Population Pharmacokinetics and Pharmacodynamic Target Attainment of Isavuconazole against Aspergillus fumigatus and Aspergillus flavus in Adult Patients with Invasive Fungal Diseases: Should Therapeutic Drug Monitoring for Isavuconazole Be Considered as Mandatory as for the Other Mold-Active Azoles?

Isavuconazole is a newer broad-spectrum triazole approved for the treatment of invasive fungal disease. The objective of this study was to conduct a population pharmacokinetic and pharmacodynamic analysis of isavuconazole in a retrospective cohort of hospitalized patients. A nonlinear mixed-effect approach with Monte Carlo simulations was conducted to assess the probability of target attainment (PTA) of an area under the concentration–time curve (AUC24 h)/minimum inhibitory concentration (MIC) ratio of 33.4 (defined as efficacy threshold against A. fumigatus and A. flavus) associated with a maintenance dose (MD) of 100, 200 and 300 mg daily after loading. The cumulative fraction of response (CFR) against the EUCAST MIC distributions of A. fumigatus and A. flavus was calculated as well. The proportion of trough concentrations (Ctrough) exceeding a defined threshold of toxicity (>5.13 mg/L) was estimated. A total of 50 patients, with a median age of 61.5 years, provided 199 plasma isavuconazole concentrations. Invasive pulmonary aspergillosis was the prevalent type of infection and accounted for 80% (40/50) of cases. No clinical covariates were retained by the model. With the standard MD of 200 mg daily, CFRs were always ≥90% during the first two months of treatment. The risk of Ctrough < 1.0 mg/L was around 1%, and that of Ctrough > 5.13 mg/L was 27.7 and 39.2% at 28 and 60 days, respectively, due to isavuconazole accumulation over time. Our findings suggest that TDM for isavuconazole should not be considered as mandatory as for the other mold-active azoles voriconazole and posaconazole.

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Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00737-21 ◽

2021 ◽

Author(s):

Antonin Praet ◽

Laurent Bourguignon ◽

Florence Vetele ◽

Valentine Breant ◽

Charlotte Genestet ◽

...

Keyword(s):

Cystic Fibrosis ◽

Dose Adjustment ◽

Total Body Weight ◽

Compartment Model ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Time Curve ◽

Population Pharmacokinetic Modeling ◽

Two Compartment Model ◽

Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

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P99 Clinical validation of published vancomycin population PK models in critically ill neonates

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.137 ◽

2019 ◽

Vol 104 (6) ◽

pp. e58.2-e59

Author(s):

A van der Veen ◽

RJ Keizer ◽

W de Boode ◽

A Somers ◽

R Brüggemann ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

A Priori ◽

Predictive Performance ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Suitable Model ◽

