Building the health-economic case for scaling up the WHO-HEARTS hypertension control package in low- and middle-income countries.

Generally, hypertension control programs are cost-effective, including in low- and middle-income countries, but country governments and civil society are not likely to support hypertension control programs unless value is demonstrated in terms of public health benefits, budget impact, and value-for-investment for the individual country context. The World Health Organization (WHO) and the Pan American Health Organization (PAHO) established a standard, simplified Global HEARTS approach to hypertension control, including preferred antihypertensive medicines and blood pressure measurement devices. The objective of this study is to report on health economic studies of HEARTS hypertension control package cost (especially medication costs), cost-effectiveness, and budget impact and describe mathematical models designed to translate hypertension control program data into the optimal approach to hypertension care service delivery and financing, especially in low- and middle-income countries. Early results suggest that HEARTS hypertension control interventions are either cost-saving or cost-effective, that the HEARTS package is affordable at between US$ 18-44 per person treated per year, and that antihypertensive medicines could be priced low enough to reach a global standard of an average

En general, los programas de control de la hipertensión son costo-eficaces, incluso en los países de ingresos bajos y medios. Aun así, es poco probable que los gobiernos nacionales y la sociedad civil apoyen los programas de control de la hipertensión a menos que se demuestre su valor en términos de beneficios para la salud pública, impacto presupuestario y valor de la inversión para el contexto individual del país. La Organización Mundial de la Salud (OMS) y la Organización Panamericana de la Salud (OPS) implementaron la iniciativa HEARTS, un enfoque mundial estandarizado y simplificado para el control de la hipertensión, que incluye los medicamentos antihipertensivos y los dispositivos de medición de la presión arterial de preferencia. El objetivo de este estudio es informar sobre los estudios en el ámbito de la economía de la salud relativos al costo de las medidas de control de la hipertensión previstas en HEARTS (especialmente, de los medicamentos), la costo-efectividad y el impacto presupuestario, así como describir los modelos matemáticos diseñados para traducir los datos de este programa en un enfoque óptimo para la prestación y el financiamiento de los servicios de atención de la hipertensión, especialmente en países de ingresos medianos y bajos. Los primeros resultados indican que las intervenciones de HEARTS para el control de la hipertensión son de bajo costo o costo-eficaces, que el conjunto de medidas HEARTS es asequible, a un precio que oscila entre US$ 18 y US$ 44 al año por paciente tratado, y que los medicamentos antihipertensivos podrían tener un precio lo suficientemente bajo como para alcanzar un estándar medio mundial de

Geralmente, os programas de controle de hipertensão são custo-efetivos, inclusive em países de baixa e média renda, mas os governos dos países e a sociedade civil provavelmente não apoiarão tais programas a menos que demonstrem valor em termos de benefícios à saúde pública, impacto orçamentário e retorno sobre o investimento no contexto individual do país. A Organização Mundial da Saúde (OMS) e a Organização Pan-Americana da Saúde (OPAS) criaram a Global HEARTS, uma abordagem padrão e simplificada ao controle da hipertensão arterial, que inclui medicamentos anti-hipertensivos preferidos e dispositivos para aferição da pressão arterial preferidos. O objetivo deste estudo é relatar os estudos de economia em saúde que analisaram o custo (especialmente custos de medicamentos), custo-benefício e impacto orçamentário do pacote HEARTS para controle da hipertensão e descrever modelos matemáticos elaborados para traduzir os dados do programa de controle de hipertensão em uma abordagem ideal para a prestação e financiamento de serviços de atenção às pessoas com hipertensão, especialmente em países de baixa e média renda. Os primeiros resultados sugerem que as intervenções HEARTS para controle da hipertensão são de baixo custo ou custo-efetivas, que o pacote HEARTS é acessível (custando de US$ 18 a 44 por pessoa tratada por ano) e que o preço dos medicamentos anti-hipertensivos poderia ser baixo o suficiente para atingir uma média global de

CYP2C19 and 3A4 Dominate Metabolic Clearance and Bioactivation of Terbinafine Based on Computational and Experimental Approaches.

Lamisil (terbinafine) is an effective, widely prescribed antifungal drug that causes rare idiosyncratic hepatotoxicity. The proposed toxic mechanism involves a reactive metabolite, 6,6-dimethyl-2-hepten-4-ynal (TBF-A), formed through three N-dealkylation pathways. We were the first to characterize them using in vitro studies with human liver microsomes and modeling approaches, yet knowledge of the individual enzymes catalyzing reactions remained unknown. Herein, we employed experimental and computational tools to assess terbinafine metabolism by specific cytochrome P450 isozymes. In vitro inhibitor phenotyping studies revealed six isozymes were involved in one or more N-dealkylation pathways. CYP2C19 and 3A4 contributed to all pathways, and so, we targeted them for steady-state analyses with recombinant isozymes. N-Dealkylation yielding TBF-A directly was catalyzed by CYP2C19 and 3A4 similarly. Nevertheless, CYP2C19 was more efficient than CYP3A4 at N-demethylation and other steps leading to TBF-A. Unlike microsomal reactions, N-denaphthylation was surprisingly efficient for CYP2C19 and 3A4, which was validated by controls. CYP2C19 was the most efficient among all reactions. Nonetheless, CYP3A4 was more selective at steps leading to TBF-A, making it more effective in terbinafine bioactivation based on metabolic split ratios for competing pathways. Model predictions did not extrapolate to quantitative kinetic constants, yet some results for CYP3A4 and CYP2C19 agreed qualitatively with preferred reaction steps and pathways. Clinical data on drug interactions support the CYP3A4 role in terbinafine metabolism, while CYP2C19 remains understudied. Taken together, knowledge of P450s responsible for terbinafine metabolism and TBF-A formation provides a foundation for investigating and mitigating the impact of P450 variations in toxic risks posed to patients.

