RESUMEN
AIMS: We propose using glomerular filtration rate (GFR) as the physiological basis for distinguishing components of renal clearance. METHODS: Gentamicin, amikacin and vancomycin are thought to be predominantly excreted by the kidneys. A mixed-effects joint model of the pharmacokinetics of these drugs was developed, with a wide dispersion of weight, age and serum creatinine. A dataset created from 18 sources resulted in 27,338 drug concentrations from 9,901 patients. Body size and composition, maturation and renal function were used to describe differences in drug clearance and volume of distribution. RESULTS: This study demonstrates that GFR is a predictor of two distinct components of renal elimination clearance: (1) GFR clearance associated with normal GFR and (2) non-GFR clearance not associated with normal GFR. All three drugs had GFR clearance estimated as a drug-specific percentage of normal GFR (gentamicin 39%, amikacin 90% and vancomycin 57%). The total clearance (sum of GFR and non-GFR clearance), standardized to 70 kg total body mass, 176 cm, male, renal function 1, was 5.58 L/h (95% confidence interval [CI] 5.50-5.69) (gentamicin), 7.77 L/h (95% CI 7.26-8.19) (amikacin) and 4.70 L/h (95% CI 4.61-4.80) (vancomycin). CONCLUSIONS: GFR provides a physiological basis for renal drug elimination. It has been used to distinguish two elimination components. This physiological approach has been applied to describe clearance and volume of distribution from premature neonates to elderly adults with a wide dispersion of size, body composition and renal function. Dose individualization has been implemented using target concentration intervention.
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Antibacterianos , Vancomicina , Recién Nacido , Adulto , Humanos , Masculino , Anciano , Antibacterianos/farmacocinética , Vancomicina/farmacocinética , Amicacina/farmacocinética , Gentamicinas/farmacocinética , Tasa de Filtración Glomerular , Tasa de Depuración Metabólica , CreatininaRESUMEN
AIM: Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus-azole antifungal interaction. METHODS: Data from heart transplant recipients (n = 87) administered the oral immediate-release formulation of tacrolimus (Prograf®) were collected. Routine drug monitoring data, principally trough concentrations, were used for model building (n = 1099). A published tacrolimus model was used to inform the estimation of Ka , V2 /F, Q/F and V3 /F. The effect of concomitant azole antifungal use on tacrolimus CL/F was quantified. Fat-free mass was implemented as a covariate on CL/F, V2 /F, V3 /F and Q/F on an allometry scale. Subsequently, stepwise covariate modelling was performed. Significant covariates influencing tacrolimus CL/F were included in the final model. Robustness of the final model was confirmed using prediction-corrected visual predictive check (pcVPC). The final model was externally evaluated for prediction of tacrolimus concentrations of the fourth dosing occasion (n = 87) from one to three prior dosing occasions. RESULTS: Concomitant azole antifungal therapy reduced tacrolimus CL/F by 80%. Haematocrit (∆OFV = -44, P < .001) was included in the final model. The pcVPC of the final model displayed good model adequacy. One recent drug concentration is sufficient for the model to guide tacrolimus dosing. CONCLUSION: A population pharmacokinetic model that adequately describes tacrolimus pharmacokinetics in heart transplant recipients, considering the tacrolimus-azole antifungal interaction was developed. Prospective evaluation is required to assess its clinical utility to improve patient outcomes.
