Total Parenteral Nutrition in Middle Eastern Cancer Patients at End of Life: Is it Justified?

PURPOSE: The use of total parenteral nutrition (TPN) in terminally ill cancer patients is considered an aggressive approach with very limited benefits. We examined the practice of TPN in our end of life cancer patients and we investigated the patient and tumor characteristics that justify this practice. To our knowledge, this is the first study describing TPN administration of Middle Eastern patients with advanced cancer. METHODS: We conducted this retrospective observational study at Hotel-Dieu de France University Hospital, Lebanon. Eligible cases included all cancer patients that died at our institution between the 1st of January and the 31st of December 2014. The patients and tumors characteristics were analyzed for their potential role as determinant of TPN administration. The patients' hospitalization and causes of death were evaluated for the analysis of TPN benefits. RESULTS: Among the 129 patients enrolled, 39% had received TPN among which TPN administration correlated negatively to hyperlipidemia (OR= 0.33; 95% CI [0.12-0.87]) and to the presence of at least three cardiovascular risk factors (OR= 0.28; 95% CI [0.10 - 0.80]). However, it correlated positively to gastrointestinal tumors (OR= 3.9; 95% CI [1.3- 11.7]) and to imaging studies during the last month of life (OR= 3.4; 95% CI [1.3 - 9.0]). The TPN administration did not correlate to hospitalization during the last two weeks of life. CONCLUSION: The adoption of an optimal palliative care approach in Middle Eastern cancer patients at the end of life remains challenging. Oncologists seem to consider cardiovascular risk factors as a probable surrogate to predict complications of TPN.

The Therapeutic use of human albumin in cancer patients' management.

Human albumin (HA) has been widely used in clinical practice due to its unique physiological characteristics and pharmacokinetics. However, with the absence of clear institutional recommendations, its uncontrolled prescription remains largely controversial. An extensive review on the albumin chemistry, pharmacology, physiology and pathology was performed, and data on commercially available HA, its cost, medical usage and the related available guidelines, particularly in oncology patients were gathered. Studies assessing the appropriate use and safety of HA in cancer patients are lacking. A retrospective survey of the appropriateness of HA infusions according to the SIMTI guidelines (2009) was performed in our department. Among 53 patients who received HA infusions, only 5.7% of the indications were appropriate for HA administration. Occasionally appropriate and inappropriate indications were considered in 10% and 84.3% of the prescriptions respectively with a relatively high cost. The adoption of strict guidelines may substantially reduce the inappropriate use and the subsequent healthcare costs.

Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is the leading infectious cause of birth defects, mental retardation and non-genetic sensorineural hearing loss. Murine models have been developed in order to understand the pathophysiological mechanisms underlying these lesions. These models are being proposed for the validation of therapeutic protocols for clinical use. The aim of this preclinical study was to assess the pharmacokinetics of the reference antiviral molecule, ganciclovir, in order to optimize these protocols and confirm the diffusion of the molecule to the appropriate target zones. METHODS: Transplacental and intracochlear diffusion of ganciclovir was evaluated in mice and rats. Pharmacokinetics was assessed in adult mice and pups after 5 consecutive days of intraperitoneal injection of ganciclovir. The occurrence of hematological side effects of ganciclovir was evaluated in the different blood cell lineages. RESULTS: In adult rats, the intracochlear diffusion of ganciclovir was shown to achieve the same concentration as in blood. In gestating mice, transplacental diffusion was observed, with a fetal-to-maternal blood ratio of 0.5. In newborn mice, the plasma concentration profile of ganciclovir showed a peak at 2 h followed by a gradual decrease. In adult mice, the concentration peaked at 1 h, but became undetectable by 2 h after injection. Counts of white blood cells, red blood cells and platelets decreased significantly in ganciclovir-treated newborn mice. CONCLUSION: Our data provide evidence for the intracochlear diffusion of the molecule, which may be relevant for the treatment of sensorineural hearing loss in congenitally-infected children.

Population pharmacokinetics and dosing optimization of vancomycin in children with malignant hematological disease.

