Memoria para optar al título de Químico Farmacéutico / El perfil farmacocinético de los adultos mayores sufre una serie de alteraciones debido a que experimentan cambios fisiológicos asociados al envejecimiento capaces de modificar la estructura y funcionamiento de los diferentes sistemas de su organismo. Dichos cambios, sumados a las co-morbilidades que pueden presentar estos pacientes al ser hospitalizados en unidades no críticas, condicionan la respuesta y éxito de las terapias farmacológicas con antimicrobianos, dado que pueden afectar el logro de un índice PK/PD óptimo. El objetivo de este estudio fue desarrollar y optimizar una metodología analítica mediante HPLC acoplado a un detector UV/Vis para cuantificar ertapenem en plasma humano, para posteriormente ser aplicado en la caracterización del perfil farmacocinético de este antibiótico en adultos mayores hospitalizados en unidades no críticas, a los que, además, se les debió determinar su composición corporal. Para llevar a cabo lo anterior se reclutó a pacientes hospitalizados en la Unidad Geriátrica de Agudos del Hospital Clínico de la Universidad de Chile, a los que se les realizaron mediciones antropométricas y se les extrajeron muestras de sangre que fueron almacenadas para su posterior análisis. Paralelamente se trabajó evaluando diferentes condiciones experimentales que influyeran en el desarrollo de la metodología analítica y que permitieran validarla según parámetros internacionales. La metodología analítica desarrollada utilizó una columna Waters Spherisorb® y una fase móvil ajustada a pH 2,4 compuesta por el 70% de buffer fosfato 10 mM y 30% de acetonitrilo. Además, la velocidad de flujo fue de 0,9 ml/min y la longitud de onda utilizada fue de 310 nm. A la metodología se le realizaron diferentes ensayos para validarla, pero no cumplió con el parámetro de exactitud y precisión inter-día, por lo que se descartó. Por otro lado, de los 3 pacientes reclutados, 2 correspondieron a hombres y la edad promedio de la muestra fue de 82,3 ± 8,0 años. El peso real se pudo determinar en solo 2 pacientes y dio un promedio de 59,2 ± 15,4 kg. A su vez, el peso y la estatura se estimaron con diferentes métodos, arrojando valores de 54,5 ± 8,1 kg y 49,8 ± 3,8 kg y de 1,65 ± 0,1 m y 1,52 ± 0,1 m, respectivamente. El IMC clasificó a la muestra como normal o con déficit de peso, dependiendo de los datos utilizados. En relación a la composición corporal y estado nutricional de cada paciente, se pudo determinar que ID#1 estaba en riesgo de desnutrición/desnutrición, ID#2 se hallaba normal e ID#3 se encontraba en desnutrición/normal / The pharmacokinetic profile of older adults suffers a series of alterations because they experience physiological changes associated with aging, capable of modifying the structure and functioning of the different systems of their organism. These changes, added to the co-morbidities that these patients can present when hospitalized in non-critical units, condition the response and success of pharmacological therapies with antimicrobials, since they can affect the achievement of an optimal PK/PD index. The objective of this study was to develop and optimize an analytical methodology using HPLC coupled to a UV/Vis detector to quantify ertapenem in human plasma, to be subsequently applied in the characterization of the pharmacokinetic profile of this antibiotic in older adults hospitalized in non-critical units, to which, in addition, their body composition should have been determined. To carry out the above, hospitalized patients were recruited in the Geriatric Acute Unit of the Hospital Clínico de la Universidad de Chile, who underwent anthropometric measurements and blood samples were taken and stored for later analysis. At the same time, we worked evaluating different experimental conditions that influenced the development of the analytical methodology and that allowed to validate it according to international parameters. The developed analytical methodology used a Waters Spherisorb® column and a mobile phase adjusted to pH 2.4 composed of 70% of 10 mM phosphate buffer and 30% of acetonitrile. In addition, the flow rate was 0.9 ml/min and the wavelength used was 310 nm. The methodology was subjected to different tests to validate it, but it did not comply with the parameter of accuracy and precision inter-day, so it was discarded. On the other hand, of the 3 patients recruited, 2 corresponded to men and the average age of the sample was 82.3 ± 8.0 years. Actual weight could be determined in only 2 patients and averaged 59.2 ± 15.4 kg. In turn, weight and height were estimated using different methods, yielding values of 54.5 ± 8.1 kg and 49.8 ± 3.8 kg and of 1.65 ± 0.1 m and 1.52 ± 0.1 m, respectively. The body mass index classified the sample as normal or with a weight deficit, depending on the data used. In relation to the body composition and nutritional status of each patient, it was determined that ID#1 was at risk of malnutrition/malnutrition, ID#2 was normal and ID#3 was malnutrition/normal

Ertapenem is a carbapenem used to treat a wide range of bacterial infections. What sets ertapenem apart from other carbapenems is its longer half-life which implies it need only be administered once daily. We developed a physiologically-based pharmacokinetic model for the distribution of ertapenem within the body. In the model, parameters such as human body weight and height, age, organ volumes, blood flow rates, and partition coefficients of particular tissues are used to examine the absorption, distribution, metabolism, and excretion of ertapenem. The total and free blood concentrations found were then compared to experimental data. We then examined the sensitivity of the total concentration in the blood to body weight, body height, and age. This analysis allows the possibility of the model being used as a basis for understanding how differing health conditions might alter the concentration of ertapenem in the body and hence dosage may need to be adjusted.

