External Evaluation of Population Pharmacokinetic Models of Piperacillin in Preterm and Term Patients from Neonatal Intensive Care.

BACKGROUND AND OBJECTIVES: Piperacillin/tazobactam is extensively used off-label to treat late-onset neonatal sepsis, but safety and pharmacokinetic data in this population are limited. Additionally, the organic immaturity of the newborns contributes to a high piperacillin pharmacokinetic variability. This affects the clinical efficacy of the antibiotic treatment and increases the probability of developing drug resistance. This study aimed to evaluate the predictive performance of reported piperacillin population pharmacokinetic models for their application in a model-informed precision dosing strategy in preterm and term Mexican neonatal intensive care patients. METHODS: Published population pharmacokinetic models for piperacillin which included neonates in their study population were identified. From the reference models, structured models, population pharmacokinetic parameters, and interindividual and residual variability data were extracted to be replicated in pharmacokinetic software (NONMEM® version 7.4). For the clinical study, a sampling schedule was designed, and 2-3 blood samples of 250 µL were taken from neonates who met the inclusion criteria. Piperacillin plasma concentrations were determined by liquid chromatography/tandem mass spectrometry. The clinical treatment data were collected, and piperacillin plasma concentrations were estimated using reference pharmacokinetic models for an a priori or Bayesian approach. Statistical methods were used in terms of bias and precision to evaluate the differences between observed and estimated neonatal piperacillin plasma concentrations with the different approaches and to identify the pharmacokinetic model that best fits the neonatal data. RESULTS: A total of 70 plasma samples were collected from 25 neonatal patients, of which 15 were preterm neonates. The overall median value (range) postnatal age, gestational age, body weight, and serum creatinine at the sampling collecting day were 12 (3-26) days, 34.2 (26-41.1) weeks, 1.78 (0.08-3.90) Kg, 0.47 (0.20-0.90) mg/dL, respectively. Three population pharmacokinetic models for piperacillin in infants up to 2 months were identified, and their predictive performance in neonatal data was evaluated. No pharmacokinetic model was suitable for our population using an a priori approach. The model published by Cohen-Wolkowiez et al. in 2014 with a Bayesian approach showed the best performance of the pharmacokinetic models evaluated in our neonatal data. The procedure requires two blood samples (predose and postdose), and, when applied, it predicted 66.6% of the observations with a relative median absolute predicted error of less than 30%. CONCLUSIONS: The population pharmacokinetic model developed by Cohen-Wolkowiez et al. in 2014 demonstrated superior performance in predicting the plasma concentration of piperacillin in preterm and term Mexican neonatal intensive care patients. The Bayesian approach, including two different piperacillin plasma concentrations, was clinically acceptable regarding bias and precision. Its application for model-informed precision dosing can be an option to optimize the piperacillin dosage in our population.

Development and Validation of UPLC Tandem Mass Spectrometry Assay for Ceftibuten and Sulbactam in Human Plasma.

A sensitive and rapid ultra-performance liquid chromatography coupled with -tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine ceftibuten (CTB) and sulbactam (SUL) in human plasma. An ACQUITY UPLC HSS T3 C18 (2.1 × 100 mm), 1.8 µm column with gradient elution of water (0.1% formic acid) and acetonitrile was used for separation at a flow rate of 0.2 mL/min. This method involves a simple sample preparation with acetonitrile. The calibration curves of CTB and SUL in plasma showed good linearity over the concentration range of 0.50-25 µg/mL and with a correlation coefficient (r2) >0.99. This method was validated in terms of selectivity, linearity, precision, accuracy and stability. High precision was obtained with coefficients of variation <15%. Excellent recovery in the range of 90-104% was achieved for CTB and SUL was 86-110%. The method has the potential utility to support pharmacometric modeling in clinical practice and biopharmaceutic studies.

Standardization and validation of a novel UPLC-MS/MS method to quantify first line anti-tuberculosis drugs in plasma and dried blood spots.