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Trasplante de Corazón , Tacrolimus , Humanos , Tacrolimus/farmacocinética , Inmunosupresores/farmacocinética , Antifúngicos , Azoles , Modelos Biológicos , Receptores de Trasplantes , Citocromo P-450 CYP3ARESUMEN
BACKGROUND AND AIM: Identification of the most appropriate population pharmacokinetic model-based Bayesian estimation is required prior to its implementation in routine clinical practice to inform tacrolimus dosing decisions. This study aimed to determine the predictive performances of relevant population pharmacokinetic models of tacrolimus developed from various solid organ transplant recipient populations in adult heart transplant recipients, stratified based on concomitant azole antifungal use. Concomitant azole antifungal therapy alters tacrolimus pharmacokinetics substantially, necessitating dose adjustments. METHODS: Population pharmacokinetic models of tacrolimus were selected (n = 17) for evaluation from a recent systematic review. The models were transcribed and implemented in NONMEM version 7.4.3. Data from 85 heart transplant recipients (2387 tacrolimus concentrations) administered the oral immediate-release formulation of tacrolimus (Prograf) were obtained up to 391 days post-transplant. The performance of each model was evaluated using: (i) prediction-based assessment (bias and imprecision) of the individual predicted tacrolimus concentration of the fourth dosing occasion (MAXEVAL = 0, FOCE-I) from 1-3 prior dosing occasions; and (ii) simulation-based assessment (prediction-corrected visual predictive check). Both assessments were stratified based on concomitant azole antifungal use. RESULTS: Regardless of the number of prior dosing occasions (1-3) and concomitant azole antifungal use, all models demonstrated unacceptable individual predicted tacrolimus concentration of the fourth dosing occasion (n = 152). The prediction-corrected visual predictive check graphics indicated that these models inadequately predicted observed tacrolimus concentrations. CONCLUSION: All models evaluated were unable to adequately describe tacrolimus pharmacokinetics in adult heart transplant recipients included in this study. Further work is required to describe tacrolimus pharmacokinetics for our heart transplant recipient cohort.
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Trasplante de Corazón , Tacrolimus , Adulto , Antifúngicos , Azoles , Teorema de Bayes , Humanos , Inmunosupresores/farmacocinética , Modelos Biológicos , Tacrolimus/farmacocinética , Receptores de TrasplantesRESUMEN
AIMS: Abacavir is part of WHO-recommended regimens to treat HIV in children under 15 years of age. In a pooled analysis across four studies, we describe abacavir population pharmacokinetics to investigate the influence of age, concomitant medications, malnutrition and formulation. METHODS: A total of 230 HIV-infected African children were included, with median (range) age of 2.1 (0.1-12.8) years and weight of 9.8 (2.5-30.0) kg. The population pharmacokinetics of abacavir was described using nonlinear mixed-effects modelling. RESULTS: Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination, and absorption described by transit compartments. Clearance was predicted around 54% of its mature value at birth and 90% at 10 months. The estimated typical clearance at steady state was 10.7 L/h in a child weighing 9.8 kg co-treated with lopinavir/ritonavir, and was 12% higher in children receiving efavirenz. During coadministration of rifampicin-based antituberculosis treatment and super-boosted lopinavir in a 1:1 ratio with ritonavir, abacavir exposure decreased by 29.4%. Malnourished children living with HIV had higher abacavir exposure initially, but this effect waned with nutritional rehabilitation. An additional 18.4% reduction in clearance after the first abacavir dose was described, suggesting induction of clearance with time on lopinavir/ritonavir-based therapy. Finally, absorption of the fixed dose combination tablet was 24% slower than the abacavir liquid formulation. CONCLUSION: In this pooled analysis we found that children on lopinavir/ritonavir or efavirenz had similar abacavir exposures, while concomitant TB treatment and super-boosted lopinavir gave significantly reduced abacavir concentrations.
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Fármacos Anti-VIH , Infecciones por VIH , Desnutrición , Niño , Preescolar , Didesoxinucleósidos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Recién Nacido , Lopinavir/uso terapéutico , RitonavirRESUMEN
Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).
