“Pespectiva da Pesquisa Clínica em Pediatria” Dúvidas denucci@gdenucci.com Arquivo “Pespectiva da Pesquisa Clínica em Pediatria” Site www.gdenucci.com

Importância de Reações Adversas a Medicamentos (RAM) 2 milhões de RAM anualmente nos EUA Cem mil mortes por ano Quarta causa de morte nos EUA (na frente de doenças pulmonares, diabetes, AIDS, acidentes automobilísticos RAM ambulatorial – incidência não estimada RAM em clínicas para idosos – 350 mil por ano

Custos associados a RAM 136 bilhões de US$ anualmente Maior do que custos com moléstias cardiovasculares ou tratamento de diabetes RAM responsável por 20% de danos ou mortes por ano em pacientes hospitalizados Custo hospitalar o dobro em relação a demais pacientes

Por que há tantos RAM? Dois terços de consultas médicas geram uma receita 2.8 bilhões de receitas no ano 2000 (10 por habitante dos EUA) RAM aumenta exponencialmente com 4 ou mais medicações

Interações Medicamentosas Representam 3-5% das internações de RAM que podem ser evitadas Importante causa no número de atendimentos ambulatórios

Creatinine clearance and drug prescriptions for the elderly Creatinine clearance and drug prescriptions for the elderly. A study of 419 patients older than 70 years admitted through the emergency department Viallon A, Guyomarch P, Marjollet O, Belin M, Robert F, Berger C, Guyomarch S, Bertrand JC. Service d'Urgence et de Reanimation, Hopital Bellevue, Saint-Etienne. alain.viallon@univ-st-etienne.fr INTRODUCTION: The incidence of drug-related adverse events increases with age. In approximately 20% of cases, these events necessitate hospitalization. By taking into account the physiological changes associated with aging when prescribing drugs, physicians can prevent some of these events. The objective of this study was to analyze the prescriptions written by general practitioners for elderly patients admitted to the emergency department in relation to the patient's creatinine clearance. PATIENTS AND METHODS: Of 968 consecutive patients older than 70 years, 419 underwent a plasma creatinine assay on admission and were included in this study. Creatinine clearance was calculated with Cockcroft's formula. The patients were classified into two groups according to creatinine clearance:<30 mL/min (group I) and >or=30 mL/min (group II). RESULTS: Creatinine clearance was<30 mL/min in 84 of the 419 patients (group I) and >or=30 mL/min in 335 (group II). Mean age was significantly higher in group I than in group II (87 +/- 6 vs 81 +/- 6 years, p<0.001), as was mean plasma creatinine concentration (113 +/- 23 vs 83 +/- 19 mmol/L, p<0.001), while mean weight was significantly lower (57 +/- 10 vs 69 +/- 13 kg, p<0.001. In group I, 82 drugs with precautions concerning renal function had been prescribed for 69 (82%) patients, and in group II, 331 such drugs for 174 (52%) patients. Of the 82 drugs prescribed in group I that required precaution, 47 (57%) were contraindicated or prescribed at an inappropriate dose in view of the creatinine clearance. Irrespective of pharmacokinetic parameters, the mean number of drugs taken per patient was 5 +/- 2 in group I and 6 +/-2 in group II. CONCLUSION: In prescribing drugs for elderly patients, especially those whose weight is low, careful attention should be paid to renal function.

Crianças = Órfãs da Terapêutica Envolvimento nas catástrofes terapêuticas causadas pela ausência de estudos de farmacocinética e farmacodinâmica nesta população. Uso off-label de medicamentos utilizados na população adulta, com extrapolação não validada com estudos adequados.

Necessidade da pesquisa clínica em crianças 50% dos medicamentos utilizados em um hospital pediátrico não são oficialmente registrados para uso em crianças 2. Em unidades neonatais, este índice aproxima-se de 90%.

FDA-proposed decision tree for the evaluation of pediatric populations. Pediatric Study Decision Tree Reasonable to assume (pediatrics vs adults) Similar disease progression? Similar response to intervetion? YES TO BOTH NO Reasonable to assume similar concentration-response (C-R) in pediatries and adults? Conduct PK studies Conduct safety/efficacy trials NO NO YES Is there a PD measurement that can be used to predict efficacy? Conduct PK studies to achieve levels similar to adults Conduct safety trials YES Conduct PK/PD studies to get C-R for PD measurement Conduct PK studies to achieve target concentrations based on C-R Conduct safety trials The AAPS Journal 2005; 7 (2) Article 48

Summary of some of the recently reported PK-PD studies undertaken in children Modelling approaches to dose estimation in children - British Journal of Clinical Pharmacology - DOI:10.1111/j.1365-2125.2005.02429.x

Data from a study investigating paracetamol clearance. Eur J Pediatr (2006) 165:741–746

Morphine clearance (SD or range)

The ED90 of succinylcholine does not change with age when expressed using the surface area and 3/4 power models

Epidural infusion rates and total clearance of bupivacaine (SD)

Hypothetical concentration versus time curves describing (A) informative data with full sampling, (B) informative data with limited sampling, (C) noninformative data with limited sampling. The AAPS Journal 2005; 7 (2) Article 48

Changes in caffeine CLu (1a) and midazolam CLu (1b) with body weight (predicted CLu : median = solid line and 95% CI = dashed line; observed CLu = ellipses) CL (L.kg.h) Modelling approaches to dose estimation in children - British Journal of Clinical Pharmacology - DOI:10.1111/j.1365-2125.2005.02429.x

Farmacologia Clínica em Pediatria 1. Estudos farmacocinéticos utilizando amostragem restrita (sensibilidade da tecnologia analítica). 2. Estudos investigando relação farmacocinética-farmacodinâmica (apreciação de histerese) 3. Estudos de farmacodinâmica 4. Estudos de interação de medicamentos

Dificuldades 1. Aspecto cultural (“...o problema é acadêmico, de fato não existe) 2. Situação aparentemente cômoda (desconhecimento por parte dos pais do desconhecimento da classe prescritora) 3. Problematização dos aspectos éticos