Tuberculosis (TB) is a high-burden infectious disease with high prevalence and mortality rates. The first-line anti-TB drugs include isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB). At present, the standard method of blood sampling for therapeutic drug monitoring (TDM) analysis is venipuncture. Dried blood spots (DBS) are a minimally invasive method for collecting small quantities of whole blood from fingertips. The aim of the current study was to develop an ultrahigh-performance liquid chromatography technique coupled to tandem mass spectrometry (UPLC-MS/MS) for simultaneous quantification of the first-line anti-TB drugs in human plasma and DBS as a sampling alternative. The separation and detection conditions were optimized to quantify INH, RMP, PZA, and EMB in both matrices in an ACQUITY UPLC H Class system coupled to a XEVO TQD detector. Chromatographic separation was performed through an Acquity HSS T3 column (2.1 × 100 mm, 1.8 µm) with 0.1% formic acid in water and acetonitrile as the mobile phase. The total run time was 7 min for both methods, with retention time in plasma of 0.85, 1.22, 3.16, and 4.04 min and 0.74, 0.87, 0.97, and 4.16 min for EMB, INH, PZA, and RMP in DBS, respectively. The bioanalytical methods developed were proved selective, linear, precise, and accurate (inter- and intra-assay); the matrix effect was demonstrated to be within the established limits. Short- and long-term stability, freeze-thaw cycles for plasma, and short-term stability for DBS were established. A total of 15 patients with 46 ± 17 (mean ± SD) years old were included, and anti-TB drug concentrations were quantified on plasma and DBS as proof of concept. Based on RMP and INH plasma concentrations (Cp), and Bayesian estimation of individual pharmacokinetic parameters, a dose adjustment was necessary for 93% of patients. The slopes of the correlation lines between plasma and DBS concentrations of RMP, EMB, INH, and PZA were 0.5321, 0.8125, 0.5680, and 0.6791, respectively. Finally, significant correlations (p < 0.05) were observed between DBS and plasma concentrations for RMP (r2 = 0.6961), EMB (r2 = 0.4369), INH (r2 = 0.8675) and PZA (r2 = 0.7363). A simple, fast, and reliable UPLC-MS/MS method was developed to quantify first-line anti-TB drugs in plasma and DBS, which provides an easy sampling and storage to be applied as a new strategy for TDM in patients with TB.

Model-informed precision dosing of antimicrobial drugs in pediatrics: experiences from a pilot scale program.

Antibiotics are among the most utilized drugs in pediatrics. Nonetheless, there is a lack in pharmacokinetics information for this population, and dosing criteria may vary between healthcare centers. Physiological variability associated with maturation in pediatrics makes it challenging to reach a consensus on adequate dosing, which is further accentuated in more vulnerable groups, such as critically ill or oncology patients. Model-informed precision dosing is a useful practice that allows dose optimization and attainment of antibiotic-specific pharmacokinetic/pharmacodynamic targets. The aim of this study was to evaluate the needs of model-informed precision dosing of antibiotics in a pediatrics unit, at a pilot scale. Pediatric patients under antibiotic treatment were monitored with either a pharmacokinetic/pharmacodynamic optimized sampling scheme or through opportunistic sampling. Clindamycin, fluconazole, linezolid, meropenem, metronidazole, piperacillin, and vancomycin plasma concentrations were quantified through a liquid chromatography coupled to mass spectrometry method. Pharmacokinetic parameters were estimated using a Bayesian approach to verify pharmacokinetic/pharmacodynamic target attainment. A total of 23 pediatric patients aged 2 to 16 years were included, and 43 dosing regimens were evaluated; 27 (63%) of them required adjustments as follows: 14 patients were underdosed, 4 were overdosed, and 9 patients needed infusion rate adjustments. Infusion rate adjustments were mostly recommended for piperacillin and meropenem; daily doses were augmented for vancomycin and metronidazole, meanwhile linezolid was adjusted for under- and overdosing. Clindamycin and fluconazole regimens were not adjusted at all.  Conclusion: Results showcase a lack of antibiotic pharmacokinetic/pharmacodynamic target attainment (particularly for linezolid, vancomycin, meropenem, and piperacillin), and the need for model-informed precision dosing in pediatrics. This study provides pharmacokinetic evidence which can further improve antibiotic dosing practices. What is Known: • Model-informed precision dosing is performed in pediatrics to optimize the treatment of antimicrobial drugs such as vancomycin and aminoglycosides, while its usefulness is debated for other groups (beta-lactams, macrolides, etc.). What is New: • Vulnerable pediatric subpopulations, such as critically ill or oncology patients, can benefit the most from model-informed precision dosing of antibiotics. • Model-informed precision dosing of linezolid, meropenem, piperacillin, and vancomycin is particularly useful in pediatrics, and further research may improve dosing practices altogether.

