A translational model-based approach to inform the choice of the dose in phase 1 oncology trials: the case study of erdafitinib.

PURPOSE: Erdafitinib (JNJ-42756493, BALVERSA) is a tyrosine kinase inhibitor indicated for the treatment of advanced urothelial carcinoma. In this work, a translational model-based approach to inform the choice of the doses in phase 1 trials is illustrated. METHODS: A pharmacokinetic (PK) model was developed to describe the time course of erdafitinib plasma concentrations in mice and rats. Data from multiple xenograft studies in mice and rats were analyzed using the Simeoni tumor growth inhibition (TGI) model. The model parameters were used to derive a range of erdafitinib exposures that might inform the choice of the doses in oncology phase 1 trials. Conversion of exposures to doses was based on preliminary PK assessments from the first-in human (FIH) study. RESULTS: A one-compartment PK disposition model, with linear absorption and dose-dependent clearance, adequately described the PK data in both mice and rats via an allometric scaling approach. The TGI model was able to describe tumor growth dynamics, providing quantitative measurements of erdafitinib antitumor potency in mice and rats. Based on these estimates, ranges of efficacious unbound concentration were identified for erdafitinib in mice (0.642-5.364 µg/L) and rats (0.782-2.565 µg/L). Based on the FIH data, it was possible to transpose exposures into doses and doses of above 4 mg/day provided erdafitinib exposures associated with significant TGI in animals. The findings were in agreement with the results of the FIH trial, in which the first hints of clinical activities were observed at 6 mg. CONCLUSION: The successful modeling exercise of erdafitinib preclinical data showed how translational PK-PD modeling might be a tool to help to inform the choice of the doses in FIH studies.

Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV.

OBJECTIVES: To characterize the population pharmacokinetics of the rilpivirine long-acting (LA) formulation after intramuscular administration. METHODS: Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies). Doses ranged from 300 to 1200 mg, as single-dose or multiple-dose regimens (every 4 or 8 weeks). In Phase III studies, an initiation injection of 900 mg followed by continuation injections of 600 mg every 4 weeks was used. Non-linear mixed-effects modelling was performed using NONMEM® software. RESULTS: A one-compartment model with linear elimination and two parallel absorption pathways (fast and slow) with sequential zero-first-order processes adequately captured rilpivirine flip-flop pharmacokinetics after intramuscular administration of the LA formulation. The estimated apparent elimination half-life of rilpivirine LA was 200 days. None of the evaluated covariates (age, body weight, BMI, sex, race, health status and needle length) had a clinically relevant impact on rilpivirine pharmacokinetics. CONCLUSIONS: The population pharmacokinetic model suitably describes the time course and associated variability of rilpivirine plasma concentrations after rilpivirine LA intramuscular administration. The monthly regimen consists of an oral lead-in period (rilpivirine 25 mg tablets once daily for 4 weeks), followed by an initiation injection of 900 mg rilpivirine LA, then 600 mg rilpivirine LA continuation injections monthly. The absence of a clinically relevant effect of covariates on rilpivirine pharmacokinetics suggests that rilpivirine LA dose adjustments for specific subgroups are not warranted.

Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics.

This article represents the first in a series of tutorials on model evaluation in nonlinear mixed effect models (NLMEMs), from the International Society of Pharmacometrics (ISoP) Model Evaluation Group. Numerous tools are available for evaluation of NLMEM, with a particular emphasis on visual assessment. This first basic tutorial focuses on presenting graphical evaluation tools of NLMEM for continuous data. It illustrates graphs for correct or misspecified models, discusses their pros and cons, and recalls the definition of metrics used.

Population Pharmacokinetics and Pharmacodynamics of the Calcimimetic Etelcalcetide in Chronic Kidney Disease and Secondary Hyperparathyroidism Receiving Hemodialysis.