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Infecciones por Virus de Epstein-Barr , Linfoma no Hodgkin , Trastornos Linfoproliferativos , Adenina/análogos & derivados , Sistema Nervioso Central , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Herpesvirus Humano 4 , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/etiología , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/etiología , Piperidinas , Linfocitos TRESUMEN
BACKGROUND: The impact of Aspergillus on lung disease in young children with cystic fibrosis is uncertain. AIMS: To determine if positive respiratory cultures of Aspergillus species are associated with: (1) increased structural lung injury at age 5 years; (2) accelerated lung function decline between ages 5 years and 14 years and (3) to identify explanatory variables. METHODS: A cross-sectional analysis of association between Aspergillus positive bronchoalveolar lavage (BAL) cultures and chest high-resolution CT (HRCT) scan findings at age 5 years in subjects from the Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study was performed. A non-linear mixed-effects disease progression model was developed using FEV1% predicted measurements at age 5 years from the ACFBAL study and at ages 6-14 years for these subjects from the Australian Cystic Fibrosis Data Registry. RESULTS: Positive Aspergillus BAL cultures at age 5 years were significantly associated with increased HRCT scores for air trapping (OR 5.53, 95% CI 2.35 to 10.82). However, positive Aspergillus cultures were not associated with either FEV1% predicted at age 5 years or FEV1% predicted by age following adjustment for body mass index z-score and hospitalisation secondary to pulmonary exacerbations. Lung function demonstrated a non-linear decline in this population. CONCLUSION: In children with cystic fibrosis, positive Aspergillus BAL cultures at age 5 years were associated contemporaneously with air trapping but not bronchiectasis. However, no association was observed between positive Aspergillus BAL cultures on FEV1% predicted at age 5 years or with lung function decline between ages 5 years and 14 years.
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Fibrosis Quística/complicaciones , Pulmón/microbiología , Aspergilosis Pulmonar/complicaciones , Adolescente , Aspergillus/aislamiento & purificación , Australia , Lavado Broncoalveolar , Niño , Preescolar , Estudios Transversales , Fibrosis Quística/microbiología , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Pulmón/patología , Masculino , Sistema de Registros , Pruebas de Función Respiratoria/métodos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown. AIM: To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years. METHODS: Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years. RESULTS: Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event. CONCLUSION: In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus.
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Antibacterianos/uso terapéutico , Fibrosis Quística/complicaciones , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/epidemiología , Pseudomonas aeruginosa , Aspergilosis Pulmonar/epidemiología , Antibacterianos/administración & dosificación , Lavado Broncoalveolar , Ceftazidima/uso terapéutico , Preescolar , Ciprofloxacina/uso terapéutico , Ácidos Clavulánicos/uso terapéutico , Estudios Transversales , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Prevalencia , Aspergilosis Pulmonar/diagnóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Factores de Riesgo , Ticarcilina/uso terapéutico , Tobramicina/uso terapéuticoRESUMEN
AIMS: Describe the pharmacokinetics (PK) of the antiretroviral drugs abacavir and lamivudine in malnourished paediatric patients and relate to viral load outcomes after 12 and 48 weeks of treatment. METHODS: Severely malnourished human immunodeficiency virus-infected children were randomized to early (within 14 days) or delayed (after nutritional recovery) initiation of antiretroviral treatment (ART) using World Health Organization weight-band dosages. Abacavir and lamivudine concentrations were measured as a secondary objective on day 1 and day 14 and patients were followed-up to week 48. Population PK of abacavir and lamivudine were described using NONMEM. RESULTS: In total, 623 abacavir and 627 lamivudine concentrations were collected from 75 paediatric patients aged 0.1-10.8 (median 1.4) years. Abacavir PK was described by a 2-compartment model, patients randomized to early ART showed increased bioavailability of 31%. Apparent clearance (CL/F, L/h/7 kg) of abacavir increased from day 1 to day 14 from 3.33 (95% confidence interval 2.71-4.12) to 5.86 (95% confidence interval 4.78-7.3). A 1-compartment model described lamivudine PK, variability on CL/F was explained by maturation with age, with age at half-matured CL/F being 4 months. For both drugs allometrically scaled total body weight was related to CL/F and apparent volume of distribution. PK exposure did not correlate with virological outcomes or death at 12 or 48 weeks. CONCLUSION: Increases in Abacavir's CL/F between day 1 to day 14, bioavailability and PK variability with early start of ART was found in this cohort of severely malnourished children; however, these changes did not influence virological outcomes. The study supports the use of weight-band dosage tables.