A comparison of pharmacokinetics software for therapeutic drug monitoring of piperacillin in patients with severe infections.

OBJECTIVE: To evaluate the predictive performance of population pharmacokinetic models for piperacillin (PIP) available in the software MwPharm, TDMx and ID-ODs for initial dosing selection and therapeutic drug monitoring (TDM) purposes. METHODS: This is a prospective observational study in adult patients with severe infections receiving PIP treatment. Plasma concentrations were quantified by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. The differences between predicted and observed PIP concentrations were evaluated with Bland-Altman plots; additionally, the relative and absolute bias and precision of the models were determined. RESULTS: A total of 145 PIP plasma concentrations from 42 patients were analysed. For population prediction, MwPharm showed the best predictive performance with a mean relative difference of 34.68% (95% CI -197% to 266%) and a root mean square error (RMSE) of 60.42 µg/mL; meanwhile TDMx and ID-ODs under-predicted PIP concentrations. For individual prediction, the TDMx model was found to be the most precise with a mean relative difference of 7.61% (95% CI -57.63 to 72.86%), and RMSE of 17.86 µg/mL. CONCLUSION: Current software for TDM is a valuable tool, but it may also include different population pharmacokinetic models in patients with severe infections, and should be evaluated before performing a model-based TDM in clinical practice. Considering the heterogeneous characteristics of patients with severe infections, this study demonstrates the need for therapy personalisation for PIP to improve pharmacokinetic/pharmacodynamic target attainment.

Amikacin pharmacokinetics in elderly patients with severe infections.

OBJECTIVE: The aim of this study was to characterize the population pharmacokinetics of amikacin in elderly patients by means of nonlinear mixed effects modelling and to propose initial dosing schemes to optimize therapy based on PK/PD targets. METHOD: A total of 137 elderly patients from 65 to 94 years receiving intravenous amikacin and routine therapeutic drug monitoring at Hospital Universitario Severo Ochoa were included. Concentration-time data and clinical information were retrospectively collected; initial doses of amikacin ranged from 5.7 to 22.5 mg/kg/day and each patient provided between 1 and 10 samples. RESULTS: Amikacin pharmacokinetics were best described by a two-compartment open model; creatinine clearance (CrCL) was related to drug clearance (2.75 L/h/80 mL/min) and it was augmented 28% when non-steroidal anti-inflammatory drugs were concomitantly administered. Body mass index (BMI) influenced the central volume of distribution (17.4 L/25 kg/m2). Relative absolute prediction error was reduced from 33.2% (base model) to 17.9% (final model) when predictive performance was evaluated with a different group of elderly patients. A nomogram for initial amikacin dosage was developed and evaluated based on stochastic simulations considering final model to achieve PK/PD targets (Cmax/MIC>10 and AUC/MIC>75) and to avoid toxic threshold (Cmin<2.5 mg/L). CONCLUSION: Initial dosing approach for amikacin was designed for elderly patients based on nonlinear mixed effects modeling to maximize the probability to attain efficacy and safety targets considering individual BMI and CrCL.

Disease activity and therapeutic drug monitoring of polyglutamates of methotrexate after daily or weekly administration of low-dose methotrexate in patients recently diagnosed with rheumatoid arthritis.