List Type ◽

A Posteriori ◽

Target Attainment

BackgroundVancomycin is commonly used for treatment of severe Gram+ neonatal infections. Currently, even with the use of optimized dosing regimens and therapeutic drug monitoring (TDM), target attainment rates are abominable, leaving patients at risk for therapeutic failure and toxicity. Model-informed precision dosing (MIPD) offers a large potential to improve therapy in the individual patient.The aim of this study was to identify a suitable model for bedside MIPD by assessing the predictive performance of published population pharmacokinetic (popPK) models.MethodsA literature search was conducted to identify parametric popPK models. PK vancomycin data were retrospectively collected from NICU patients at the Radboud University Hospital, Nijmegen, The Netherlands. The model predictive performance was assessed by comparison of predictions to observations, calculation of bias (Mean Percentage Errors, MPE) and imprecision (Normalized Root Mean Squared Errors, NRMSE). Evaluations included both a priori (model covariate input) and a posteriori (model covariate and TDM concentration input) scenarios.Results265 TDM measurements from 65 neonates (median postmenstrual age:32 weeks [range:25–45 weeks]; median weight:1281g [range:597–5360g]; median serum creatinine:0,48 mg/dL [range:0,15–1,28 mg/dL]) were used for model evaluation. Six popPK models were evaluated1–6. A posteriori predictions of all models were consistently more accurate and precise compared to the a priori (starting dose) predictions. PopPK models of Frymoyer et al. and Capparelli et al. consistently performed best through all evaluations in both the a priori and a posteriori scenario (MPE ranging from -18 to 6,4% in a priori scenario and -6,5 to -3,8% in a posteriori scenario; NRMSE ranging from 34 to 40% in a priori scenario and 23 to 24% in a posteriori scenario).ConclusionLarge differences in predictive performance of popPK models were observed. Repeated therapeutic drug monitoring remains necessary to increase target attainment rate. Best performing models for bedside MIPD were identified in our patient population.ReferencesZhao W, Lopez E, Biran V, et al. ( 2013). Vancomycin continuous infusion in neonates: Dosing optimisation and therapeutic drug monitoring. Arch Dis Child;98(6):449–453.Capparelli EV, Lane JR, Romanowski GL, et al. ( 2001). The influences of renal function and maturation on vancomycin elimination in newborns and infants. J Clin Pharmacol, 41:927–934.De Cock RFW, Allegaert K, Brussee JM, et al. ( 2014). Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration. Pharm Res;31(10):2642–2654.Frymoyer A, Hersh AL, El-Komy MH, et al. ( 2014). Association between vancomycin trough concentration and area under the concentration-time curve in neonates. Antimicrob Agents Chemother, 58(11):6454–6461.Anderson BJ, Allegaert K, Van Den Anker JN, Cossey V, Holford NHG. ( 2006). Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. Br J Clin Pharmacol;63(1):75–84.Germovsek E, Osborne L, Gunaratnam F, Lounis SA, Busquets FB, Sinha AK. ( 2019). Development and external evaluation of a population pharmacokinetic model for continuous and intermittent administration of vancomycin in neonates and infants using prospectively collected data. J Antimicrob Chemother, 1–9.Disclosure(s)R. Keizer is an employee and stockholder of InsightRX.

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Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01647-17 ◽

2018 ◽

Vol 62 (4) ◽

pp. e01647-17 ◽

Cited By ~ 10

Author(s):

Sheng-Hsuan Tseng ◽

Chuan Poh Lim ◽

Qi Chen ◽

Cheng Cai Tang ◽

Sing Teang Kong ◽

...

Keyword(s):

Steady State ◽

Trough Concentration ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Time Curve ◽

Content Type ◽

Concentration Time ◽

Vancomycin Trough ◽

Trough Concentrations ◽

The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

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Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study)

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00514-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4568-4576 ◽

Cited By ~ 34

Author(s):

Laura L. Kovanda ◽

Amit V. Desai ◽

Qiaoyang Lu ◽

Robert W. Townsend ◽

Shahzad Akhtar ◽

...

Keyword(s):

Nonparametric Estimation ◽

Invasive Fungal Disease ◽

Fungal Disease ◽

Water Soluble ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Dosing Regimen ◽

Open Label ◽

Time Curve ◽

Content Type

ABSTRACTIsavuconazonium sulfate (Cresemba; Astellas Pharma Inc.), a water-soluble prodrug of the triazole antifungal agent isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis. A population pharmacokinetic (PPK) model was constructed using nonparametric estimation to compare the pharmacokinetic (PK) behaviors of isavuconazole in patients treated in the phase 3 VITAL open-label clinical trial, which evaluated the efficacy and safety of the drug for treatment of renally impaired IA patients and patients with invasive fungal disease (IFD) caused by emerging molds, yeasts, and dimorphic fungi. Covariates examined were body mass index (BMI), weight, race, impact of estimated glomerular filtration rate (eGFR) on clearance (CL), and impact of weight on volume. PK parameters were compared based on IFD type and other patient characteristics. Simulations were performed to describe the MICs covered by the clinical dosing regimen. Concentrations (n= 458) from 136 patients were used to construct a 2-compartment model (first-order absorption compartment and central compartment). Weight-related covariates affected clearance, but eGFR did not. PK parameters and intersubject variability of CL were similar across different IFD groups and populations. Target attainment analyses demonstrated that the clinical dosing regimen would be sufficient for total drug area under the concentration-time curve (AUC)/MIC targets ranging from 50.5 forAspergillusspp. (up to the CLSI MIC of 0.5 mg/liter) to 270 and 5,053 forCandida albicans(up to MICs of 0.125 and 0.004 mg/liter, respectively) and 312 for non-albicans Candidaspp. (up to a MIC of 0.125 mg/liter). The estimations forCandidaspp. were exploratory considering that no patients withCandidainfections were included in the current analyses. (The VITAL trial is registered at ClinicalTrials.gov under number NCT00634049.)