An increase in vancomycin dose has been proposed in adults with malignant hematological disease. As pediatric data are limited, our aim was to evaluate the population pharmacokinetics of vancomycin in order to define the appropriate dosing regimen in children with malignant hematological disease. Vancomycin concentrations were collected prospectively during therapeutic monitoring. Population pharmacokinetic analysis was performed using NONMEM software. Seventy children (age range, 0.3 to 17.7 years) were included. With the current recommended dosing regimen of 40 to 60 mg/kg/day, 53 children (76%) had subtherapeutic steady-state trough concentrations (Css/min of <10 mg/liter). A one-compartment model with first-order elimination was developed. Systematic covariate analysis identified that weight significantly influenced clearance (CL) and volume of distribution (V) with power functions of 0.677 for CL and 0.838 for V. Vancomycin CL also significantly increased with increases in creatinine clearance and seemed to be higher in children with malignant hematological disease than in the general pediatric population. The model was validated internally. Its predictive performance was further confirmed in an external validation by Bayesian estimation. A patient-tailored dosing regimen was developed based on the final pharmacokinetic model and showed that a higher proportion of patients reached the target Css/min than with the traditional mg/kg-basis dose (60% versus 49%) and that the risks associated with underdosing or overdosing were reduced. This is the first population pharmacokinetic study of vancomycin in children with malignant hematological disease. An optimized dosing regimen, taking into account patient weight, creatinine clearance, and susceptibility of the pathogens involved, could routinely be used to individualize vancomycin therapy in this vulnerable population.

External Evaluation of Population Pharmacokinetic Models of Vancomycin in Neonates: The transferability of published models to different clinical settings.

BACKGROUND: Vancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings. METHOD: Published neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of 6 models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics (visual predictive check [VPC] and normalized prediction distribution errors [NPDE]). RESULTS: Differences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for 6 evaluated models were 1.35, -0.22, -0.36, 0.24, 0.66, 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still need to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin. CONCLUSION: The importance of analytical techniques for serum creatinine concentrations and vancomycin as a predictor of vancomycin concentrations in neonates has been confirmed. Dosage individualisation of vancomycin in neonates should consider not only patients' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin.

Vancomycin continuous infusion in neonates: dosing optimisation and therapeutic drug monitoring.

OBJECTIVE: Because pharmacokinetic data are limited, continuous infusions of vancomycin in neonates are administered using different dosing regimens. The aim of this work was to evaluate the results of vancomycin therapeutic drug monitoring (TDM) under three different dosing regimens and to optimise vancomycin therapy. METHODS: Vancomycin TDM concentrations were noted and compared prospectively in three hospitals. Population pharmacokinetic analysis was performed to optimise dosing using NONMEM software. Patient-tailored optimised dosing regimens were evaluated in a prospective study. RESULTS: Two hundred and seven serum vancomycin concentrations from 116 neonates were analysed. Only 48 neonates (41%) had serum vancomycin concentrations within the therapeutic range of 15-25 mg/l using a current dosing regimen. Concentrations ranged from 5.1 to 61.5 mg/l. Loading doses were required to decrease the risk of sub-therapeutic levels during early treatment. An optimised dosing regimen, taking into account birth weight, current weight, postnatal age and serum creatinine, was developed based on a one-compartment pharmacokinetic model. A prospective validation study in 58 neonates demonstrated a higher percentage of neonates (70.7%, n=41) reaching the therapeutic range and early dosage adaptation (6-12 h post-dose) using an optimised dosing regimen. CONCLUSIONS: A patient-tailored optimised dosing regimen should be used routinely to individualise vancomycin continuous infusion therapy in neonates.

Limited sampling strategy using Bayesian estimation for estimating individual exposure of the once-daily prolonged-release formulation of tacrolimus in kidney transplant children.