Comprehensive kinetic and modeling analyses revealed CYP2C9 and 3A4 determine terbinafine metabolic clearance and bioactivation.

Terbinafine N-dealkylation pathways result in formation of 6,6-dimethyl-2-hepten-4-ynal (TBF-A), a reactive allylic aldehyde, that may initiate idiosyncratic drug-induced liver toxicity. Previously, we reported on the importance of CYP2C19 and 3A4 as major contributors to TBF-A formation. In this study, we expanded on those efforts to assess individual contributions of CYP1A2, 2B6, 2C8, 2C9, and 2D6 in terbinafine metabolism. The combined knowledge gained from these studies allowed us to scale the relative roles of the P450 isozymes in hepatic clearance of terbinafine including pathways leading to TBF-A, and hence, provide a foundation for assessing their significance in terbinafine-induced hepatotoxicity. We used in vitro terbinafine reactions with recombinant P450s to measure kinetics for multiple metabolic pathways and calculated contributions of all individual P450 isozymes to in vivo hepatic clearance for the average human adult. The findings confirmed that CYP3A4 was a major contributor (at least 30% total metabolism) to all three of the possible N-dealkylation pathways; however, CYP2C9, and not CYP2C19, played a critical role in terbinafine metabolism and even exceeded CYP3A4 contributions for terbinafine N-demethylation. A combination of their metabolic capacities accounted for at least 80% of the conversion of terbinafine to TBF-A, while CYP1A2, 2B6, 2C8, and 2D6 made minor contributions. Computational approaches provide a more rapid, less resource-intensive strategy for assessing metabolism, and thus, we additionally predicted terbinafine metabolism using deep neural network models for individual P450 isozymes. Cytochrome P450 isozyme models accurately predicted the likelihood for terbinafine N-demethylation, but overestimated the likelihood for a minor N-denaphthylation pathway. Moreover, the models were not able to differentiate the varying roles of the individual P450 isozymes for specific reactions with this particular drug. Taken together, the significance of CYP2C9 and 3A4 and to a lesser extent, CYP2C19, in terbinafine metabolism is consistent with reported drug interactions. This finding suggests that variations in individual P450 contributions due to other factors like polymorphisms may similarly contribute to terbinafine-related adverse health outcomes. Nevertheless, the impact of their metabolic capacities on formation of reactive TBF-A and consequent idiosyncratic hepatotoxicity will be mitigated by competing detoxification pathways, TBF-A decay, and TBF-A adduction to glutathione that remain understudied.

Lamisil (terbinafine) toxicity: Determining pathways to bioactivation through computational and experimental approaches.

Lamisil (terbinafine) may cause idiosyncratic liver toxicity through a proposed toxicological mechanism involving the reactive metabolite 6,6-dimethyl-2-hepten-4-ynal (TBF-A). TBF-A toxicological relevance remains unclear due to a lack of identification of pathways leading to and competing with TBF-A formation. We resolved this knowledge gap by combining computational modeling and experimental kinetics of in vitro hepatic N-dealkylation of terbinafine. A deep learning model of N-dealkylation predicted a high probability for N-demethylation to yield desmethyl-terbinafine followed by N-dealkylation to TBF-A and marginal contributions from other possible pathways. We carried out steady-state kinetic experiments with pooled human liver microsomes that relied on development of labeling methods to expand metabolite characterization. Those efforts revealed high levels of TBF-A formation and first order decay during metabolic reactions; actual TBF-A levels would then reflect the balance between those processes as well as reflect the impact of stabilizing adduction with glutathione and other biological molecules. Modeling predictions and experimental studies agreed on the significance of N-demethylation and insignificance of N-denaphthylation in terbinafine metabolism, yet differed on importance of direct TBF-A formation. Under steady-state conditions, the direct pathway was the most important source of the reactive metabolite with a Vmax/Km of 4.0 pmol/min/mg protein/µM in contrast to model predictions. Nevertheless, previous studies show that therapeutic dosing leads to accumulation of desmethyl-terbinafine in plasma, which means that likely sources for TBF-A would draw from metabolism of both the major metabolite and parent drug based on our modeling and experimental studies. Through this combination of novel modeling and experimental approaches, we are the first to identify pathways leading to generation of TBF-A for assessing its role in idiosyncratic adverse drug interactions.