Etelcalcetide is a novel calcimimetic in development for the treatment of secondary hyperparathyroidism (SHPT). A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed relating etelcalcetide exposures to markers of efficacy (parathyroid hormone [PTH]) and safety (calcium) using data from three clinical studies. The semimechanistic model was developed that included allosteric activation pharmacology and understanding of calcium homeostasis. The temporal profiles for all biomarkers were well described by the model. The cooperativity constant was 4.94, confirming allosteric activation mechanism. Subjects with more severe disease (higher PTH baseline) were predicted to experience less pronounced reduction in PTH (percentage change from baseline), but more reduction in calcium (Ca; percentage change from baseline). There was no evidence that dose adjustment by any covariate was needed. Model-based simulations provided quantitative support to several elements of dosing, such as starting dose, monitoring, and titration timing for registration trials.

[Stability study of oxaliplatin and doxorubicin for intraperitoneal administration with hyperthermia]. / Estudio de estabilidad de oxaliplatino y doxorrubicina para su administración intraperitoneal con hipertermia.

OBJECTIVE: To evaluate the in vitro physicochemical stability of oxaliplatin and doxorubicin when the in vivo hyperthermic intraperitoneal conditions are reproduced. METHODS: Three solutions were prepared, A (oxaliplatin 200 mg/L), B(doxorubicin 15 mg/L) and C (oxaliplatin 200 mg/L with doxorubicin 15mg/L) in glucose 5%. The three solutions were subjected to the maximum temperature reached in vivo (49° C) for two hours. Physical stability was focused on visual control of particles or precipitates in solutions, discharge of gases, odor and color. Samples were taken every 15 minutes and the chemical stability was evaluated by determining the concentration of oxaliplatin and doxorubicin remaining in the samples. Oxaliplatin concentrations were determined by atomic absorption graphite chamber while doxorubicin was determined by high performance liquid chromatography.The chemical stability criteria selected was the one described by the American Pharmacopoeia, which sets a permissible variation range between the 90-110% of the initial concentration. RESULTS: During the assay there was no appearance of particles, precipitates in the samples, discharge of gases, nor colour changes in the solutions. The samples showed a remaining concentration of oxaliplatin and doxorubicin within the 90-110% limit. The stability of the samples that follow to two cycles of freeze-thaw after hyperthermia was also found within the specified limits. CONCLUSION: A, B and c solutions in 5% glucose, are physically and chemically stable at 49° C for two hours. Under these conditions, these solutions could be used with guarantees of stability in patients with peritoneal carcinomatosis subsidiary of intraperitoneal hyperthermic chemotherapy based in these antineoplastic agents.

Objetivo: Determinar in vitro la estabilidad físico-química de oxaliplatino ydoxorrubicina en las condiciones de hipertermia utilizadas in vivo duranteel tratamiento de pacientes con carcinomatosis peritoneal, tras cirugía citorreductora.Métodos: Se prepararon tres disoluciones: A (oxaliplatino 200 mg/L), B(doxorrubicina 15 mg/L) y C (oxaliplatino 200 mg/L + doxorrubicina 15 mg/L)en glucosa al 5%. Las tres disoluciones se sometieron a la temperaturamáxima alcanzada in vivo (49º C) durante dos horas. La estabilidad física secentró en el control visual de partículas y/o precipitados en las disoluciones,el desprendimiento de gases, olor y color. Para controlar la estabilidad química,se extrajeron muestras cada 15 minutos desde el inicio del estudio yse determinó la concentración remanente de oxaliplatino y doxorrubicina enlas mismas. Las concentraciones de oxaliplatino se determinaron por absorciónatómica con cámara de grafito mientras que doxorrubicina se determinómediante cromatografía líquida de alta resolución. Como criterio deestabilidad química se seleccionó el establecido en la Farmacopea Americanaque establece un margen de variación permitido entre el 90-110% de laconcentración inicial.Resultados: Durante el tiempo de ensayo, no se observó la aparición departículas o precipitados, ni el desprendimiento de gases o cambios decolor en las disoluciones. Las muestras analizadas presentaron una concentraciónremanente de oxaliplatino y doxorrubicina dentro del límite de 90-110%. La estabilidad de las muestras sometidas a dos ciclos de congelación-descongelación tras la hipertermia también se encontró dentro de loslímites especificados.Conclusiones: Las disoluciones A, B y C en glucosa al 5%, son establesfísica y químicamente a 49º C, durante dos horas. En estas condiciones,podrían ser utilizadas con garantías de estabilidad en pacientes con carcinomatosisperitoneal subsidiarios de recibir quimioterapia intraperitonealcon hipertermia basada en estos agentes antineoplásicos.