Rapid and simple HPLC-UV and LC-MS methods were developed and validated for the quantification of ertapenem (Invanz™) in human plasma. Ertapenem is a unique drug in that current dosing recommendations call for a 1g dose for normal renal function patients, despite body weight. These assays, which involve a protein precipitation followed by liquid-liquid extraction, allow for fast therapeutic drug monitoring of ertapenem in patients, which is especially useful in special populations. Both methods were sufficient to baseline resolve meropenem (internal standard) and ertapenem, and were validated over 3days using a six-point calibration curve (0.5-50μg/mL). Validation was collected using four different points on the calibrations curve yielding acceptable precision (<15% inter-day and intra-day; <20% for lower limit of quantitation, LLOQ) as well as accuracy (<15% inter-day and intra-day; <20% for LLOQ). The lower limit of detection (LOD) was determined to be 0.1 and 0.05μg/mL for the HPLC-UV and LC-MS methods, respectively. The developed HPLC-UV and LC-MS methods for ertapenem quantification are fast, accurate and reproducible over the calibration range and can be used to determine ertapenem plasma concentrations for monitoring clinical efficacy.

Rapid and simple HPLC-UV and LC-MS methods were developed and validated for the quantification of ertapenem (Invanz™) in human plasma. Ertapenem is a unique drug in that current dosing recommendations call for a 1g dose for normal renal function patients, despite body weight. These assays, which involve a protein precipitation followed by liquid-liquid extraction, allow for fast therapeutic drug monitoring of ertapenem in patients, which is especially useful in special populations. Both methods were sufficient to baseline resolve meropenem (internal standard) and ertapenem, and were validated over 3days using a six-point calibration curve (0.5-50μg/mL). Validation was collected using four different points on the calibrations curve yielding acceptable precision (<15% inter-day and intra-day; <20% for lower limit of quantitation, LLOQ) as well as accuracy (<15% inter-day and intra-day; <20% for LLOQ). The lower limit of detection (LOD) was determined to be 0.1 and 0.05μg/mL for the HPLC-UV and LC-MS methods, respectively. The developed HPLC-UV and LC-MS methods for ertapenem quantification are fast, accurate and reproducible over the calibration range and can be used to determine ertapenem plasma concentrations for monitoring clinical efficacy.

Carbapanems are a class of β-lactam antibiotics with broad-spectrum potency and high β-lactamase resistance. Ertapenem, a member of this class, sold under the trade name Invanz™, has been of interest in the world of antibiotic therapeutic drug monitoring owing to its highly standardized 1 g dose and its high degree of plasma protein binding. Owing to the relative newness of this drug, fewer than 30 methods for ertapenem quantification have been published. Among these about half utilize biological matrices at the sample type. Liquid-liquid extraction and protein precipitation prevail as the most frequently used sample preparation techniques, despite their low recoveries compared with solid-phase extraction. Additionally, high-performance liquid chromatography with ultraviolet detection (HPLC-UV) is the instrumentation choice for most ertapenem assays. While these approaches may not achieve the highest possible sensitivity for ertapenem quantification, they provide clinically relevant tools for monitoring ertapenem in real patients. Sample stability is an ongoing concern for laboratories that handle ertapenem analysis, with buffering being of paramount importance, as well as low temperature (

Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections and is part of a broader class of antibiotics called carbapenems. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. Previously, a physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose in normal height, normal weight males. Due to the absorption properties of ertapenem, the amount of fat in the body can influence how the drug binds, how quickly the drug passes through the body, and thus how effective the drug might be. Thus, we have revised the model so that it is applicable to males and females of differing body mass index (BMI). Simulations were performed to consider the distribution of the antibiotic in males and females with varying body mass indexes. These results could help to determine if there is a need for altered dosing regimens in the future.

Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections, which is part of a broader class of antibiotics called carbapenem. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. A physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose. PBPK modeling incorporates known physiological parameters such as body weight, organ volumes, and blood ow rates in particular tissues. Furthermore, ertapenem is highly bound in human blood plasma; therefore, nonlinear binding is incorporated in the model since only the free portion of the drug can saturate tissues and, hence, is the only portion of the drug considered to be medicinally effective. Parameters in the model were estimated using a least squares inverse problem formulation with published data for blood concentrations of ertapenem for normal height, normal weight males. Finally, an uncertainty analysis of the parameter estimation and model predictions is presented.

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