BACKGROUND: A limited sampling strategy (LSS) for estimating the area under the curve (AUC) of the prolonged-release formulation of tacrolimus (tacrolimus(PR)) is not available in pediatric patients, although the method is of real benefit to children. The objective of this study was to develop and validate a reliable and clinically applicable LSS using Bayesian estimation for estimating tacrolimus(PR) AUC in pediatric kidney transplant patients METHODS: The original tacrolimus pharmacokinetic dataset consisted of 22 full profiles from 22 pediatric kidney transplant patients. The Bayesian estimation method was used to develop the LSS. External validation was performed in an independent validation group which consisted of 20 full pharmacokinetic profiles from 12 pediatric kidney transplant patients. RESULTS: Bayesian estimator using C0h C2h and C3h gave the best predictive performance with a mean prediction error of 2.2 % in the external validation dataset. There was no correlation between the prediction error and age. The Bland-Altman analysis showed that the mean difference between the reference and Bayesian-estimated AUC0-24 was 3.5 (95 % confidence interval -3.5-10.5) ng h/mL CONCLUSIONS: A reliable and clinically applicable LSS for estimating AUC0-24 of tacrolimus(PR) was determined and validated in children. The prediction was unbiased and precise. It can be used as a routine procedure to perform AUC-based tacrolimus(PR) dosage optimization in pediatric renal transplant patients.

Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients.

BACKGROUND AND OBJECTIVES: Tacrolimus(PR) is a new prolonged-release once-daily formulation of the calcineurin inhibitor tacrolimus, currently used in adult transplant patients. As there are no pharmacokinetic data available in pediatric kidney transplant recipients, the aims of this study were to develop a population pharmacokinetic model of tacrolimus(PR) in pediatric and adolescent kidney transplant recipients and to identify covariates that have a significant impacts on tacrolimus(PR) pharmacokinetics, including CYP3A5 polymorphism. METHODS: Pharmacokinetic samples were collected from 22 pediatric kidney transplant patients. Population pharmacokinetic analysis was performed using NONMEM. Pharmacogenetic analysis was performed on the CYP3A5 gene. RESULTS: The pharmacokinetic data were best described by a one-compartment model with first order absorption and lag-time. The weight normalized oral clearance CL/F [CL/F/ (weight/70)(0.75)] was lower in patients with CYP3A5 3/3 as compared to patients with the CYP3A5 1/3 (32.2 ± 10.1 vs. 53.5 ± 20.2 L/h, p = 0.01). CONCLUSIONS: The population pharmacokinetic model of tacrolimus(PR) was developed and validated in pediatric and adolescent kidney transplant patients. Body weight and CYP3A5 polymorphism were identified as significant factors influencing pharmacokinetics. The developed model could be useful to optimize individual pediatric tacrolimus (PR) dosing regimen in routine clinical practice.

Pharmacogenetic determinant of the drug interaction between tacrolimus and omeprazole.

A 17-year-old adolescent with acute nephrotoxicity had CYP3A4-5, CYP2C19, and ABCB1 genotyping performed to understand a suspected drug interaction between tacrolimus and omeprazole. The determinant role of individual pharmacogenetic profile in the occurrence of tacrolimus nephrotoxicity is presented and discussed.

Individualization of valganciclovir prophylaxis for cytomegalovirus infection in pediatric kidney transplant patients.

BACKGROUND: Valganciclovir is used for the prophylaxis of cytomegalovirus infection in pediatric solid transplant patients. The current pediatric dose regimen resulted in large variability in drug exposure. A posterior dosage adaptation was required in children to achieve the daily target area under the curve (AUC) of 40-50 µg·h·mL(-1). However, a clinically feasible tool for valganciclovir dosage adjustment based on individual AUC is not available. The objective of this study was to develop and validate a reliable and clinically applicable limited sampling strategy using Bayesian estimation for individualizing valganciclovir dose in pediatric kidney transplant patients. METHODS: The Bayesian estimator to calculate ganciclovir AUC was developed using the original pharmacokinetic dataset consisting of 28 full profiles from 22 pediatric kidney transplant patients. External validation was prospectively performed in an independent validation group consisting of 14 full pharmacokinetic profiles from 14 pediatric kidney transplant patients. RESULTS: The Bayesian estimator of exposure using T0-T2-T4 gave the best predictive performance. The mean prediction error was of 3.1% and Bland-Altman analysis shows that the average difference between referenced and estimated AUCs was 0.4 µg·h·mL(-1). CONCLUSION: Valganciclovir dosage adaptation was required in children to achieve target AUC. The Bayesian estimator of valganciclovir, using 3 concentrations measured at T0-T2-T4 after drug intake, was validated and could be used to accurately estimate individual AUC. This approach will be useful for individualizing valganciclovir prophylaxis in pediatric kidney transplant patients.

