Evaluation of limited-sampling strategies to calculate AUC(0-24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimus.

Background: Kidney transplantation (KTx) requires immunosuppressive drugs such as Tacrolimus (TAC) which is mainly metabolized by CYP3A5. TAC is routinely monitored by trough levels (C0) although it has not shown to be a reliable marker. The area-under-curve (AUC) is a more realistic measure of drug exposure, but sampling is challenging in pediatric patients. Limited-sampling strategies (LSS) have been developed to estimate AUC. Herein, we aimed to determine AUC(0-24) and CYP3A5 genotype in Chilean pediatric kidney recipients using extended-release TAC, to evaluate different LSS-AUC(0-24) formulas and dose requirements. Patients and methods: We analyzed pediatric kidney recipients using different extended-release TAC brands to determine their trapezoidal AUC(0-24) and CYP3A5 genotypes (SNP rs776746). Daily TAC dose (TAC-D mg/kg) and AUC(0-24) normalized by dose were compared between CYP3A5 expressors (*1/*1 and *1/*3) and non-expressors (*3/*3). We evaluated the single and combined time-points to identify the best LSS-AUC(0-24) model. We compared the performance of this model with two pediatric LSS-AUC(0-24) equations for clinical validation. Results: Fifty-one pharmacokinetic profiles were obtained from kidney recipients (age 13.1 ± 2.9 years). When normalizing AUC(0-24) by TAC-D significant differences were found between CYP3A5 expressors and non-expressors (1701.9 vs. 2718.1 ng*h/mL/mg/kg, p < 0.05). C0 had a poor fit with AUC(0-24) (r 2 = 0.5011). The model which included C0, C1 and C4, showed the best performance to predict LSS-AUC(0-24) (r 2 = 0.8765) and yielded the lowest precision error (7.1% ± 6.4%) with the lowest fraction (9.8%) of deviated AUC(0-24), in comparison to other LSS equations. Conclusion: Estimation of LSS-AUC(0-24) with 3 time-points is an advisable and clinically useful option for pediatric kidney recipients using extended-release TAC to provide better guidance of decisions if toxicity or drug inefficacy is suspected. The different CYP3A5 genotypes associated with variable dose requirements reinforce considering genotyping before KTx. Further multi-centric studies with admixed cohorts are needed to determine the short- and long-term clinical benefits.

Limnological and ecological methods: approaches, and sampling strategies for middle Xingu River in the area of influence of future Belo Monte Power Plant / Estudo limnológico e da biota aquática no Rio Xingu na área de influência de UHE Belo Monte: metodologia e abordagens

In this paper the authors describe the limnological approaches, the sampling methodology, and strategy adopted in the study of the Xingu River in the area of influence of future Belo Monte Power Plant. The river ecosystems are characterized by unidirectional current, highly variable in time depending on the climatic situation the drainage pattern an hydrological cycle. Continuous vertical mixing with currents and turbulence, are characteristic of these ecosystems. All these basic mechanisms were taken into consideration in the sampling strategy and field work carried out in the Xingu River Basin, upstream and downstream the future Belo Monte Power Plant Units.(AU)

Neste trabalho os autores descrevem as abordagens limnológicas e a metodologia e estratégia de amostragem adotadas no estudo do Rio Xingu, na área de influência da futura Usina da Belo Monte (UHE Belo Monte). O ecossistema de rios é caracterizado por velocidade unidirecional de correntes, muitas flutuações de fluxos dependendo do clima do padrão de drenagem e do ciclo hidrológico. Mistura vertical permanente e turbulências ocorrem constantemente devido a correntes predominantes. Todos estes mecanismos gerais e específicos característicos do Rio Xingu, foram levados em consideração no plano de estudos limnológicos e amostragens desenvolvidas na área de influência de UHE Belo Monte a montante e a jusante do futuro empreendimento.(AU)

Limnological and ecological methods: approaches, and sampling strategies for middle Xingu River in the area of influence of future Belo Monte Power Plant

Abstract In this paper the authors describe the limnological approaches, the sampling methodology, and strategy adopted in the study of the Xingu River in the area of influence of future Belo Monte Power Plant. The river ecosystems are characterized by unidirectional current, highly variable in time depending on the climatic situation the drainage pattern an hydrological cycle. Continuous vertical mixing with currents and turbulence, are characteristic of these ecosystems. All these basic mechanisms were taken into consideration in the sampling strategy and field work carried out in the Xingu River Basin, upstream and downstream the future Belo Monte Power Plant Units.