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Fármacos Anti-VIH/farmacocinética , Trastornos de la Nutrición del Niño/metabolismo , Didesoxinucleósidos/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Lamivudine/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Disponibilidad Biológica , Peso Corporal , Niño , Trastornos de la Nutrición del Niño/diagnóstico , Trastornos de la Nutrición del Niño/etiología , Trastornos de la Nutrición del Niño/rehabilitación , Preescolar , Didesoxinucleósidos/administración & dosificación , Didesoxinucleósidos/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Cálculo de Dosificación de Drogas , Femenino , Estudios de Seguimiento , VIH/aislamiento & purificación , Infecciones por VIH/sangre , Infecciones por VIH/complicaciones , Infecciones por VIH/mortalidad , Humanos , Lactante , Lamivudine/administración & dosificación , Lamivudine/efectos adversos , Masculino , Modelos Biológicos , Apoyo Nutricional , Índice de Severidad de la Enfermedad , Sudáfrica/epidemiología , Factores de Tiempo , Tiempo de Tratamiento , Resultado del Tratamiento , Carga ViralRESUMEN
AIMS: To evaluate 3 Bayesian forecasting (BF) programs-TDMx, InsightRx and DoseMe-on their user-friendliness and common liked and disliked features through a survey of hospital pharmacists. METHODS: Clinical pharmacists across 3 Australian hospitals that did not use a BF program were invited to a BF workshop and complete a survey on programs they trialled. Participants were given 4 case scenarios to work through and asked to complete a 5-point Likert scale survey evaluating the program's user-friendliness. Liked and disliked features of each program were ascertained through written responses to open-ended questions. Survey results were compared using a χ2 test of equal or given proportions to identify significant differences in response. RESULTS: Twenty-seven pharmacists, from hospitals, participated. BF programs were rated overall as user-friendly with 70%, 41% and 37% (P = .02) of participants recording a Likert score of 4 or 5 for DoseMe, TDMx and InsightRx, respectively. Participants found it easy to access all required information to use the programs, understood dosing recommendations and visualisations given by each program, and thought programs supported decision-making with >50% of participants scoring a 4 or 5 across the programs in these categories. Common liked features across all programs were the graphical displays and ease of data entry, while common disliked features were related to the units, layout and information display. CONCLUSION: Although differences exist between programs, all 3 programs were most commonly rated as user-friendly across all themes evaluated, which provides useful information for healthcare facilities wanting to implement a BF program.
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Técnicas de Apoyo para la Decisión , Monitoreo de Drogas/métodos , Farmacéuticos/estadística & datos numéricos , Servicio de Farmacia en Hospital/organización & administración , Adulto , Australia , Teorema de Bayes , Estudios Transversales , Educación Continua en Farmacia , Femenino , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
AIMS: To (i) describe tacrolimus (TAC) pre-dose concentrations (C0), (ii) calculate apparent oral TAC clearance (CL/FHCT) adjusted for measured haematocrit (HCTi) and standardised to a HCT of 45%, across three observation time points and (iii) explore if low TAC C0 or high mean CL/FHCT are associated with an increased risk of rejection episodes early after lung transplantation. METHODS: TAC whole blood concentration-time profiles and transbronchial biopsies were performed prospectively at weeks 3, 6 and 12 after lung transplantation. The TAC pre-dose concentration (C0) was measured, and CL/FHCT was determined using non-compartmental analysis. The associations between TAC C0 and CL/FHCT and rejection status were explored using repeated measures logistic regression. RESULTS: Eighteen patients provided 377 TAC whole blood concentrations. Considerable variability around the median (IQR) CL/FHCT 6.8 (4.2-15.9) L h-1, and the median C0 12.7 (9.9-16.6) µg L-1 was noted. Despite adjustment for haematocrit, a significant decrease was observed in CL/FHCT in all patients over time: CL/FHCT 14 (5.4-23) at week 3, CL/FHCT 7.7 (4.5-12) at week 6 and CL/FHCT 3.9 (2.4-11) L h-1 at week 12 (p < 0.01). Seven (38.9%) patients experienced a single grade 2 rejection, whilst 11 (61.1%) patients experienced no rejection. Higher TAC C0 were associated with a reduced risk of rejection OR 0.68 (95% CI 0.51-0.91, p = 0.02), and greater mean CL/FHCT was associated with an increased risk of rejection OR 1.34 (95% CI 1.01-1.81 p = 0.04). CONCLUSION: Monitoring TAC C0, HCT and CL/FHCT in patients after lung transplantation may assist clinicians in detecting patients at risk of acute rejection and may guide future research into TAC and HCT monitoring after lung transplantation.