Building the health-economic case for scaling up the WHO-HEARTS hypertension control package in low- and middle-income countries / Argumentos de la economía de la salud para ampliar las medidas de control de la hipertensión de la iniciativa HEARTS de la OMS en los países de ingresos medianos y bajos / Ampliação do pacote de controle da hipertensão OMS-HEARTS em países de baixa e média renda: argumentos a partir da perspectiva da economia em saúde

ABSTRACT Generally, hypertension control programs are cost-effective, including in low- and middle-income countries, but country governments and civil society are not likely to support hypertension control programs unless value is demonstrated in terms of public health benefits, budget impact, and value-for-investment for the individual country context. The World Health Organization (WHO) and the Pan American Health Organization (PAHO) established a standard, simplified Global HEARTS approach to hypertension control, including preferred antihypertensive medicines and blood pressure measurement devices. The objective of this study is to report on health economic studies of HEARTS hypertension control package cost (especially medication costs), cost-effectiveness, and budget impact and describe mathematical models designed to translate hypertension control program data into the optimal approach to hypertension care service delivery and financing, especially in low- and middle-income countries. Early results suggest that HEARTS hypertension control interventions are either cost-saving or cost-effective, that the HEARTS package is affordable at between US$ 18-44 per person treated per year, and that antihypertensive medicines could be priced low enough to reach a global standard of an average <US$ 5 per patient per year in the public sector. This health economic evidence will make a compelling case for government ownership and financial support for national scale hypertension control programs.

RESUMEN En general, los programas de control de la hipertensión son costo-eficaces, incluso en los países de ingresos bajos y medios. Aun así, es poco probable que los gobiernos nacionales y la sociedad civil apoyen los programas de control de la hipertensión a menos que se demuestre su valor en términos de beneficios para la salud pública, impacto presupuestario y valor de la inversión para el contexto individual del país. La Organización Mundial de la Salud (OMS) y la Organización Panamericana de la Salud (OPS) implementaron la iniciativa HEARTS, un enfoque mundial estandarizado y simplificado para el control de la hipertensión, que incluye los medicamentos antihipertensivos y los dispositivos de medición de la presión arterial de preferencia. El objetivo de este estudio es informar sobre los estudios en el ámbito de la economía de la salud relativos al costo de las medidas de control de la hipertensión previstas en HEARTS (especialmente, de los medicamentos), la costo-efectividad y el impacto presupuestario, así como describir los modelos matemáticos diseñados para traducir los datos de este programa en un enfoque óptimo para la prestación y el financiamiento de los servicios de atención de la hipertensión, especialmente en países de ingresos medianos y bajos. Los primeros resultados indican que las intervenciones de HEARTS para el control de la hipertensión son de bajo costo o costo-eficaces, que el conjunto de medidas HEARTS es asequible, a un precio que oscila entre US$ 18 y US$ 44 al año por paciente tratado, y que los medicamentos antihipertensivos podrían tener un precio lo suficientemente bajo como para alcanzar un estándar medio mundial de <US$ 5 por paciente al año en el sector público. Estos datos del ámbito de la economía de la salud serán argumentos convincentes para que los gobiernos se involucren en los programas de control de la hipertensión a escala nacional y les brinden apoyo financiero.

RESUMO Geralmente, os programas de controle de hipertensão são custo-efetivos, inclusive em países de baixa e média renda, mas os governos dos países e a sociedade civil provavelmente não apoiarão tais programas a menos que demonstrem valor em termos de benefícios à saúde pública, impacto orçamentário e retorno sobre o investimento no contexto individual do país. A Organização Mundial da Saúde (OMS) e a Organização Pan-Americana da Saúde (OPAS) criaram a Global HEARTS, uma abordagem padrão e simplificada ao controle da hipertensão arterial, que inclui medicamentos anti-hipertensivos preferidos e dispositivos para aferição da pressão arterial preferidos. O objetivo deste estudo é relatar os estudos de economia em saúde que analisaram o custo (especialmente custos de medicamentos), custo-benefício e impacto orçamentário do pacote HEARTS para controle da hipertensão e descrever modelos matemáticos elaborados para traduzir os dados do programa de controle de hipertensão em uma abordagem ideal para a prestação e financiamento de serviços de atenção às pessoas com hipertensão, especialmente em países de baixa e média renda. Os primeiros resultados sugerem que as intervenções HEARTS para controle da hipertensão são de baixo custo ou custo-efetivas, que o pacote HEARTS é acessível (custando de US$ 18 a 44 por pessoa tratada por ano) e que o preço dos medicamentos anti-hipertensivos poderia ser baixo o suficiente para atingir uma média global de <US$ 18 por paciente por ano no setor público. Estas evidências do campo da economia em saúde serão um argumento convincente para que os governos se responsabilizem por programas de controle de hipertensão em escala nacional e os dotem de recursos financeiros.