Low-dose methotrexate can be challenging to treat rheumatoid arthritis due to side effects, lack of adherence and risk of medication errors. The aim of this study was to explore the safety and efficacy of low-dose methotrexate administered daily or weekly in patients with rheumatoid arthritis. Patients were randomized according to a total oral dose of 12.5 mg of methotrexate administered: (A) divided in 5 days/week and (B) once per week. Patients were assessed along 24 weeks after starting treatment. Polyglutamates of methotrexate were quantified by ultrahigh-performance liquid chromatography coupled to tandem mass spectrometer. Patients from groups A and B showed a good response to methotrexate treatment in 29% and 25.5%, respectively, and a global frequency of adverse events of 37%. Methotrexate polyglutamate 3 concentrations were higher in normal weight (body mass index 18.5-24.9 kg/m2 ) than in obese (body mass index 30 kg/m2 ) patients with a median (interquartile range) of 28 (17.95-45.15) and 10.35 (5.22-30.88) nM without differences between dosage groups. Daily dosage regimen represents a therapeutic alternative without compromising the efficacy and safety of methotrexate treatment and with similar adherence patterns than weekly dosage regimen; further, methotrexate polyglutamate 3 concentrations could be a useful tool for therapeutic drug monitoring purposes.

Simultaneous determination of four serotonin selective reuptake inhibitors by an UPLC MS-MS method with clinical application in therapeutic drug monitoring.

An analytical method of ultra-high performance liquid chromatography coupled to tandem mass spectrometry detection was developed and validated for the simultaneous quantification in plasma of four selective serotonin reuptake inhibitor antidepressants: sertraline, escitalopram, paroxetine, fluoxetine, and its metabolite norfluoxetine. A simple protein precipitation was performed with acetonitrile containing 100 ng/mL of indomethacin, which was used as internal standard. Chromatographic separation was carried out on an Acquity BEH C18 column with isocratic elution of the mobile phase consisting of 5 mmol/L ammonium acetate with 0.1% formic acid (A) and acetonitrile (B) at a 60:40 proportion, respectively. The flow rate was 0.4 mL/min with a run time of 5 min. A positive electrospray ionization source was used for detection. The method was linear in a range of 5-800 ng/mL, with determination coefficients greater than 0.991. The accuracy ranged from 91% to 112% for intra-assay and from 89% to 112% for inter-assay. The variation coefficients ranged from 3.1% to 14.88% for intra-assay and from 3.60% to 14.74% for inter-assay precision. The method was successfully applied for the analysis of 73 samples from patients under treatment with these antidepressants; 36.9% of the samples had concentrations outside therapeutic ranges. This method can be applied for routine analysis in clinical practice, simplifying sample processing, reducing analysis time and consequently the costs associated with it.

Factors associated with fluoxetine and norfluoxetine plasma concentrations and clinical response in Mexican patients with mental disorders.

Over the last few years, fluoxetine has been one of the most prescribed medications for the treatment of diverse psychiatric conditions in Mexico. Fluoxetine therapeutic effect is consequence of the joint action of the parent drug and its active metabolite, norfluoxetine. However, the clinical efficacy of fluoxetine, can be affected due to diverse factors, such as drug-drug interactions and the large interindividual variability in the pharmacokinetics of this drug. The aim of this study was to determine the factors associated with variability in plasma concentrations of fluoxetine and norfluoxetine and its association with the therapeutic response. Fluoxetine and norfluoxetine plasma concentrations were quantified by liquid chromatography in 81 Mexican patients with mental disorders; 25% of the patients had no medication adherence and 40% were below the reference range of fluoxetine plus norfluoxetine plasma concentrations. The results showed that concentrations can be affected by fluoxetine metabolism caused by CYP2D6 phenotype and the concomitant administration of olanzapine. Furthermore, CYP3A5 and CYP2C19 phenotype were associated with lower anxiety and depression control during treatment with fluoxetine. This study can be a starting point to elucidate the causes of fluoxetine variable response in Mexican patients with mental disorders, as well as to detect and support medication adherence.

Optimizing Meropenem Therapy for Severe Nosocomial Infections in Neonates.

