Population Pharmacokinetics of Praziquantel in Pregnant and Lactating Filipino Women Infected with Schistosoma japonicum.

An estimated 40 million women of reproductive age are infected with one of three species of the waterborne parasite Schistosoma spp. Treatment with praziquantel (PZQ) via mass drug administration (MDA) campaigns is the mainstay of schistosomiasis control for populations living in areas of endemicity. The World Health Organization recommends that pregnant and lactating women be included in schistosomiasis MDA programs, and several recent studies have evaluated the safety and efficacy of PZQ use during pregnancy. To date, there are no data describing PZQ pharmacokinetics (PK) during pregnancy or among lactating postpartum women. As part of a randomized controlled trial investigating the safety and efficacy of PZQ during human pregnancy, we examined the PK of this therapeutic drug among three distinct cohorts of women infected with S. japonicum in Leyte, Philippines. Specifically, we studied the PK properties of PZQ among early- and late-gestation pregnant women (n = 15 each) and lactating postpartum women (n = 15) with schistosomiasis. We found that women in early pregnancy had increased apparent clearance and lower area-under-the-curve (AUC0-24) values that may be related to physiological changes in drug clearance and/or changes in oral bioavailability. There was no relationship between body weight and apparent clearance. The mean ± standard deviation partition ratio of plasma to breast milk was 0.36. ± 0.13. The estimated median infant PZQ daily dose would be 0.037 mg/kg of body weight ingested from breast milk, which is significantly lower than the dosage required for antischistosomal activity and not known to be harmful to the infant. Our PK data do not support the suggestion to delay breastfeeding 72 h after taking PZQ. Results can help inform future drug efficacy studies in pregnant and lactating women with schistosomiasis.

Praziquantel for the treatment of schistosomiasis during human pregnancy.

In 2014, an estimated 40 million women of reproductive age were infected with Schistosoma haematobium, S. japonicum and/or S. mansoni. In both 2003 and 2006, the World Health Organization (WHO) recommended that all schistosome-infected pregnant and breastfeeding women be offered treatment, with praziquantel, either individually or during treatment campaigns. In 2006, WHO also stated the need for randomized controlled trials to assess the safety and efficacy of such treatment. Some countries have yet to follow the recommendation on treatment and many programme managers and pregnant women in other countries remain reluctant to follow the recommended approach. Since 2006, two randomized controlled trials on the use of praziquantel during pregnancy have been conducted: one against S. mansoni in Uganda and the other against S. japonicum in the Philippines. In these trials, praziquantel treatment of pregnant women had no significant effect on birth weight, appeared safe and caused minimal side-effects that were similar to those seen in treated non-pregnant subjects. Having summarized the encouraging data, on efficacy, pharmacokinetics and safety, from these two trials and reviewed the safety data from non-interventional human studies, we recommend that all countries include pregnant women in praziquantel treatment campaigns. We identify the barriers to the treatment of pregnant women, in countries that already include such women in individual treatments and mass drug administration campaigns, and discuss ways to address these barriers.

En 2014, on estimait que 40 millions de femmes en âge de procréer étaient infectées par Schistosoma haematobium, S. japonicum et/ou S. mansoni. En 2003 et 2006, l'Organisation mondiale de la Santé (OMS) a recommandé qu'un traitement au praziquantel soit offert, individuellement ou dans le cadre de campagnes de traitement, à toutes les femmes enceintes et allaitantes infectées par le schistosome. En 2006, l'OMS a également affirmé la nécessité d'essais contrôlés randomisés pour évaluer l'innocuité et l'efficacité de ce traitement. Néanmoins, certains pays ne suivent toujours pas la recommandation relative au traitement et dans d'autres pays, bon nombre de gestionnaires de programme et de femmes enceintes demeurent réticents à suivre l'approche recommandée. Depuis 2006, deux essais contrôlés randomisés sur l'utilisation du praziquantel au cours de la grossesse ont été menés: l'un sur S. mansoni en Ouganda et l'autre sur S. japonicum aux Philippines. Dans le cadre de ces essais, le traitement au praziquantel des femmes enceintes n'a pas eu d'effet notable sur le poids à la naissance, s'est révélé sans danger et a provoqué des effets secondaires minimes, similaires à ceux constatés chez les femmes traitées qui n'étaient pas enceintes. Ayant résumé les données encourageantes sur l'efficacité, la pharmacocinétique et l'innocuité tirées de ces deux essais et examiné les données de sécurité provenant d'études non interventionnelles sur l'homme, nous recommandons que tous les pays incluent les femmes enceintes dans des campagnes de traitement au praziquantel. Nous mettons en évidence les obstacles qui empêchent le traitement des femmes enceintes ­ dans des pays les incluant déjà dans des traitements individuels et des campagnes d'administration massive de médicaments ­ et décrivons des moyens permettant de surmonter ces obstacles.