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Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02625-16 ◽

2017 ◽

Vol 61 (6) ◽

Cited By ~ 12

Author(s):

Abdullah Alsultan ◽

Rada Savic ◽

Kelly E. Dooley ◽

Marc Weiner ◽

William Whitworth ◽

...

Keyword(s):

Body Weight ◽

Therapeutic Target ◽

Volume Of Distribution ◽

Current Treatment ◽

Population Pharmacokinetic ◽

Maximum Plasma ◽

Target Attainment ◽

Time Curve ◽

The Mean ◽

Higher Doses

ABSTRACT The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration (C max) of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) C max was 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC0–24) was 307 (83) μg · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution (V/F) than men, and both clearance (CL/F) and V/F increased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a C max of >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.

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Factors Influencing Pharmacokinetics of Prophylactic Posaconazole in Patients Undergoing Allogeneic Stem Cell Transplantation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01027-09 ◽

2009 ◽

Vol 54 (1) ◽

pp. 207-212 ◽

Cited By ~ 48

Author(s):

V. Kohl ◽

C. Müller ◽

O. A. Cornely ◽

K. Abduljalil ◽

U. Fuhr ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Body Height ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Cell Transplant ◽

Mixed Effect ◽

Hematopoietic Stem ◽

Factors Influencing

ABSTRACT The objectives of the present study were to elucidate the factors influencing the pharmacokinetics of prophylactically administered posaconazole in allogeneic hematopoietic stem cell transplant (SCT) recipients. Between May 2007 and November 2008, clinical data were obtained from all SCT recipients at the University Hospital of Cologne undergoing therapeutic drug monitoring (TDM) of serum prophylactic posaconazole concentrations. The posaconazole concentrations were determined by high-performance liquid chromatography. We developed a population pharmacokinetic model using nonlinear mixed-effect modeling (NONMEM). The list of covariates tested included age; body weight; body height; gender; posaconazole dose; race; coadministration of antineoplastic chemotherapy; day of stem cell transplantation; concomitant ranitidine, pantoprazole, cyclosporine, or tacrolimus administration; coincident fever; diarrhea; and plasma gamma-glutamyltransferase activity. A total of 149 serum posaconazole concentrations from 32 patients were obtained. A one-compartment model with first-order absorption and elimination as the basic structural model appropriately described the data, with the apparent clearance being 75.8 liters/h (95% confidence interval [CI], 65.2 to 86.4 liters/h) and the apparent volume being distribution of 835 liters (95% CI, 559 to 1,111 liters). Among the covariates tested, significant effects were found for age (decrease in the volume of distribution of 123 liters per year of age) and the presence of diarrhea (59% loss of bioavailability). A basis for prediction of the mean posaconazole concentrations in allogeneic SCT recipients with hematological malignancies is provided for a given dose. Corresponding adjustments of the starting dose according to the presence of diarrhea and according to age appear to be justified before TDM results are available.

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Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00194-11 ◽

2011 ◽

Vol 55 (11) ◽

pp. 5314-5324 ◽

Cited By ~ 34

Author(s):

Almudena Sánchez ◽

Salvador Cabrera ◽

Dolores Santos ◽

M. Paz Valverde ◽

Aurelio Fuertes ◽

...

Keyword(s):

High Performance ◽

Plasma Concentrations ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Nucleotide Polymorphisms ◽

Mixed Effect ◽

Factors Affecting ◽

Nonlinear Mixed Effect ◽

Study Population ◽

Major Factors

ABSTRACTDespite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C→T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 − 0.00279·GGT)·0.602CYP2B6*6 [G/T]·0.354CYP2B6*6 [T/T]·0.793MRP4 1497C→T, where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C→T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.

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Population Pharmacokinetics, Exposure–Response, and Probability of Target Attainment Analyses for Tedizolid in Adolescent Patients With Acute Bacterial Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00895-21 ◽

2021 ◽

Author(s):

Dan Li ◽

Philip E. Sabato ◽

Benjamin Guiastrennec ◽

Aziz Ouerdani ◽

Hwa-Ping Feng ◽

...