[Influence of genetic polymorphisms in UGT1A1, UGT1A7 and UGT1A9 on the pharmacokynetics of irinotecan, SN-38 and SN-38G]. / Influencia de los polimorfismos genéticos en UGT1A1, UGT1A7 y UGT1A9 sobre la farmacocinética de irinotecán, SN-38 y SN-38G.

OBJECTIVE: To evaluate the influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on the population pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G. METHODS: Plasma concentrations of irinotecan, SN-38 and SN- 38G from 72 patients were pooled to develop a population pharmacokinetic model using NONMEM VII. M3 method was used to account for plasma concentrations below the limit quantification. The effect of age, sex, body surface area, total bilirubin, co-medication, tumor type, and UGT1A1, UGT1A7 and UGT1A9 genotypes on the model parameters was evaluated. The model was internally validated using normalized visual predictive check (NVPC) and normalized predictive distribution errors (NPDE). RESULTS: The typical values (between-subject variability; %) of the irinotecan, SN-38 and SN-38G clearances were 42,9 L/h (56,4%), 1340 L/h (76,8%) and 188 L/h (70,1%), respectively. The presence of UGT1A1*28, UGT1A7*3, UGT1A9*22 genotypes decreases SN-38 clearance between 20 and 36%. Internal validation confirms the population pharmacokinetic model describe the time course of irinotecan, SN-38 and SN-38G plasma concentration and their associated variability in cancer patients. CONCLUSION: The inclusion of pharmacokinetic-pharmacogenomic information can add value to the individualized dose adjustment of irinotecan, because it will let quantitatively handle dose reductions in patients with iatrogenic toxicity due to UGT1A1 genetic polymorphisms.

Objetivo: Evaluar la influencia de los polimorfismos genéticos en UGT1A1, UGT1A7 y UGT1A9 sobre la farmacocinética poblacional de irinotecán y sus metabolitos, SN-38 y SN-38G. Metodología: Las concentraciones plasmáticas de irinotecán, SN-38 y SN-38G determinadas en 72 pacientes se utilizaron para desarrollar un modelo farmacocinético poblacional en el programa NONMEM VII. Se empleó el método M3 para incluir en el análisis las concentraciones por debajo del límite de cuantificación de la técnica analítica. Se evaluó el efecto de la edad, sexo, superficie corporal, bilirrubina total, medicación concomitante, tipo de tumor y polimorfismos genéticos en UGT1A1, UGT1A7 y UGT1A9 sobre los parámetros farmacocineticos del modelo. La validación interna del modelo farmacocinético se realizó mediante normalized visual predictive check (NVPC) y normalized predictive distribution error (NPDE). Resultados: El valor medio (variabilidad interpaciente, %) del aclaramiento de irinotecán, SN-38 y SN-38G ha sido 42,9 (56,4%), 1340 (76,8%) y 188 L/h (70,1%), respectivamente. La presencia de alelos con baja actividad enzimática (UGT1A1*28, UGT1A7*3 y UGT1A9*22) redujo el aclaramiento de SN-38 entre un 20 y un 36%. La validación interna ha confirmado que el modelo farmacocinético poblacional resulta adecuado para describir la evolución temporal de las concentraciones plasmáticas de irinotecán, SN-38 y SN-38G y su variabilidad en pacientes oncológicos. Conclusión: La inclusión de información farmacocinética-farmacogenética puede añadir valor a la personalización de la dosificación de irinotecán por cuanto que permitirá manejar cuantitativamente las reducciones de dosis en pacientes con toxicidad iatrogénica debido a los polimorfismos genéticos en UGT1A1.

[Population pharmacokinetics applied to optimising cisplatin doses in cancer patients]. / Farmacocinética poblacional de cisplatino aplicada a la personalización de su dosificación en pacientes oncológicos.