Meropenem pharmacokinetics in neonates exhibits large interindividual variability due to developmental changes occurring during the first month of life. The objective was to characterize meropenem pharmacokinetics through a population approach to determine effective dosing recommendations in neonates with severe nosocomial infections. Three blood samples from forty neonates were obtained once steady-state blood levels were achieved and plasma concentrations were determined with a validated chromatographic method. Data were used to develop and validate the one-compartment with first-order elimination population pharmacokinetic model obtained by non-linear mixed effect modeling. The final model was Clearance (L/h) = 2.23 × Creatinine Clearance (L/h) and Volume of distribution(L) = 6.06 × Body Surface Area(m2) × (1 + 0.60 if Fluticasone comedication). Doses should be adjusted based on said covariates to increase the likelihood of achieving therapeutic targets. This model explains 12.9% of the interindividual variability for meropenem clearance and 19.1% for volume of distribution. Stochastic simulations to establish initial dosing regimens to maximize the time above the MIC showed that the mean probabilities to achieve the PK/PD target (PTA) for microorganisms with a MIC of 2 and 8 µg/mL were 0.8 and 0.7 following i.v. bolus of 250 and 500 mg/m2/dose q8h, respectively. Meropenem extended 4h infusion would improve PTA in neonates with augmented creatinine clearance.

Clinical utility of ABCB1 and ABCG2 genotyping for assessing the clinical and pathological response to FAC therapy in Mexican breast cancer patients.

PURPOSE: Resistance to neoadjuvant chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) in some patients with locally advanced breast cancer remains one of the main obstacles to first-line treatment. We investigated clinical and pathological responses to FAC neoadjuvant chemotherapy in Mexican women with breast cancer and their possible association with SNPs present in ABC transporters as predictors of chemoresistance. MATERIALS: A total of 102 patients undergoing FAC neoadjuvant chemotherapy were included in the study. SNP analysis was performed by RT-PCR from genomic DNA. Two SNPs were analyzed: ABCB1 rs1045642 (3435 C > T) and ABCG2 rs2231142 (421 G > T). RESULTS: In clinical response evaluation, significant associations were found between the ABCB1 C3435T genotype and breast cancer chemoresistant and chemosensitive patients (p < 0.05). In the early clinical response, patients with genotype C/C or C/T were more likely to be chemosensitive to neoadjuvant therapy than patients with genotype T/T (OR = 4.055; p = 0.0064). Association analysis between the ABCB1 gene polymorphism and the pathologic response to FAC chemotherapy showed that the C/C + C/T genotype was a protective factor against chemoresistance (OR = 3.714; p = 0.0104). Polymorphisms in ABCG2 indicated a lack of association with resistance to chemotherapy (p = 0.2586) evaluating the clinical or pathological response rate to FAC neoadjuvant chemotherapy. CONCLUSION: The early clinical response and its association with SNPs in the ABCB1 transporter are preserved until the pathological response to neoadjuvant chemotherapy; therefore, it could be used as a predictor of chemoresistance in locally advanced breast cancer patients of the Mexican population.

Methotrexate Triglutamate as a Determinant of Clinical Response in Mexican Patients With Rheumatoid Arthritis: Pharmacokinetics and Dose Recommendation.

Methotrexate is the gold standard treatment in rheumatoid arthritis. Once absorbed, it is internalized in cells, where glutamate residues are added to produce polyglutamated forms, which are responsible for the effect of methotrexate. The aim of the current study is to determine the relationship between methotrexate triglutamate concentrations and the clinical evolution in rheumatoid arthritis patients, as well as to characterize the variability in both features to propose strategies for low-dose methotrexate optimization. The quantification of methotrexate triglutamate concentration in red blood cells was performed through ultra-performance liquid chromatography coupled with mass spectrometry. Polymorphisms of genes involved in the formation of polyglutamates were determined by real-time polymerase chain reaction. A multivariate regression was performed to determine the covariates involved in the variability of methotrexate triglutamate concentrations and a population pharmacokinetics model was developed through nonlinear mixed-effects modeling. Disease activity score changed according to methotrexate triglutamate concentrations; patients with good response to treatment had higher concentrations than moderate or nonresponding patients. The methotrexate triglutamate concentrations were related to time under treatment, dose, red blood cells, and body mass index. A 1-compartment open model was selected to estimate the pharmacokinetic parameters; the typical total clearance (L/day) was determined as 1.45 * (body mass index/28 kg/m2 ) * (red blood cells/4.6 × 106 cells/µL) and the volume of distribution was 52.4 L, with an absorption rate of 0.0346/day and a fraction metabolized of 1.03%. Through the application of the model, the initial dose of methotrexate is proposed on the basis of stochastic simulations and considering methotrexate triglutamate concentrations found in responders patients.

