant populations were quantified in 48-h static-concentration time-kill studies (inoculum, 107.5 CFU/ml). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem [MICimipenem] of 16 mg/liter and MICtobramycin of 32 mg/liter, i.e., both 98th percentiles according to the EUCAST database). Against this isolate, imipenem (1.5× MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded ≥2-log10 more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by ≥0.88× MICimipenem in combination with a median of 0.75× MICtobramycin (range, 0.032× to 2.0× MICtobramycin) or 0.50× MICamikacin (range, 0.25× to 0.50× MICamikacin). The MBM indicated that aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold; achieving 50% of this synergistic effect required aminoglycoside concentrations of 1.34 mg/liter (if the aminoglycoside MIC was 4 mg/liter) and 4.88 mg/liter (for MICs of 8 to 32 mg/liter). An optimized combination regimen (continuous infusion of imipenem at 5 g/day plus a 0.5-h infusion with 7 mg/kg of body weight tobramycin) was predicted to achieve >2.0-log10 killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, >4.0 log10 CFU/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.

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Population Pharmacokinetics of Ceftizoxime Administered by Continuous Infusion in Clinically Ill Adult Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.7.1783 ◽

1998 ◽

Vol 42 (7) ◽

pp. 1783-1787 ◽

Cited By ~ 17

Author(s):

Bryan Facca ◽

Bill Frame ◽

Steve Triesenberg

Keyword(s):

Serum Creatinine ◽

Continuous Infusion ◽

Population Pharmacokinetics ◽

Bacterial Infections ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Beta Lactam ◽

Serum Samples ◽

Mixed Effect

ABSTRACT Ceftizoxime is a widely used beta-lactam antimicrobial agent, but pharmacokinetic data for use with clinically ill patients are lacking. We studied the population pharmacokinetics of ceftizoxime in 72 clinically ill patients at a community-based, university-affiliated hospital. A population pharmacokinetic model for ceftizoxime was created by using a prospective observational design. Ceftizoxime was administered by continuous infusion to treat patients with proven or suspected bacterial infections. While the patients were receiving infusions of ceftizoxime, serum samples were collected for pharmacokinetic analysis with the nonlinear mixed-effect modeling program NONMEM. In addition to clearance and volume of distribution, various comorbidities were examined for their influence on the kinetics. All 72 subjects completed the study, and 114 serum samples were collected. Several demographic and comorbidity variables, namely, age, weight, serum creatinine levels, congestive heart failure, and long-term ventilator dependency, had a significant impact on the estimate for ceftizoxime clearance. A mixture model, or two populations for estimation of ceftizoxime clearance, was discovered. One population presented with an additive clearance component of 1.6 liters per h. In addition, a maximizer function for serum creatinine levels was found. In summary, two models for ceftizoxime clearance, mixture and nonmixture, were found and are presented. Clearance for ceftizoxime can be estimated with commonly available clinical information and the models presented. From the clearance estimates, the dose of ceftizoxime to maintain the desired concentration in serum can be determined. Work is needed to validate the model for drug clearance and to evaluate its predictive performance.

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Optimal Dosing of Ceftriaxone in Infants Based on a Developmental Population Pharmacokinetic-Pharmacodynamic Analysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01412-20 ◽

2020 ◽

Vol 64 (11) ◽

Author(s):

Ya-Kun Wang ◽

Yue-E Wu ◽

Xue Li ◽

Li-Yuan Tian ◽

Muhammad Wasim Khan ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Sampling Strategy ◽

Optimal Dose ◽

Community Acquired Pneumonia ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Evidence Based ◽

Open Label ◽

Large Variability ◽

Pharmacodynamic Analysis

ABSTRACT Ceftriaxone is a third-generation cephalosporin used to treat infants with community-acquired pneumonia. Currently, there is a large variability in the amount of ceftriaxone used for this purpose in this particular age group, and an evidence-based optimal dose is still unavailable. Therefore, we investigated the population pharmacokinetics of ceftriaxone in infants and performed a developmental pharmacokinetic-pharmacodynamic analysis to determine the optimal dose of ceftriaxone for the treatment of infants with community-acquired pneumonia. A prospective, open-label pharmacokinetic study of ceftriaxone was conducted in infants (between 1 month and 2 years of age), adopting an opportunistic sampling strategy to collect blood samples and applying high-performance liquid chromatography to quantify ceftriaxone concentrations. Developmental population pharmacokinetic-pharmacodynamic analysis was conducted using nonlinear mixed effects modeling (NONMEM) software. Sixty-six infants were included, and 169 samples were available for pharmacokinetic analysis. A one-compartment model with first-order elimination matched the data best. Covariate analysis elucidated that age and weight significantly affected ceftriaxone pharmacokinetics. According to the results of a Monte Carlo simulation, with a pharmacokinetic-pharmacodynamic target of a free drug concentration above the MIC during 70% of the dosing interval (70% fT>MIC), regimens of 20 mg/kg of body weight twice daily for infants under 1 year of age and 30 mg/kg twice daily for those older than 1 year of age were suggested. The population pharmacokinetics of ceftriaxone were established in infants, and evidence-based dosing regimens for community-acquired pneumonia were suggested based on developmental pharmacokinetics-pharmacodynamics.