OBJECTIVE: To develop and internally validate a population pharmacokinetics model for cisplatin and assess its prediction capacity for personalising doses in cancer patients. METHOD: Cisplatin plasma concentrations in forty-six cancer patients were used to determine the pharmacokinetic parameters of a two-compartment pharmacokinetic model implemented in NONMEN VI software. Pharmacokinetic parameter identification capacity was assessed using the parametric bootstrap method and the model was validated using the nonparametric bootstrap method and standardised visual and numerical predictive checks. The final model's prediction capacity was evaluated in terms of accuracy and precision during the first (a priori) and second (a posteriori) chemotherapy cycles. RESULTS: Mean population cisplatin clearance is 1.03 L/h with an interpatient variability of 78.0%. Estimated distribution volume at steady state was 48.3 L, with inter- and intrapatient variabilities of 31,3% and 11,7%, respectively. Internal validation confirmed that the population pharmacokinetics model is appropriate to describe changes over time in cisplatin plasma concentrations, as well as its variability in the study population. The accuracy and precision of a posteriori prediction of cisplatin concentrations improved by 21% and 54% compared to a priori prediction. CONCLUSION: The population pharmacokinetic model developed adequately described the changes in cisplatin plasma concentrations in cancer patients and can be used to optimise cisplatin dosing regimes accurately and precisely.

Romiplostim dose response in patients with immune thrombocytopenia.

A pharmacodynamic model was developed for platelet counts in 52 patients with immune thrombocytopenia (ITP) receiving subcutaneous romiplostim in 3 phase I/II studies (dose range, 0.2-10 µg/kg). The model consisted of a drug-sensitive progenitor cell compartment linked to a peripheral blood compartment through 4 transition compartments. The baseline platelet count, mean transit time, and kinetics of drug effect constant were 11.1 × 10(9)/L, 170 hours, and 0.6 day(-1), respectively. The ITP patients had a shorter platelet life span and lower progenitor cell production rates than healthy volunteers. Romiplostim response was described for 2 subpopulations. The romiplostim stimulatory effect in ITP patients was 351%/100 µg/wk and 12%/100 µg/wk in 68% and 32% of patients, respectively. Visual and numerical predictive checks suggested accurate prediction of platelet time course and durable response rate in ITP patients. Model-based simulations confirmed the effectiveness of dose reduction to prevent platelet counts >400 × 10(9)/L.

[Population pharmacokinetics of gemcitabine applied to personalize the dosage used in cancer patients]. / Farmacocinética poblacional de gemcitabina aplicada a la personalización de su dosificación en pacientes oncológicos.

OBJECTIVE: To develop and internally validate a population pharmacokinetic model for gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU); and to evaluate its predictive perfomance for personalizing the dosage used in cancer patients. METHODS: Gemcitabine and dFdU plasma concentrations were determined in 18 cancer patients. A 2-compartment pharmacokinetic model was implemented in the NONMEN VI program to determine the appropriate pharmacokinetic parameters. The power to identify the parameters was assessed by parametric bootstrap, and the internal model validation was performed using nonparametric bootstrap and visual and numerical predictive check methods. The final predictive performance of the model was assessed for accuracy and precision during the first (a priori) and second (a posteriori) chemotherapy cycles. RESULTS: The mean and interpatient variability of gemcitabine and dFdU clearance was 2.70 L/min (31.0%) and 0.0515 L/min (35.8%), respectively. The estimated distribution volume at steady state was 30 L for gemcitabine and 238 L for dFdU. Internal validation confirmed that the population pharmacokinetic model was appropriate for describing the plasma concentrations of gemcitabine and dFdU over time, as well as its variability in the study population. The accuracy and precision of a posteriori gemcitabine plasma concentrations improved by 67% and 46%, respectively, compared to the a priori prediction. CONCLUSION: The population pharmacokinetic model adequately characterised the gemcitabine and dFdU plasma concentrations in the study population over time, and can be used to accurately and precisely optimise gemcitabine dosing regimens in cancer patients.

[Populational pharmacokinetics of doxorubicin applied to personalised its dosing in cancer patients]. / Farmacocinética poblacional de doxorubicina aplicada a la personalización de su dosificación en pacientes oncológicos.