Physiopathology of idiopathic nephrotic syndrome: lessons from glucocorticoids and epigenetic perspectives.

Idiopathic nephrotic syndrome (INS) has been studied for decades in attempt to understand the physiopathological mechanisms explaining the disease. It is recognized as a multifactorial disease, with immunological components targeting kidney functions. Many hypotheses have been discussed or tested, including the role of a circulating factor, polymorphisms of genes implicated in lymphocyte maturation and differentiation, and DNA epigenetic modifications. In the present review, the data supporting these different (and probably combinatorial) hypotheses have been reviewed in order to identify and discuss the possible pathways implicated in the physiopathology of INS.

Limited sampling strategy for estimating individual exposure of tacrolimus in pediatric kidney transplant patients.

BACKGROUND: Limited sampling strategies (LSS) for estimating the area under the curve (AUC(0-12h)) of tacrolimus and optimizing dosage adjustment are not currently used or fully validated in pediatric patients, although the method is of real benefit to children. The objective of the present study was to develop and validate reliable and clinically applicable LSS using Bayesian estimation and the multiple regression analysis for estimating tacrolimus AUC in pediatric kidney transplant patients. METHODS: The original tacrolimus pharmacokinetic dataset consists of 50 full profiles from 50 pediatric kidney transplant patients. Two LSS based on Bayesian estimator or multiple regression analysis to calculate tacrolimus AUC were developed and then compared. External validation was prospectively performed in an independent validation group, which consisted of 42 full pharmacokinetic profiles from 20 pediatric kidney transplant patients. RESULTS: Bayesian estimators using C(0h), C(1h) or C(2h), and C(3h) gave the best predictive performance, the external validation having a mean prediction bias of 1% and mean imprecision of 5.5%. The multiple regression analysis using C(0h), C(1h), and C(3h) gave the best correlation (r² = 0.953) between estimated and referenced AUCs with a mean prediction bias of 4.2% and mean precision of 8.3% in external validation dataset. CONCLUSIONS: The prediction of AUC using developed LSS was unbiased and precise. The age and time after transplantation did not influence the predictive performance. Such LSS approach will help guiding tacrolimus therapeutic drug monitoring based on AUC in pediatric kidney transplant patients.

Pharmacogenetics and individualized therapy in children: immunosuppressants, antidepressants, anticancer and anti-inflammatory drugs.

Pharmacogenetic polymorphisms that change the amino acid sequences in coding regions only account for part of the interindividual differences in disease susceptibility and drug response. Additional pharmacogenomic and epigenetic factors are also involved. In children, pharmacogenetic studies are limited, although it has been clear for many years that the interactions between developmental patterns of drug-metabolizing enzymes and transporters have a major impact on dose exposure with age-specific dosage requirements. This article will analyze the factors affecting variability in drug response in children and focus on the pharmacogenetic polymorphisms of immunosuppressants, antidepressants, anticancer and anti-inflammatory drugs. Additional pharmacogenetic and epigenetic studies should be performed to allow the individualization of therapy in children.

Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy.

AIMS: 6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) on 6-MP metabolism and response. METHODS: Sixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2+21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis. RESULTS: During maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 × 10(8) RBC) than in older children (600 pmol/8 × 10(8) RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862 pmol/8 × 10(8) RBC), intermediate in wild-type patients and high (16468 pmol/8 × 10(8) RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000 pmol/8 × 10(8) RBC was associated with an increased risk of hepatotoxicity. CONCLUSION: In this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children.

Determination of ciprofloxacin in plasma by micro-liquid chromatography-mass spectrometry: an adapted method for neonates.