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Population Pharmacokinetics of Ciprofloxacin in Neonates and Young Infants Less than Three Months of Age

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03568-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6572-6580 ◽

Cited By ~ 26

Author(s):

Wei Zhao ◽

Helen Hill ◽

Chantal Le Guellec ◽

Tim Neal ◽

Sarah Mahoney ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Newborn Infants ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Studies ◽

Dosing Regimen ◽

Creatinine Concentration ◽

Young Infants

ABSTRACTCiprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.

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Bone Penetration of Amoxicillin and Clavulanic Acid Evaluated by Population Pharmacokinetics and Monte Carlo Simulation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01119-08 ◽

2009 ◽

Vol 53 (6) ◽

pp. 2569-2578 ◽

Cited By ~ 18

Author(s):

Cornelia B. Landersdorfer ◽

Martina Kinzig ◽

Jürgen B. Bulitta ◽

Friedrich F. Hennig ◽

Ulrike Holzgrabe ◽

...

Keyword(s):

Monte Carlo ◽

Cortical Bone ◽

Population Pharmacokinetics ◽

Clavulanic Acid ◽

Cancellous Bone ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Bone Infections ◽

Drug Concentrations ◽

Amoxicillin Clavulanic Acid

ABSTRACT Amoxicillin (amoxicilline)-clavulanic acid has promising activity against pathogens that cause bone infections. We present the first evaluation of the bone penetration of a beta-lactam by population pharmacokinetics and pharmacodynamic profiling via Monte Carlo simulations. Twenty uninfected patients undergoing total hip replacement received a single intravenous infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid before surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen with a cryogenic mill, including an internal standard. The drug concentrations in serum and total bone were analyzed by liquid chromatography-tandem mass spectrometry. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and a target time of the non-protein-bound drug concentration above the MIC for ≥50% of the dosing interval for near-maximal bactericidal activity in serum. The median of the ratio of the area under the curve (AUC) for bone/AUC for serum was 20% (10th to 90th percentile for between-subject variability [variability], 16 to 25%) in cortical bone and 18% (variability, 11 to 29%) in cancellous bone for amoxicillin and 15% (variability, 11 to 21%) in cortical bone and 10% (variability, 5.1 to 21%) in cancellous bone for clavulanic acid. Analysis in S-ADAPT yielded similar results. The equilibration half-lives between serum and bone were 12 min for amoxicillin and 14 min for clavulanic acid. For a 30-min infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid every 4 h, amoxicillin achieved robust (≥90%) probabilities of target attainment (PTAs) for MICs of ≤12 mg/liter in serum and 2 to 3 mg/liter in bone and population PTAs above 95% against methicillin-susceptible Staphylococcus aureus in bone and serum. The AUC of amoxicillin-clavulanic acid was 5 to 10 times lower in bone than in serum, and amoxicillin-clavulanic acid achieved a rapid equilibrium and favorable population PTAs against pathogens commonly encountered in bone infections.

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Plasma and Intracellular Population Pharmacokinetic Analysis of Tenofovir in HIV-1-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05317-11 ◽

2011 ◽

Vol 55 (11) ◽

pp. 5294-5299 ◽

Cited By ~ 53

Author(s):

Gautam Baheti ◽

Jennifer J. Kiser ◽

Peter L. Havens ◽

Courtney V. Fletcher

Keyword(s):

Rate Constant ◽

Sequential Analysis ◽

Plasma Concentrations ◽

Elimination Rate ◽

Distribution Volume ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Response Model ◽

Indirect Response Model ◽

Indirect Response

ABSTRACTThe relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n= 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h−1; apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (Emax), the TFV concentration producing 50% ofEmax(EC50), and the intracellular elimination rate constant (kout) of 300 fmol/106cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h−1, respectively. The estimatedkoutgave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

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