OBJECTIVE: To develop and internally validate a population pharmacokinetic model for doxorubicin and to evaluate its predictive performance for dose individualization in cancer patients. METHODS: Doxorubicin plasma concentrations were determined in thirty-three cancer patients treated with intravenous doxorubicin. A three-compartment pharmacokinetic model was implemented in the NONMEN VI programme to determine the doxorubicin pharmacokinetic parameters. The identifiability of the parameters was assessed by parametric bootstrap and model validation was performed using nonparametric bootstrap, visual predictive check, and numerical predictive check. The final model's predictive performance was evaluated in terms of accuracy and precision of plasma concentration predictions during the first and second cycles of chemotherapy. RESULTS: Doxorubicin clearance was 58.8 L/h, with interpatient variability of 29.2% and intrapatient variability of 18.9%. The estimated volume of distribution at steady state was 2294 L, with inter-and intrapatient variability of 7.3% and 26.1%, respectively. Internal validation confirmed that the population pharmacokinetic model is appropriate to describe the time course of the doxorubicin plasma concentrations and its variability in this population. The accuracy and precision of an a posteriori prediction of doxorubicin plasma concentrations improved by 63% and 41% compared to the a priori prediction. CONCLUSION: The Bayesian population pharmacokinetic model characterised the time course of doxorubicine plasma concentrations and can be accurately and precisely used to optimise doxorubicine dosing regimens in cancer patients.

Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of trabectedin (ET-743, Yondelis) induced neutropenia.

Myelosuppression was found to be one of the main toxicities of trabectedin (ET-743, Yondelis) during phase I/II studies. Our objective was to develop a pharmacokinetic-pharmacodynamic (PK/PD) model that describes the time course of the absolute neutrophil counts (ANCs) in cancer patients receiving trabectedin. Data from 699 patients who received intravenous trabectedin as monotherapy (dose range: 0.006-1.8 mg/m2) as a 1-, 3-, or 24-h infusion every 21 days; 1- or 3-h infusion on days 1, 8, and 15 every 28 days; or a 1-h infusion daily for 5 consecutive days every 21 days were used to develop (N=405; ANCs=7,291) and validate (N=294; ANCs=5,029) the model. The PK/PD model comprised a trabectedin-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments representing the maturation chain in the bone marrow. To capture the rebound effect due to endogenous growth factors, the model included a feedback mechanism. The model estimated three system-related parameters: ANC at baseline (Circ0), mean transit time in bone marrow (MTT), and a feedback parameter (gamma). A first-order process quantified by the rate constant k(e0) described the trabectedin concentrations at the effect compartment (C(e)), which were assumed to reduce the proliferation rate and/or to increase the killing rate of the progenitor cells according to the function alphaC(e)beta. The model was qualified and simulations were undertaken to evaluate the neutropenia schedule dependency and the effects of selected covariates. NONMEM software was used to perform the modeling and simulation analyses. For a typical man of 70 kg, the mean values (between-subject variability; %) of the Circ0, MTT, gamma, k(e0), alpha, and beta were estimated to be 4.46 x 10(9)/l (37.9%), 4.0 days (37.5%), 0.218 (41.8%), 2.09 h(-1) (77.9%), 2.00 l/microg (85.1%), and 1.26, respectively. Although in women, k(e0) was reduced by 29% and a 25% increase in body weight resulted in a 12.6% reduction in the beta parameter, the clinical relevance of these effects is limited. The model evaluation procedure indicated accurate prediction of the observed incidence of neutropenia grades 3 and 4 across the dosing regimens evaluated. Simulations indicated that trabectedin dose and interdose interval, but not infusion duration, are the main determinants of the neutropenia severity. The model-predicted time course of the ANC and its variability confirmed that neutropenia is reversible, of short duration, and non-cumulative. The extent and time course of neutropenia following six different dosing regimens of trabectedin were well predicted by the semiphysiological PK/PD model.

Modelling intestinal absorption of salbutamol sulphate in rats.