Quantification of pyrazinamide, isoniazid, acetyl-isoniazid, and rifampicin by a high-performance liquid chromatography method in human plasma from patients with tuberculosis.

The aim of this study was to establish and validate an alternative high-performance liquid chromatography method for simultaneous quantification of pyrazinamide, isoniazid, acetyl-isoniazid and rifampicin in plasma of patients under treatment for tuberculosis. The performed method was lineal (r2  > 0.99) in the range of 2.00-50.00 µg/mL for pyrazinamide, 0.50-20.00 µg/mL for both acetyl-isoniazid and isoniazid, and 1.20-25.00 µg/mL for rifampicin. Precision and trueness were demonstrated with coefficient of variation < 15% and deviations < 15%, respectively, for quality controls samples. The lower limits of quantification were 2.00, 0.50, 0.50, and 1.20 µg/mL for pyrazinamide, isoniazid, acetyl-isoniazid and rifampicin, respectively. The method was applied for the analysis of plasma from patients with tuberculosis. This method allowed ensuring reliable quantification of the target compounds and their pharmacokinetics parameters. In general, the mean values of maximum concentration of each antituberculosis drug were located within their respective reference therapeutic ranges. However, patients with sub-therapeutic plasma concentrations of isoniazid and rifampicin were detected. This is the first analytical technique that simultaneously quantifies isoniazid, acetyl-isoniazid, rifampicin, and pyrazinamide concentrations from plasma samples by high-performance liquid chromatography with ultraviolet/visible. The proposed method could be applied for therapeutic drug monitoring and pharmacokinetics studies of the four compounds throughout the treatment of tuberculosis patients.

A population approach of rifampicin pharmacogenetics and pharmacokinetics in Mexican patients with tuberculosis.

The aim of this study was to develop a population pharmacokinetic model of rifampicin (RMP) in Mexican patients with tuberculosis (TB) to evaluate the influence of anthropometric and clinical covariates, as well as genotypic variants associated with MDR1 and OATP1B1 transporters. A prospective study approved by Research Ethics Committee was performed at Hospital Central in San Luis Potosí, Mexico. TB patients under DOTS scheme and who signed informed consent were consecutively included. Anthropometric and clinical information was retrieved from medical records. Single nucleotide polymorphisms in MDR1 (C3435T) and SLCO1B1 (A388G and T521C) genes were evaluated. RMP plasma concentrations and time data were assessed with NONMEM software. A total of 71 Mexican TB patients from 18 to 72 years old were included for RMP quantification from 0.3 to 12 h after dose; 329 and 97 plasma concentrations were available for model development and validation, respectively. Sequential process includes a typical lag time of 0.25 h prior to absorption start with a Ka of 1.24 h-1 and a zero-order absorption of 0.62 h to characterize the gradual increase in RMP plasma concentrations. Final model includes total body weight in volume of distribution (0.7 L/kg, CV = 26.8%) and a total clearance of 5.96 L/h (CV = 38.5%). Bioavailability was modified according to time under treatment and generic formulation administration. In conclusion, a population pharmacokinetic model was developed to describe the variability in RMP plasma concentrations in Mexican TB patients. Genetic variants evaluated did not showed significant influence on pharmacokinetic parameters. Final model will allow therapeutic drug monitoring at early stages.

Population pharmacokinetics of isoniazid and dose recommendations in Mexican patients with tuberculosis.