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Rechazo de Injerto/metabolismo , Inmunosupresores/farmacocinética , Trasplante de Pulmón , Tacrolimus/farmacocinética , Enfermedad Aguda , Administración Oral , Adulto , Femenino , Humanos , Inmunosupresores/sangre , Masculino , Persona de Mediana Edad , Tacrolimus/sangreRESUMEN
OBJECTIVES: To evaluate the impact of an antimicrobial stewardship (AMS) intervention, involving introduction of new guidelines on the treatment of febrile neutropenia (FN), on improving the use of gentamicin in paediatric oncology patients. DESIGN AND INTERVENTION: Updated guidelines for gentamicin usage in paediatrics with FN were implemented at a tertiary children's teaching hospital, in Brisbane, Australia. Data on gentamicin usage before and after the guideline change were collected retrospectively from children with cancer admitted to hospital with FN between January 2012 and December 2013. Gentamicin use, duration of gentamicin therapy and therapeutic monitoring practice were compared against bacterial culture status for admissions before and after the guideline change to assess the impact on practice. RESULTS: Data were collected from 227 children corresponding to 453 separate admissions, 195 preguideline and 257 post-guideline change. Following guideline change, the proportion of admissions in which gentamicin was administered reduced from 79.0 to 20.9% (P-value < 0.001) and administrations not associated with a cultured Gram-negative organism dropped from 87.2 to 58.2% (P-value < 0.001), indicating a change in practice according to the new guideline. Following guideline change, admissions in which gentamicin was used for >48 hr despite the absence of a confirmed Gram-negative infection decreased from 85.6 to 46.9% (P-value < 0.001). CONCLUSIONS: Guideline changes driven through an AMS initiative involving paediatric oncology patients significantly improved targeted- and nontargeted-antimicrobial use potentially reducing the risk of emergence of resistance against gentamicin in this cohort.
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Neutropenia Febril/tratamiento farmacológico , Gentamicinas/administración & dosificación , Bacterias Gramnegativas , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Niño , Preescolar , Neutropenia Febril/microbiología , Neutropenia Febril/patología , Femenino , Infecciones por Bacterias Gramnegativas/microbiología , Infecciones por Bacterias Gramnegativas/patología , Adhesión a Directriz , Humanos , Masculino , Neoplasias/microbiología , Neoplasias/patología , Neoplasias/terapia , Guías de Práctica Clínica como Asunto , Estudios RetrospectivosRESUMEN
AIMS: Glomerular filtration rate (GFR) is estimated daily in paediatric oncology patients; however, few equations, particularly ones that do not include serum creatinine, have been evaluated in this population. We aimed to compare the predictive performance of different equations available to estimate GFR in paediatric oncology patients. METHODS: GFR was measured (mGFR) in paediatric oncology patients based on a chromium 51-labeled ethylene diamine tetraacetic acid excretion test. GFR was estimated (eGFR) in these same patients using equations identified from the literature. mGFR and eGFR values were compared, and the predictive performance of various eGFR equations was assessed in terms of their bias, precision and accuracy. RESULTS: In total, 124 mGFR values ranging from 7 to 146 mL/min were available for analysis from 73 children. Twenty-two equations were identified from the literature. The Flanders metadata equation displayed the lowest absolute bias (mean error of 0.9 mL/min) and the greatest precision (root mean square error of 13.1 mL/min). The univariate Schwartz equation predicted the highest percentage (81.5%) of eGFR values within 30% of mGFR values, and the Rhodin fat-free mass equation predicted the highest percentage (37.1%) of eGFR values within 10% of mGFR values. CONCLUSIONS: A number of equations were identified that could be used to estimate renal function in paediatric oncology patients; however, none was found to be highly accurate. The Flanders metadata equation and univariate Schwartz performed the best in this study, and we would suggest that these two equations may be used cautiously in paediatric oncology patients for clinical decision making, understanding their limitations.