The objective was to develop a semiphysiological population pharmacokinetic model that describes the complex salbutamol sulphate absorption in rat small intestine. In situ techniques were used to characterize the salbutamol sulphate absorption at different concentrations (range: 0.15-18 mM). Salbutamol sulphate at concentration of 0.29 mM was administered in presence of verapamil (10 and 20 mM), grapefruit juice and sodium azide (NaN3) (0.3, 3 and 6 mM). Different pharmacokinetic models were fitted to the dataset using NONMEM. Parametric and non-parametric bootstrap analyses were employed as internal model evaluation techniques. The validated model suggested instantaneous equilibrium between salbutamol sulphate concentrations in lumen and enterocyte, and the salbutamol sulphate absorption was best described by a simultaneous passive diffusion (ka = 0.636 h(-1)) and active absorption (VMax = 0.726 mM/h, Km = 0.540 mM) processes from intestinal lumen to enterocyte, together with an active capacity-limited P-gp efflux (V'max = 0.678 mM/h, K'm = 0.357 mM) from enterocyte to intestinal lumen. The extent of salbutamol sulphate absorption in rat small intestine can be improved by NaN3, grapefruit juice and verapamil.

Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer.

PURPOSE: To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer (CRC) in a multicenter, double-blind, prospective randomized study. PATIENTS AND METHODS: Three hundred sixty-eight patients were randomly assigned to R115777 (300 mg twice daily) orally for 21 days every 28 days or placebo in a 2:1 ratio. All patients received best supportive care. The primary end point was overall survival; secondary end points were progression free survival, tumor response, toxicity, and quality of life. RESULTS: The two treatment groups were well balanced for baseline demographics, including previous chemotherapy for advanced CRC. The median overall survival for R115777 was 174 days (95% CI, 157 to 198 days), and 185 days (95% CI, 158 to 238 days) for those patients receiving placebo (P =.376). One patient achieved a partial response in the R115777 arm. Stable disease (> 3 months) was observed in 24.3% patients in the R115777 group compared to 12.8% in the placebo arm. This did not translate into a statistically significant increase in progression-free survival. Overall, treatment was well tolerated. There was an increased incidence of reversible myelosuppression (neutropenia, thrombocytopenia), rash, and grade 1 to 2 diarrhea in the R115777 arm. There was no statistically significant difference in quality of life between arms. CONCLUSION: Single agent R115777, given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.

[Cyclosporin pharmacokinetic modeling in renal transplant patients]. / Modelado farmacocinético de ciclosporina en pacientes con trasplante renal.

AIM: To characterize the pharmacokinetic behavior of oral cyclosporin (CsA) in renal transplant patient, based on through blood concentration (C0) value, and to develop and to evaluate a Bayesian method for the individualized adjustment of CsA daily dose (DD). METHODS: Sixty-seven renal allograft recipients (42 men and 25 women) who had been treated with CsA (Sandimmun Neoral) associated with mycophenolate mofetil (2g daily) and prednisone (0,5-1 mg/kg daily) were randomly divided into two groups. Group A (N=48) was used to characterize CsA pharmacokinetic behavior and Group B (N=19) to evaluate Bayesian predictive performance for the model developed. We evaluated different structural models using non linear mixed effects modeling implemented in the NONMEN computer program in order to quantify the relationship between DD and C0. Accuracy and precision were evaluated by the mean standardized prediction error and its standard deviation. RESULTS: The Michaelis-Menten model was found to be optimum for quantifying the relationship between DD and C0. This model includes time-dependent parameters such as the Michaelis-Menten constant (Km) and daily maximum dose (Dmax) as well as first order autoregressive terms DD and C0 included in the structural model in an additive way. In the final model, the Dmax parameter is affected by plasmatic urea values and shows a half-life stabilization time of 90.90 days (95% CI: 52.60 to 250 days). Plasmatic urea values of 50 mg/dL are related to an initial Dmax value of 3 mg/kg daily (95% CI: 1.81 to 4.19 mg/kg daily) which decreases exponentially throughout the post-transplant period until it reaches a constant value of 2.16 mg/kg daily (95% CI: 1.41 to 2.91 mg/kg daily) In the same way, the Km parameter presents a central tendency value of 93.60 ng/mL (95% CI: 28.60 to 158.60 ng/mL) and the half-life necessary for its stabilization is 12.70 days (95% CI: 9.80 to 17.90 days). The residual variability of the model is 8.2%. The mean value of standardized prediction errors for populations and its standard deviation, as well as its confidence intervals of 95%, confirm the appropriate accuracy and precision of both a priori and a posteriori predictions with this model. Also, it reached between 70 and 100% a posteriori sequential predictions with prediction errors below 10%. CONCLUSION: The characterization of the pharmacokinetic behavior of CsA requires us to consider parameters such as Dmax and Km as non lineal functions of time, while the first order autoregressive terms DD and C0 must also be incorporated into the model.