There are many limitations to conducting pharmacokinetic studies in neonates, both ethical and technical. Regarding technical aspects, the number and volume of samples are limited, and the analytical method to measure drug concentration should be both specific and highly sensitive. In the present report, an analytical method adapted to neonates was developed for the determination of ciprofloxacin plasma concentration. After a simple protein precipitation, analytes were separated on a micro-liquid chromatography and quantified by mass spectrometry, with D8-ciprofloxacin as internal standard. The calibration range was linear from 25 to 3000 ng/mL. Intra- and inter-day precision was less than 2.4 and 4.1%, respectively. The acceptance criteria of accuracy (between 85 and 115%) were met in all cases. A plasma volume of 150 µL was required to achieve the limit of quantification of 25 ng/mL. The method was successfully applied to routine monitoring of ciprofloxacin in pediatric patients and also used in preclinical studies. It will be used to determine the population pharmacokinetic parameters of ciprofloxacin in neonates.

Developmental pharmacogenetics of immunosuppressants in pediatric organ transplantation.

Cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil are the primary immunosuppressants used on pediatric organ transplantation. Therapeutic drug monitoring is used in daily practice, because their clinical use is hampered by a narrow therapeutic index and large variability. Tailoring immunosuppressive therapy to the individual patient to optimize efficacy and minimize toxicity is therefore essential. Because research in pharmacogenetics already identified polymorphisms impacting their pharmacokinetic parameters in adults, developmental pharmacogenetics of immunosuppressants holds promises for optimizing dosage regimens and improving clinical outcome in children. In this review, we focus on the impact of age and pharmacogenetics on these immunosuppressants in children undergoing organ transplantation.

[Therapeutic drug monitoring of 6-thioguanine nucleotides in paediatric acute lymphoblastic leukaemia: interest and limits]. / Suivi thérapeutique pharmacologique des 6-thioguanine nucléotides dans les leucémies aigues lymphoblastiques de l'enfant: intérêt et limites.

6-mercaptopurine, a key drug for the treatment of acute lymphoblastic leukaemia in children, is a prodrug metabolized into 6-thioguanine (6-TGN) which are the active compounds and into methylated metabolites, primary by thiopurine S-methyltransferase enzyme (TPMT). This enzyme displays important inter subject variability linked to a genetic polymorphism: when treated with standard doses of thiopurine, TPMT-deficient and heterozygous patients are at great risk for developing severe and potentially life-threatening toxicity (hematopoietic, hepatic, mucositis...) but show a better survival rate while patients with high TPMT activity (wild type) present lower peripheral red blood cells 6-TGN concentrations and a higher risk of leukemia relapse. Genotyping remains crucial before 6-MP administration at diagnosis to identify patients with homozygous mutant TPMT genotype and therefore prevent severe and life-threatening toxicity, and to individualize therapy according to TMPT genotype. Follow-up of ALL treatment should preferentially be based on repeated determinations of intracellular active metabolites (6-thioguanine nucleotides) and methylated metabolites in addition to haematological surveillance.

Population pharmacokinetics and pharmacogenetics of mycophenolic acid following administration of mycophenolate mofetil in de novo pediatric renal-transplant patients.

The objective was to develop a population pharmacokinetic-pharmacogenetic model of mycophenolic acid following administration of mycophenolate mofetil (MMF) in de novo pediatric renal-transplant patients and identify factors that explain variability. The pharmacokinetic samples were collected from 89 de novo pediatric renal-transplant patients treated with MMF and studied during the first 60 postoperative days. All patients were genotyped for UGT1A8-A9, UGT2B7, and ABCC2. Population pharmacokinetic analysis was performed with the NONMEM and was validated using bootstrap visual predictive check. The pharmacokinetic data were best described by a 2-compartment model with Erlang distribution to describe the absorption phase. The covariate analysis identified body weight as an individual factor influencing central volume of distribution and concomitant immunosuppressive medication and identified body weight and UGT2B7 802C>T genotype as individual factors influencing apparent oral clearance (CL/F) of MMF. CL/F in cyclosporine-MMF-treated patients was 33% higher than in tacrolimus-MMF-treated patients. The CL/F was significantly lower in patients with UGT2B7 802 C/C genotype compared with patients with UGT2B7 802 C/T and 802T/T genotypes, and this effect was independent of concomitant immunosuppressive medication or body weight. The population pharmacokinetic-pharmacogenetic model of mycophenolic acid was validated. Body weight, concomitant medication, and UGT2B7 genotype contribute significantly to the interindividual variability of MMF disposition in pediatric renal-transplant patients.