Resumo Neste trabalho os autores descrevem as abordagens limnológicas e a metodologia e estratégia de amostragem adotadas no estudo do Rio Xingu, na área de influência da futura Usina da Belo Monte (UHE Belo Monte). O ecossistema de rios é caracterizado por velocidade unidirecional de correntes, muitas flutuações de fluxos dependendo do clima do padrão de drenagem e do ciclo hidrológico. Mistura vertical permanente e turbulências ocorrem constantemente devido a correntes predominantes. Todos estes mecanismos gerais e específicos característicos do Rio Xingu, foram levados em consideração no plano de estudos limnológicos e amostragens desenvolvidas na área de influência de UHE Belo Monte a montante e a jusante do futuro empreendimento.

Limnological and ecological methods: approaches, and sampling strategies for middle Xingu River in the area of influence of future Belo Monte Power Plant / Estudo limnológico e da biota aquática no Rio Xingu na área de influência de UHE Belo Monte: metodologia e abordagens

In this paper the authors describe the limnological approaches, the sampling methodology, and strategy adopted in the study of the Xingu River in the area of influence of future Belo Monte Power Plant. The river ecosystems are characterized by unidirectional current, highly variable in time depending on the climatic situation the drainage pattern an hydrological cycle. Continuous vertical mixing with currents and turbulence, are characteristic of these ecosystems. All these basic mechanisms were taken into consideration in the sampling strategy and field work carried out in the Xingu River Basin, upstream and downstream the future Belo Monte Power Plant Units.

Neste trabalho os autores descrevem as abordagens limnológicas e a metodologia e estratégia de amostragem adotadas no estudo do Rio Xingu, na área de influência da futura Usina da Belo Monte (UHE Belo Monte). O ecossistema de rios é caracterizado por velocidade unidirecional de correntes, muitas flutuações de fluxos dependendo do clima do padrão de drenagem e do ciclo hidrológico. Mistura vertical permanente e turbulências ocorrem constantemente devido a correntes predominantes. Todos estes mecanismos gerais e específicos característicos do Rio Xingu, foram levados em consideração no plano de estudos limnológicos e amostragens desenvolvidas na área de influência de UHE Belo Monte a montante e a jusante do futuro empreendimento.

Limnological and ecological methods: approaches, and sampling strategies for middle Xingu River in the area of influence of future Belo Monte Power Plant / Estudo limnológico e da biota aquática no Rio Xingu na área de influência de UHE Belo Monte: metodologia e abordagens

Abstract In this paper the authors describe the limnological approaches, the sampling methodology, and strategy adopted in the study of the Xingu River in the area of influence of future Belo Monte Power Plant. The river ecosystems are characterized by unidirectional current, highly variable in time depending on the climatic situation the drainage pattern an hydrological cycle. Continuous vertical mixing with currents and turbulence, are characteristic of these ecosystems. All these basic mechanisms were taken into consideration in the sampling strategy and field work carried out in the Xingu River Basin, upstream and downstream the future Belo Monte Power Plant Units.

Resumo Neste trabalho os autores descrevem as abordagens limnológicas e a metodologia e estratégia de amostragem adotadas no estudo do Rio Xingu, na área de influência da futura Usina da Belo Monte (UHE Belo Monte). O ecossistema de rios é caracterizado por velocidade unidirecional de correntes, muitas flutuações de fluxos dependendo do clima do padrão de drenagem e do ciclo hidrológico. Mistura vertical permanente e turbulências ocorrem constantemente devido a correntes predominantes. Todos estes mecanismos gerais e específicos característicos do Rio Xingu, foram levados em consideração no plano de estudos limnológicos e amostragens desenvolvidas na área de influência de UHE Belo Monte a montante e a jusante do futuro empreendimento.