Keyword(s):

Body Weight ◽

Phase 1 ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Target Attainment ◽

Time Curve ◽

Once Daily ◽

Skin Structure ◽

Lower Body Weight ◽

Safety Event

Tedizolid phosphate is an oxazolidinone antibacterial agent approved for treatment of gram-positive acute bacterial skin and skin structure infections (ABSSSIs) in patients aged ≥12 years. To support the use of tedizolid phosphate in adolescents with ABSSSIs, a population pharmacokinetic (PK) model, developed using adult and pediatric data, was updated to include PK data from a phase 3 clinical trial (PN012) that evaluated the safety and efficacy of once-daily oral or intravenous 200-mg tedizolid phosphate in adolescents (12 to <18 years) with ABSSSIs, along with emerging data from a phase 1 trial (PN013) in children (2 to <12 years). Updated PK parameter estimates remained similar to the previous model. Body weight was a statistically significant covariate on clearance and volume parameters, with no clinically meaningful effects on exposure in adolescents. Tedizolid exposures in adolescents from PN012 were slightly higher with largely overlapped area under the concentration–time curve distribution compared with adults from previous phase 2 and 3 trials. The probability of PK/pharmacodynamic target attainment at the minimum inhibitory concentration susceptibility breakpoint of 0.5 μg/mL for Staphylococcus and Streptococcus was 100%. As most participants from the PN012 trial were cured, no significant exposure–efficacy relationship was identified. Tedizolid exposures were similar between participants with and without a safety event from PN012; no clear relationship was detected between exposure and safety. Despite lower body weight and higher exposures in adolescents, safety profiles in adolescents were similar to adults. These results support the 200-mg, once-daily intravenous or oral dose of tedizolid phosphate in adolescents with ABSSSIs.

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Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02367-19 ◽

2020 ◽

Vol 64 (10) ◽

Author(s):

Sujata M. Bhavnani ◽

Jeffrey P. Hammel ◽

Elizabeth A. Lakota ◽

M. Courtney Safir ◽

Brian D. VanScoy ◽

...

Keyword(s):

Compartment Model ◽

Simulated Patients ◽

Population Pharmacokinetic ◽

Total Drug ◽

Target Attainment ◽

Time Curve ◽

Content Type ◽

Concentration Time

ABSTRACT ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PKPD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

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Analysis of the Pharmacokinetic Interaction between Cephalexin and Quinapril by a Nonlinear Mixed-Effect Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.6.1463 ◽

1998 ◽

Vol 42 (6) ◽

pp. 1463-1469 ◽

Cited By ~ 22

Author(s):

C. Padoin ◽

M. Tod ◽

G. Perret ◽

O. Petitjean

Keyword(s):

Competitive Inhibition ◽

Pharmacokinetic Interaction ◽

Angiotensin Converting Enzyme Inhibitors ◽

Oral Route ◽

Elimination Kinetics ◽

Time Curve ◽

Converting Enzyme Inhibitors ◽

Mixed Effect ◽

Nonlinear Mixed Effect ◽

The Mean

ABSTRACT Oligopeptidic drugs such as β-lactams and angiotensin-converting enzyme inhibitors share the same carriers in humans and animals, which results in possible pharmacokinetic interactions. To model such interactions, the effects of quinapril on cephalexin pharmacokinetics were investigated in rats. Blood cephalexin concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method and by fitting a bicompartmental model by a nonlinear mixed-effect modeling approach. Five groups of eight rats were examined. In the first three groups, cephalexin elimination kinetics after intra-arterial administration alone or in combination with quinapril given by the parenteral or the oral route were studied, and the occurrence of a pharmacokinetic interaction was not revealed. The absence of an effect of quinapril on cephalexin elimination after parenteral administration might be explained either by the higher affinity of cephalexin for the renal anionic transport system than that of quinapril or by the much higher concentrations of cephalexin than those of quinapril. In the last two groups, cephalexin was administered by the oral route alone or in combination with quinapril. The mean area under the concentration-time curve (AUC) for cephalexin was increased by ca. 30% by coadministration of quinapril (40.1 versus 31.4 mg · h/liter;P = 0.04). The mean elimination clearance of cephalexin was significantly decreased by quinapril, from 0.81 to 0.64 liter/h/kg of body weight (P < 0.05), probably by competitive inhibition of cephalexin secretion at the tubular level. The mean absorption rate constant of cephalexin was significantly lowered by quinapril (from 0.249 to 0.177 h−1;P < 0.01), without modification of the extent of absorption (89%). This pharmacokinetic interaction could be explained by competitive inhibition of cephalexin active transport by quinapril at the intestinal level.

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