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Algoritmos , Pruebas Diagnósticas de Rutina/métodos , Tasa de Filtración Glomerular , Pediatría , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasias , Valor Predictivo de las Pruebas , Insuficiencia Renal CrónicaRESUMEN
Several population pharmacokinetic models describe the dose-exposure relationship of tobramycin in pediatric patients. Before the implementation of these models in clinical practice for dosage adjustment, their predictive performance should be externally evaluated. This study tested the predictive performance of all published population pharmacokinetic models of tobramycin developed for pediatric patients with an independent patient cohort. A literature search was conducted to identify suitable models for testing. Demographic and pharmacokinetic data were collected retrospectively from the medical records of pediatric patients who had received intravenous tobramycin. Tobramycin exposure was predicted from each model. Predictive performance was assessed by visual comparison of predictions to observations, by calculation of bias and imprecision, and through the use of simulation-based diagnostics. Eight population pharmacokinetic models were identified. A total of 269 concentration-time points from 41 pediatric patients with cystic fibrosis were collected for external evaluation. Three models consistently performed best in all evaluations and had mean errors ranging from -0.4 to 1.8 mg/liter, relative mean errors ranging from 4.9 to 29.4%, and root mean square errors ranging from 47.8 to 66.9%. Simulation-based diagnostics supported these findings. Models that allowed a two-compartment disposition generally had better predictive performance than those that used a one-compartment disposition model. Several published models of the pharmacokinetics of tobramycin showed reasonable low levels of bias, although all models seemed to have some problems with imprecision. This suggests that knowledge of typical pharmacokinetic behavior and patient covariate values alone without feedback concentration measurements from individual patients is not sufficient to make precise predictions.
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Antibacterianos/farmacocinética , Tobramicina/farmacocinética , Administración Intravenosa , Adolescente , Adulto , Antibacterianos/administración & dosificación , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Estudios Retrospectivos , Tobramicina/administración & dosificación , Adulto JovenRESUMEN
Fixed tobramycin (mg/kg) dosing is often inappropriate in patients with cystic fibrosis (CF), as pharmacokinetics are highly variable. The area under the concentration-time curve (AUC) is an exposure metric suited to monitoring in this population. Bayesian strategies to estimate AUC have been available for over 20 years but are not standard practice in the clinical setting. To assess their suitability for use in clinical practice, three AUC estimation methods using limited sampling were compared to measured true exposure by using intensive sampling tobramycin data. Adults prescribed once daily intravenous tobramycin had eight concentrations taken over 24 h. An estimate of true exposure within one dosing interval was calculated using the trapezoidal method and compared to three alternate estimates determined using (i) a two-sample log-linear regression (LLR) method (local hospital practice); (ii) a Bayesian estimate using one concentration (AUC1); and (iii) a Bayesian estimate using two concentrations (AUC2). Each method was evaluated against the true measured exposure by a Bland-Altman analysis. Twelve patients with a median (range) age and weight of 25 (18 to 36) years and 66.5 (51 to 76) kg, respectively, were recruited. There was good agreement between the true exposure and the three alternate estimates of AUC, with a mean AUC bias of <10 mg/liter · h in each case, i.e., -8.2 (LLR), 3.8 (AUC1), and 1.0 (AUC2). Bayesian analysis-based and LLR estimation methods of tobramycin AUC are equivalent to true exposure estimation. All three methods may be suitable for use in the clinical setting; however, a one-sample Bayesian method may be most useful in ambulatory patients for which coordinating blood samples is difficult. Suitably powered, randomized clinical trials are required to assess patient outcomes.
