A influência do sobrepeso/ obesidade sobre o uso do levonorgestrel como método contraceptivo de emergência / The influence of overweight/obesity over the use of levonorgestrel as an emergency contraceptive method

A contracepção de emergência tem como objetivo prevenir uma gravidez indesejada após uma relação sexual desprotegida, falha do método contraceptivo regular ou agressão sexual. Dentre os métodos disponíveis atualmente, destaca-se a pílula hormonal de levonorgestrel (LNG) como uma das principais estratégias utilizadas, tendo em vista o perfil de segurança desse fármaco e a facilidade de acesso e utilização dele. No entanto, embora o efeito de tal molécula seja satisfatório, pesquisas sugerem que altos índices de massa corporal implicam uma redução da eficácia contraceptiva da pílula de LNG. Nesse sentido, esse estudo visa evidenciar, mediante revisão de literatura, a relação entre esse fármaco e sua competência em mulheres com sobrepeso ou obesidade, bem como expor quais medidas devem ser tomadas para evitar a gravidez indesejada nessas pacientes. Embora existam divergências, foi observado que a maior parte dos estudos indica que a composição corporal das pacientes pode influenciar na eficácia contraceptiva da molécula de LNG, de forma sinérgica ou não com outros fatores, especialmente quando considerado o IMC > 25 kg/m² ou peso > 75 kg, uma vez que o risco de gravidez pode aumentar de 1,5 até 4,4 vezes quando comparado aos padrões de normalidade, com tendência de crescimento em relação aos parâmetros de sobrepeso/obesidade.(AU)

The main goal of the emergency contraceptive is to prevent a non-planned pregnancy after the sexual relationship without condom, after the fail of the usual contraceptive or the sexual assault. Among all the currently available methods, the hormonal pill of levonorgestrel (LNG) has its importance as one of the most used strategies, due of its safety, easy access and use. However, in spite of the fact that this molecule has a good effect, some researches suggest that a high level of the body mass reduces the efficacy of the contraceptive pill of LNG. In this context, this study objective is to clarify, by using literature review, the relation between this drug and its competence in overweight/obese women, as well to expose which other options could be taken to avoid a non-planned pregnancy in those patients. Despite of the fact that there are divergences, the most part of the studies shows that patient's body composition can influence on the contraceptive effectiveness of the LNG molecule, sinergically or not to other factors, especially when the IMC > 25 kg/m² or the body weight > 75 kg, once the pregnancy risk can be raised from 1,5 to 4,4 times when compared to regular standards, with growth tendency when related to overweigh/obesity parameters.(AU)

Influence of CYP3A4/5 polymorphisms in the pharmacokinetics of levonorgestrel: a pilot study / Influencia de polimorfismos genéticos de CYP3A4/5 en la farmacocinética de levonorgestrel: estudio piloto

Introduction.Levonorgestrel a synthetic progestagen used for endometriosis, dysmenorrhea and emergency contraception, is quickly and completely absorbed in the digestive tract. levonorgestrel is predominantly metabolised through hepatic routes that utilise the CYP3A system (CYP3A4 and CYP3A5). Objective.This study aimed to evaluate the association between variant alleles of CYP3A4*1B and CYP3A5*3 polymorphisms and the pharmacokinetics of levonorgestrel. Materials and methods. A group of 17 adult female healthy volunteers who signed an informed consent were genotyped for CYP3A4 and CYP3A5 through PCR-RFLP. Volunteers were submitted to pharmacokinetic analysis where, after a 12-hour overnight fast, they received a single oral dose of 0.75 mg of levonorgestrel. Serial blood samples were obtained (0 to 24 hours), and levonorgestrel concentrations were determined by UPLC-MS/MS to determine pharmacokinetic parameters. The procedures employed herein were performed according to the Declaration of Helsinki and Good Clinical Practices standards. Results. Observed genotype frequencies in the studied group for CYP3A4*1B were 11.8% for *1B/*1B, 5.8% for *1/*1B and 82.4% for *1/*1. CYP3A5*3 frequencies were 70.5% for *3/*3, 23.5% for *1/*3 and 6.5% for *1/*1. A high pharmacokinetic variability between volunteers was observed, but no statistical association of pharmacokinetic parameters was found within the studied CYP3A4/5 polymorphisms. Conclusions. Genetic polymorphisms could be important factors in determining inter-patient variability in plasma levonorgestrel concentrations, which in this study were not significantly associated with the presence of CYP3A4*1B and CYP3A5*3 polymorphisms. Therefore, due to the significant inter-patient variability that we observed during the course of this study, it is necessary to carry out studies with larger number of volunteers.