Background The standardized doses of isoniazid in therapy against tuberculosis are determined based on total body weight, without considering genetic polymorphisms of the metabolic enzyme N-acetyltransferase-2 that contribute to the wide pharmacokinetic variability of isoniazid. Objective The aim of this work was to build a population pharmacokinetic model of isoniazid in Mexican patients with tuberculosis to characterize typical estimates of pharmacokinetics, as well as inter-individual and residual variability of isoniazid considering the genetic factors associated with the N-acetyltransferase-2 enzyme. Setting A prospective study was conducted at the Department of Internal Medicine in Hospital Central, San Luis Potosí, México. Methods Plasma concentrations of isoniazid were measured by high performance liquid chromatography. The acetylator phenotype was predicted through single nucleotide polymorphisms in the N-acetyltransferase-2 gene. Genetic, anthropometric and clinical covariates were used to develop a pharmacokinetic model. Main outcome measure Isoniazid plasma concentration. Results A total of 69 patients with tuberculosis were included. Blood samples were drawn from 20 min to 12 h post dose to determinate the isoniazid plasma concentration. Typical pharmacokinetics parameters were characterized through two-compartment open model with first-order absorption and linear elimination. Clearance was different for each predicted N-acetyltransferase-2 phenotype being 11.4, 19.2 and 27.4 L/h for slow, intermediate and rapid acetylators, respectively. Central volume of distribution was determined as 1.5 * body mass index (L). Through the application of the model, external validation was performed and initial dose regimen of isoniazid is proposed based on stochastic simulations. Conclusion A validated population pharmacokinetic model of isoniazid was developed in Mexican patients with tuberculosis. Through the application of the final model, initial dose recommendations were provided considering body mass index and N-acetyltransferase-2 phenotype.

Dosing Recommendations Based on Population Pharmacokinetics of Lamotrigine in Mexican Adult Patients With Epilepsy.

Dose individualization is essential in epilepsy treatment, especially in antiepileptic drugs that present high interindividual variability such as lamotrigine. We aimed an observational study to develop a population pharmacokinetic model for quantitative evaluation of the factors that influence lamotrigine pharmacokinetics in Mexican adults with epilepsy. Patients on stable treatment with lamotrigine therapy were included, plasma concentrations were analyzed by a high-performance liquid chromatography method and UGT2B7-161C > T polymorphism was determined. The data were analyzed by NONMEM® 7.3, model validation was performed using bootstrap approach and visual predictive check. Finally, stochastic simulations were carried out to propose dosage regimens. A total of 73 lamotrigine plasma concentrations from 2 h after last dose and up to 0.5 h prior to next administration were fitted to a one-compartment open model. The final population pharmacokinetic model for lamotrigine indicates that concomitant treatment with valproic acid and carbamazepine should be considered to individualize epilepsy treatment with this drug. Based on this model, we proposed dosage regimens to achieve trough lamotrigine concentrations within reference interval (2.5-15 mg/L). These results provide clinical useful data to give more rational anticonvulsant therapy in our population.

Population pharmacokinetics of mycophenolic acid in Mexican patients with lupus nephritis.

BACKGROUND: Mycophenolic acid (MPA) is an effective oral immunosuppressive drug used to treat lupus nephritis (LN), which exhibits large pharmacokinetic variability. This study aimed to characterize MPA pharmacokinetic behaviour in Mexican LN patients and to develop a population pharmacokinetic model which identified factors that influence MPA pharmacokinetic variability. METHODS: Blood samples from LN patients treated with mycophenolate mofetil (MMF) were collected pre dose and up to six hours post dose. MPA concentrations were determined by a validated ultra-performance liquid chromatography tandem mass spectrometry technique. Patients were genotyped for polymorphisms in enzymes (UGT1A8, 1A9 and 2B7) and transporters (ABCC2 and SLCO1B3). The anthropometric, clinical, genetic and co-medication characteristics of each patient were considered as potential covariates to explain the variability. RESULTS: A total of 294 MPA concentrations from 40 LN patients were included in the development of the model. The data were analysed using NONMEM software and were best described by a two-compartment linear model. MPA CL, Vc, Vp, Ka and Q were 15.4 L/h, 22.86 L, 768 L, 1.28 h-1 and 20.3 L/h, respectively. Creatinine clearance and prednisone co-administration proved to have influence on clearance, while body weight influenced Vc. The model was internally validated, proving to be stable. MMF dosing guidelines were obtained through stochastic simulations performed with the final model. CONCLUSIONS: This is the first MPA population pharmacokinetic model to have found that co-administration of prednisone results in a considerable increase on clearance. Therefore, this and the other covariates should be taken into account when prescribing MMF in order to optimize the immunosuppressant therapy in patients with LN.

Population pharmacokinetics of mycophenolic acid in adult kidney transplant patients under prednisone and tacrolimus regimen.