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Antibacterianos/farmacocinética , Fibrosis Quística/tratamiento farmacológico , Infecciones por Pseudomonas/tratamiento farmacológico , Tobramicina/farmacocinética , Adolescente , Adulto , Antibacterianos/sangre , Área Bajo la Curva , Teorema de Bayes , Fibrosis Quística/complicaciones , Fibrosis Quística/microbiología , Fibrosis Quística/patología , Esquema de Medicación , Cálculo de Dosificación de Drogas , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Estudios Prospectivos , Infecciones por Pseudomonas/complicaciones , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/patología , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/crecimiento & desarrollo , Análisis de Regresión , Tobramicina/sangreRESUMEN
Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.).
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Antituberculosos/farmacocinética , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple , Rifabutina/farmacocinética , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Antituberculosos/administración & dosificación , Antituberculosos/sangre , Área Bajo la Curva , Recuento de Linfocito CD4 , Coinfección , Etambutol/administración & dosificación , Femenino , Expresión Génica , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , Isoniazida/administración & dosificación , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Método de Montecarlo , Transportadores de Anión Orgánico/metabolismo , Pirazinamida/administración & dosificación , Rifabutina/administración & dosificación , Rifabutina/sangre , Rifampin/administración & dosificación , Factores Sexuales , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patologíaRESUMEN
OBJECTIVES: Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV PIs and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated TB, with concurrently administered PIs. METHODS: Individual-level data from 13 published studies were pooled and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin) and drug-drug interaction with PIs in healthy volunteers and patients who had HIV and TB (TB/HIV). RESULTS: Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation of the metabolite (increased by 224% in patients), volume of distribution (increased by 606%) and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, clearance was reduced by 35%-76% and volume of distribution increased by 67%-240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of PIs and 280% with ritonavir-boosted PIs. CONCLUSIONS: Given together with non-boosted or ritonavir-boosted PIs, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant PIs and may achieve peak concentrations within an acceptable therapeutic range. Although 300 mg of rifabutin every 3 days with boosted PI achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.
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Fármacos Anti-VIH/uso terapéutico , Antituberculosos/uso terapéutico , Interacciones Farmacológicas , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Rifabutina/uso terapéutico , Tuberculosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/farmacocinética , Antituberculosos/farmacocinética , Femenino , Infecciones por VIH/complicaciones , Inhibidores de la Proteasa del VIH/farmacocinética , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Rifabutina/farmacocinética , Tuberculosis/complicaciones , Adulto JovenRESUMEN
BACKGROUND: The pharmacokinetics of gentamicin in pediatric patients with febrile neutropenia is described, and the adequacy of initial dosing of once-daily gentamicin assessed at Queensland's largest Children's Hospital. METHODS: Data were retrospectively collected from all pediatrics with febrile neutropenia admitted over a 2-year period who had at least 2 gentamicin concentration-time measurements (a paired set within 1 dosing interval). Gentamicin clearance, volume of distribution, area under the concentration-time curve from 0 to 24 hours postdose (AUC0-24), and maximum concentration values were estimated with log-linear regression using each paired set. The percentage of paired sets associated with gentamicin exposure within predefined hospital targets was calculated, and exposure was examined in relation to the bacterial culture status. RESULTS: Data were collected from 69 patients [median (interquartile range) age 3.7 years (2.2-8.9)] and comprised 121 paired concentration sets characterizing 80 separate admissions. Median (interquartile range) gentamicin clearance and volume of distribution were 8.1 L·h·70 kg (5.8-12.4) and 21.8 L/70 kg (16.9-29.5), respectively. Predefined hospital exposure targets were achieved for both AUC0-24 and maximum concentration for 10% of paired sets; one or the other of these targets were met for 36% of paired sets, and neither target was achieved for 54% of paired sets. Achievement of targets improved with repeated monitoring during the same admission. Median AUC0-24 achieved was significantly higher in patients with a confirmed Gram-negative infection compared with those without 71 (50-91) mg·h·L versus 55 (40.8-67.5) mg·h·L, respectively (P = 0.003). Over the study period, a median gentamicin dose of 10.8 and 6.4 mg/kg was estimated to be necessary to achieve an AUC target of 80 mg·h·L in children ≤10 years and >10 years of age. CONCLUSIONS: Based on a log-linear method of analysis, current dosing seems to be consistently producing gentamicin exposure below predefined pharmacokinetic targets, suggesting that an increase in the recommended starting dose of gentamicin may be required.