[Weight monitoring in parenteral nutrition]. / Control gravimétrico en la nutrición parenteral.

OBJECTIVE: To assess the usefulness of weight monitoring as a routine quality assurance method in the preparation of parenteral nutrient units (PUNs). MATERIAL AND METHODS: In accordance with their frequency of use, two parenteral nutrition formulations were chosen, one prepared externally (NP-I) and the other internally (NPH-2500). The relative difference between the experimental weight and the theoretical weight was used as the response variable. This difference, expressed as a percentage, defines the preparation gravimetric error (EGP in its Spanish acronym) Weight monitoring was effected on 615 PUNs, of which 337 (55%) corresponded to the NPH-2500 formulation and 278 (45%) to the NP-I formulation. The quality of the preparation of the PUNs was established by means of the calculation of the exactness (mean EGP) and precision (square root of the mean of the squares of the EGP values), and the alert and invalidation limits for these parameters were defined. The usefulness of weight monitoring was established by the time needed to detect a preparation gravimetric error of more than 5%. RESULTS: The overall prevalence of EGP in excess of 5% was less than 0.6% (95% CI: 0.0 to 0.6%). The overall exactness was 1.01% (95% CI: 0.96 to 1.05%). The difference between the exactness of NPH-2500, 0.66% (95% CI: 0.62 to 0.70%), and NP-I, 1.42% (95% CI: 1.36 to 1.49%), was statistically significant. The percentage of PUNs located outside the limits of invalidation for precision was significantly higher in the NPH-2500 formulation, 2.67% (95% CI: 2.36 to 3.00%), than in the NP-I formulation, 0.36% (95% CI: 0.25 to 0.49%). No statistically significant differences were detected in the remaining cases. CONCLUSION: Weight monitoring is a strategy that, possibly in combination with other methods, may complement the quality assurance processes defined to improve the preparation of parenteral nutrient units.

[Bioequivalence and therapeutic exchange of pharmaceutical specialties: application to cyclosporin in renal transplantation]. / Bioequivalencia e intercambio terapéutico de especialidades farmacéuticas: aplicación a ciclosporina en trasplante renal.

The aim of this study was to perform a quantitative meta-analysis of the average bioequivalence criteria between Sandimmun and Sandimmun Neoral in kidney transplant patients, and to review the new bioequivalence criteria and their application to generic formulation of cyclosporin. In Medline, we searched for clinical trials evaluating the bioequivalence between Sandimmun and Sandimmun Neoral in kidney transplant patients and we collected the information regarding the bioequivalence, study design, sample size, and time post-transplant. The effect was measured by the Wolf method; publication bias was evaluated by the Galbraith method and the Rosenthal formula was used to calculate the number of additional studies with no statistical differences needed to get a statistically non-significant overall estimation. We selected 6 clinical trials with a latin square design and 4 clinical trials with sequential design. The average bioequivalence criteria between Sandimmun Neoral and Sandimmun were 1.327 (90% CI: 1,311 a 1,344), 1,663 (90% CI: 1,635 a 1,692) and 0.559 hours (90% CI: 0.544 a 0.574 hours) for logharitmic transformation of area under the curve and maximum concentration, and time to maximum concentration, respectively. For these three outcomes, we found statistical differences between different study designs and for area under the curve and maximum concentration, the average bioequivalence criteria significantly fall with the post-transplant time. We conclude Sandimmun Neoral and Sandimmun are not bioequivalents and the experience reached with these two drugs is not applicable to the evaluation of generic formulations of cyclosporin.