Mycophenolate mofetil (MMF) is typically used in combination with prednisone and tacrolimus to avoid graft rejection in kidney transplant patients. The aim of this study was to develop and validate a population pharmacokinetic model of mycophenolic acid (MPA) in kidney transplant patients to investigate the influence of clinical and genetic covariates and to propose a dosage regimen based on the final model. Adult kidney transplant patients (>18 years old) receiving combination of MMF, prednisone and tacrolimus regimen were included. The population pharmacokinetic model was built using a two-compartment model and First Order Conditional Estimation method with Interaction (FOCEI though NONMEM v.7.4.). A total of 343 MPA concentrations at steady state from 77 kidney transplant patients were included in the analysis. MPA CL/F, V1/F, Q/F, V2/F, and Ka were 12.4 L/h, 45.6 L, 29.9 L/h, 658 L, and 1.67 h-1, respectively. It was found that CL/F increases with serum creatinine and uric acid levels and V1/F is modified by blood urea nitrogen and the UGT1A9 genotype. In the final model the interindividual variabilities associated to CL/F and V1/F were 56.5% and 105.8%, respectively. The residual variability was 41.8%. Evaluation by bootstrapping showed that the final model was stable. The predictive performance was evaluated by goodness-of-fit plots and visual predictive check. Dosage regimens for MMF were proposed based on the final model and would be appropriate for a prospective evaluation. In conclusion, it was built a population pharmacokinetic model for MPA in kidney transplant patients, which include clinical and genetic covariates.

Population Pharmacokinetics and Dosing Recommendations of Levetiracetam in Adult and Elderly Patients With Epilepsy.

The objective was to develop and externally validate a population pharmacokinetic model of levetiracetam in adult and elderly patients with epilepsy, and to perform dosing simulations to propose individualized dosing regimens more likely to achieve therapeutic concentrations. This prospective study included 367 plasma samples from 107 patients receiving oral levetiracetam. Samples were analyzed by HPLC-UV. Pharmacokinetic data, as well as patient demographic, clinical characteristics, other drug therapy, and the use of innovator or generic products of levetiracetam, were collected. Population modeling was performed with NONMEM and included internal and external validations of the final model. Simulations were used to propose optimized dosing regimens. The pharmacokinetics of levetiracetam was described by a one-compartment model with first-order absorption and linear elimination. Body surface area had a significant effect on the apparent volume of distribution, as did creatinine clearance (CrCL) over the drug clearance (p < 0.01). The final model performed adequately during external validation testing. The final model showed a better predictive performance. Dosing simulations support 1000 mg 12-hourly dosing of levetiracetam for patients with CrCL ~60-75 mL/min with higher dose needed for higher values (1500 mg 12-hourly for CrCL ~93-111 mL/min). Dosing regimens should be personalized to the patient's CrCL to maximize the likelihood of therapeutic concentrations.

Population Pharmacokinetics of Amikacin Administered Once Daily in Patients with Different Renal Functions.

The aim of this work was to evaluate the pharmacokinetics of amikacin in Mexican patients with different renal functions receiving once-daily dosing regimens and the influence of clinical and demographical covariates that may influence the optimization of this antibiotic. A prospective study was performed in a total of 63 patients with at least one determination of amikacin plasma concentration. Population pharmacokinetic (PK) parameters were estimated by nonlinear mixed-effects modeling; validations were performed for dosing recommendation purposes based on PK/pharmacodynamic simulations. The concentration-versus-time data were best described by a one-compartment open model with proportional interindividual variability associated with amikacin clearance (CL) and volume of distribution (V); residual error followed a homoscedastic trend. Creatinine clearance (CLCR) and ideal body weight (IBW) demonstrated significant influence on amikacin CL and V, respectively. The final model [CL (liters/h) = 7.1 × (CLCR/130)0.84 and V (liters) = 20.3 × (IBW/68)2.9] showed a mean prediction error of 0.11 mg/liter (95% confidence interval, -3.34, 3.55) in the validation performed in a different group of patients with similar characteristics. There is a wide variability in amikacin PK parameters in Mexican patients. This leads to inadequate dosing regimens, especially in patients with augmented renal clearance (CLCR of >130 ml/min). Optimization based on the final population PK model in Mexican patients may be useful, since reliability and clinical applicability have been demonstrated in this study.