Introducción. El levonorgestrel, un progestágeno sintético usado para endometriosis, dismenorrea y anticoncepción de emergencia, es rápida y completamente absorbido en el tubo digestivo. Su metabolismo es principalmente hepático, mediante las enzimas CYP3A4 y CYP3A5. Objetivo. El presente estudio tuvo como objetivo evaluar la asociación entre la farmacocinética de levonorgestrel y las variantes alélicas de CYP3A4*1B y CYP3A5*3. Materiales y métodos. En un grupo de 17 mujeres adultas sanas, que firmaron un consentimiento informado, se practicó genotipificación para CYP3A4*1B y CYP3A5*3 mediante PCR. Posteriormente, las voluntarias fueron sometidas a un estudio farmacocinético donde, luego de 12 horas de ayuno, recibieron una dosis de 0,75 mg de levonorgestrel. Se extrajeron muestras sanguíneas seriadas (0 a 24 horas) y se determinaron las concentraciones de levonorgestrel mediante un método validado de UPLC-ms/ms, para luego obtener los parámetros farmacocinéticos. Todos los procedimientos consideraron los aspectos éticos de la Declaración de Helsinki y las buenas prácticas clínicas. Resultados. Las frecuencias genotípicas observadas para el grupo de estudio fueron 11,8 % para *1B/*1B; 5,8 % para *1/*1B, y 82,4 % para *1/*1 de CYP3A4*1B. Para CYP3A5*3, las frecuencias genotípicas fueron 70,5 % para *3/*3; 23,5 % para *1/*3, y 6,5 % para *1/*1. Se observa una interesante variabilidad entre las voluntarias que sugiere una relación con las variantes genéticas CYP3A, pero que no permite establecer una asociación estadísticamente significativa, presumiblemente debido al bajo número de individuos homocigotos mutados de CYP3A4 y silvestres de CYP3A5. Conclusiones. Los polimorfismos genéticos podrían ser factores relevantes en la determinación de la variabilidad entre pacientes en las concentraciones plasmáticas de levonorgestrel, lo cual, sin embargo, no pudo ser establecido estadísticamente en este estudio. Por lo tanto, resulta necesario continuar este tipo de estudios con mayor número de voluntarios para establecer una asociación entre la variabilidad observada y la presencia de estos polimorfismos.

Bioequivalence study of postcoital emergency contraceptions containing levonorgestrel.

OBJECTIVE: The progestogen-only method of emergency contraception, levonorgestrel, is one of the effectiveness in preventing expected pregnancies. The comparative bioavailability was carried out on levonorgestrel tablets (0.75 mg) from two different sources (Hungarian and Thai made). METHOD: Eighteen healthy female volunteers were given a single oral dose of 0.75 mg tablets in a crossover design. Serum levonorgestrel concentration was determined by radio-immunoassay. The pharmacokinetic analysis of serum levonorgestrel concentration from each treatment was established. The comparative bioavailability of the two products was determined by the analysis of variance (ANOVA) for two way crossover design. RESULTS: The results found that the mean peak (X +/- SD) serum concentration (Cmax) of the Thai-made pill and Hungarian-pill were 1.18 +/- 0.12 and 1.14 +/- 0.10 ng/ml, respectively. The 90% confidence intervalfor the difference of log Cmax mean was 99.54-120.78%. The time to peak serum concentration (Tmax) of the Thai-made pill and Hungarian-pill were 1.56 +/- 0.73 and 1.58 +/- 0.67 hrs, respectively. The different time of peak serum levonorgestrel concentration was 1.27%. The mean area under the curve (AUC) of Thai-made pill and Hungarian-pill were 2.14 +/- 0.21 and 2.09 +/- 0.16 ng.h/ml, respectively. The 90% confidence interval for the difference of log AUC mean was 103.27 - 121.89%. CONCLUSION: The present study revealed that the 90% confidence interval for the difference of log Cmax mean and log AUC mean were in the criteria of acceptance, which should be within 80-125%. So, the authors can conclude that the Thai-made pill was bioequivalent to the Hungarian-pill.

Clinical studies of [procopper iud] and in-vivo evaluation of levonorgestrel and copper levels in different biological fluids

The clinical studies of procopper IUDs revealed that they decreased the menstrual flow, but not to the extent of amenorrhea, no pregnancy was reported and they diminished pelvic inflammatory disease [PID]. The in vivo release study of both levonorgestrel as well as copper released from procopper IUDs in biological fluids indicated that neither levonorgestrel nor copper interfered with the release of each other, indicating that there is no interaction between them