[Parenteral nutrition and identification of subpopulations with similar nutritional needs]. / Nutrición parenteral e identificación de subpoblaciones con necesidades nutricionales similares.

The aim of this study is to identify patients subpopulations with similar caloric and proteic needs (CPN) and developing and assessing the utility of standarized formulations of total parenteral nutrition (TPN) with equivalents supplies to the average patients needs of each identified subpopulation. CPN of one hundred metabolically stables adults patients in treatment with TPN were evaluated consecutively. Caloric supplies were calculated with the Harris-Benedict equation, with the Long corrections and proteics supplies were evaluated according to stress level. The identification of patients subpopulation according to the CPN was made through the cluster analysis with partitioning around methods algorithm. We considered the formulation with equivalent supplies to the average needs of each subpopulation was adequate to the patients caloric-proteic requirements when their difference was lower than 20%. The percentage of patients who received adequate supplies were compared between the subpopulations identified. In case of two subpopulations, glucose, lipids and amino acid needs are: 275 (CI 95%: 265-285) g, 83 (CI 95%: 78-88) g and 89 (CI 95%: 86-92) g in subpopulation 1 (N = 35), and 195 (CI 95%: 187-203) g, 58 (CI 95%: 56-61) g and 74 (CI 95%: 72-77) g in subpopulation 2 (N = 65), respectively. In case of three subpopulations, in subpopulation 1 (N = 19), glucose, lipids and amino acid needs are: 295 (CI 95%: 283-306) g, 91 (CI 95%: 84-97) g and 91 (CI 95%: 86-95); 234 (CI 95%: 227-240) g, 67 (CI 95%: 64-70) g and 84 (CI 95%: 82-86) g to the subpopulation 2 (N = 45) and 172 (CI 95%: 165-179) g, 55 (CI 95%: 52-57) g, and 68 (CI 95%: 64-71) g to the subpopulation 3 (N = 36) respectively. In general, caloric and proteic supplies are equal to the patients needs, but there was a tendeny to overfeeding in patients with lower CPN. The utilization of one, two or three formulations with equivalent supplies to the average needs of each subpopulation was adequate to the patients in the 45% (CI 95%: 36%-55%), 75% (CI 95%: 65%-83%) and 82% (CI 95%: 74%-89%), respectively. Therefore, the development of three normalized formulations of total parenteral nutrition allows to satisfy the patients nutritional needs at least the 74% of the patients.

[Risk factors associated with survival in patients in a peritoneal dialysis program]. / Factores de riesgo asociados con la supervivencia en pacientes en programa de diálisis peritoneal.

The aim of this study was to quantify the effect of different mortality risk factors in peritoneal dialysis and to establish a prognostic index that could predict mortality risk when patients start dialysis. A prospective study was performed on 103 patients included in our peritoneal dialysis program. The mean follow-up time was 26 +/- 21 months. A multivariate analysis (Cox regression was made to identify different risk factors that could influence patient survival during peritoneal dialysis. Age, gender, parathyroid hormone, albumin, cholesterol, and the presence of diabetes mellitus were evaluated as potential risk factors. Patients were distributed in three groups (high, medium and low risk), according to the risk factors with a significant influence in multivariate analysis, and patient survival was studied depending on the prognostic index using Kaplan-Meier estimator. Overall patient survival was 90% (95%CI: 83 to 96%) after the first year and 40% (95%IC: 32 to 58%) after 5 years of follow-up. The Cox regression analysis identified albumin below 4 g/dL (RR: 2.57; 95% CI: 1.16 to 5.72), age older than 65 years RR: 3.10; 95%IC: 1.20 to 7.98) and diabetes mellitus (relative risk, RR: 4.36; 95%IC: 1.43 to 13.31) as independent risk factors for mortality in patients receiving peritoneal dialysis. Patient survival after two years was 40% (95%IC: 31 to 59%), 73% (95%IC: 60 a 86%) and 100% (p < 0.05), respectively. Malnutrition and related factors in patients receiving peritoneal dialysis are associated with a higher mortality rate.