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Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Neutropenia Febril/tratamiento farmacológico , Gentamicinas/farmacocinética , Gentamicinas/uso terapéutico , Área Bajo la Curva , Niño , Preescolar , Esquema de Medicación , Neutropenia Febril/metabolismo , Femenino , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/metabolismo , Hospitales Pediátricos , Humanos , Masculino , Queensland , Estudios RetrospectivosRESUMEN
A systematic review was performed (i) to describe the reported overall rate of progression of CF lung disease quantified as FEV1%predicted decline with age, (ii) to summarise identified influencing risk factors and (iii) to review methods used to analyse CF lung disease progression data. A search of publications providing FEV1%predicted values over age was conducted in PUBMED and EMBASE. Baseline and rate of FEV1%predicted decline were summarised overall and by identified risk factors. Thirty-nine studies were included and reported variable linear rates of lung function decline in patients with CF. The overall weighted mean FEV1%predicted over age was graphically summarised and showed a nonlinear, time-variant decline of lung function. Compared to their peers, Pseudomonas aeruginosa infection and pancreatic insufficiency were most commonly associated with lower baseline and more rapid FEV1%predicted declines respectively. Considering nonlinear models and drop-out in lung disease progression, analysis is lacking and more studies are warranted.
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Fibrosis Quística/fisiopatología , Volumen Espiratorio Forzado/fisiología , Pulmón/fisiopatología , Niño , Progresión de la Enfermedad , Humanos , Pruebas de Función Respiratoria , Factores de RiesgoRESUMEN
AIMS: The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models. METHODS: Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting. RESULTS: Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h−1 [95% CI 12.6, 18.0 l h−1]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of −1.2% (95% CI −3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range. CONCLUSION: A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation.
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Inmunosupresores/farmacocinética , Trasplante de Riñón , Modelos Biológicos , Tacrolimus/farmacocinética , Adulto , Teorema de Bayes , Disponibilidad Biológica , Citocromo P-450 CYP3A/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Prednisolona/administración & dosificaciónRESUMEN
OBJECTIVES: The aims of this study were to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant recipients, to use this model to compare cytochrome P450 3A5 (CYP3A5) genotype-based initial dosing of tacrolimus with standard per-kilogram-based dosing, and to predict the best starting dose of tacrolimus based on patient genotype to achieve a trough concentration between 6 and 10 µg/L by day 5 posttransplantation. METHODS: Population analysis was performed using the software program NONMEM. Tacrolimus dosing regimens were compared by predicting tacrolimus trough concentrations in a simulated data set by running NONMEM with population parameters fixed at the final model estimates. Data from 173 patients with 1554 tacrolimus concentration-time measurements were modeled. RESULTS: Tacrolimus disposition was well described by a 2-compartment model with first-order elimination and first-order absorption after a lag time. Patient CYP3A5 genotype (rs776746), weight, hematocrit, and postoperative day were identified as significant covariates effecting tacrolimus apparent oral clearance (CL/F), with higher CL/F in CYP3A5*1 allele carriers, heavier patients, patients with low hematocrit, and in the immediate posttransplantation period. Typical population estimates for tacrolimus CL/F in CYP3A5*1 allele carriers and noncarriers were 40.8 and 25.5 L/h, respectively. CONCLUSIONS: In patients carrying the CYP3A5*1 allele, a per-kilogram dose of 0.075 mg/kg twice daily seemed too much low with approximately 65% of simulated subjects predicted to achieve a trough below 6 µg/L at day 5 posttransplantation. To reduce the risk of under immunosuppression in the immediate posttransplantation period, carriers of a CYP3A5*1 allele are likely to benefit from a tacrolimus starting dose of either 10 mg or 0.115 mg/kg twice daily.