En 2014, se estima que 40 millones de mujeres en edad reproductiva estaban infectadas con Schistosoma haematobium, S. japonicum y/o S. mansoni. Tanto en 2003 como en 2006, la Organización Mundial de la Salud (OMS) recomendó que todas las mujeres embarazadas y lactantes infectadas con esquistosoma recibieran tratamiento, con praziquantel, ya fuera individualmente o durante las campañas de tratamiento. En 2006, la OMS también informó de la necesidad de ensayos aleatorizados controlados para evaluar la seguridad y la eficacia de dicho tratamiento. Algunos países todavía tienen que seguir la recomendación sobre el tratamiento y muchos gestores de programas y mujeres embarazadas en otros países siguen siendo reacios a seguir el enfoque recomendado. Desde 2006, se han llevado a cabo dos ensayos aleatorizados controlados sobre el uso de praziquantel durante el embarazo: uno contra el S. mansoni en Uganda y el otro contra el S. japonicum en Filipinas. En estos ensayos, el tratamiento con praziquantel en mujeres embarazadas no tuvo un efecto significativo sobre el peso en el momento del nacimiento, pareció seguro y causó efectos secundarios mínimos, similares a los observados en sujetos no embarazadas tratadas. Después de resumir los alentadores datos sobre la eficacia, la farmacocinética y la seguridad de estos dos ensayos y revisar los datos de seguridad de los estudios observacionales en humanos, recomendamos que todos los países incluyan a mujeres embarazadas en las campañas de tratamiento con praziquantel. Identificamos las barreras para el tratamiento de mujeres embarazadas, en países que ya incluyen a mujeres en los tratamientos individuales y en las campañas masivas de administración de medicamentos, y analizamos las formas de abordar estas barreras.

Assessment of minority frequency pretreatment HIV drug-resistant variants in pregnant women and associations with virologic non-suppression at term.

OBJECTIVE: To assess in ART-naïve pregnant women randomized to efavirenz- versus raltegravir-based ART (IMPAACT P1081) whether pretreatment drug resistance (PDR) with minority frequency variants (<20% of individual's viral quasispecies) affects antiretroviral treatment (ART)-suppression at term. DESIGN: A case-control study design compared PDR minority variants in cases with virologic non-suppression (plasma HIV RNA >200 copies/mL) at delivery to randomly selected ART-suppressed controls. METHODS: HIV pol genotypes were derived from pretreatment plasma specimens by Illumina sequencing. Resistance mutations were assessed using the HIV Stanford Database, and the proportion of cases versus controls with PDR to their ART regimens was compared. RESULTS: PDR was observed in 7 participants (11.3%; 95% CI 4.7, 21.9) and did not differ between 21 cases and 41 controls (4.8% vs 14.6%, p = 0.4061). PDR detected only as minority variants was less common (3.2%; 95% CI 0.2, 11.7) and also did not differ between groups (0% vs. 4.9%; p = 0.5447). Cases' median plasma HIV RNA at delivery was 347c/mL, with most (n = 19/22) showing progressive diminution of viral load but not ≤200c/mL. Among cases with viral rebound (n = 3/22), none had PDR detected. Virologic non-suppression at term was associated with higher plasma HIV RNA at study entry (p<0.0001), a shorter duration of ART prior to delivery (p<0.0001), and randomization to efavirenz- (versus raltegravir-) based ART (p = 0.0085). CONCLUSIONS: We observed a moderate frequency of PDR that did not significantly contribute to virologic non-suppression at term. Rather, higher pretreatment plasma HIV RNA, randomization to efavirenz-based ART, and shorter duration of ART were associated with non-suppression. These findings support early prenatal care engagement of pregnant women and initiation of integrase inhibitor-based ART due to its association with more rapid suppression of plasma RNA levels. Furthermore, because minority variants appeared infrequent in ART-naïve pregnant women and inconsequential to ART-suppression, testing for minority variants may be unwarranted.

Determination of Benznidazole in Human Dried Blood Spots by Liquid Chromatography-Mass Spectrometry to Monitor Adherence to Trypanosoma cruzi Infection Treatment in Infants and Children.

Medication adherence is critical to the effectiveness of benznidazole (BZ) therapy for the treatment of Chagas disease. Assessing BZ adherence using traditional plasma sampling methods presents numerous challenges in resource-limited settings. Dried blood spot (DBS) sampling of BZ can be used to overcome logistical barriers and provides a less invasive method for assessing BZ levels. A BZ DBS assay using liquid chromatography-tandem mass spectrometry was developed and applied to a clinical study of infants and children being treated with BZ for Trypanosoma cruzi infection in Argentina. The assay was validated over a concentration range of 9.8-5,000 ng/mL. Inter-assay and intra-assay measures ranged from -2.9% to 2.7% and 0.5% to 8.3% for accuracy and from 3.5% to 12% and 1.6% to 13.6% for precision, respectively. The mean recovery of BZ was greater than 91%. Partitioning ratios for DBSs/plasma ranged from 0.95 to 1.02. A cohort of 10 infants and six children with T. cruzi infection being treated with BZ had median BZ concentrations of 1.2 (IQR 0.29, 2.14) µg/mL with seven of 65 (11%) samples above the BZ treatment goal of 3 µg/mL for adults. The reported DBS assay is a simple and accurate method for the quantitative measurement of BZ that can be applied to facilitate urgently needed clinical studies of BZ for the treatment of Chagas disease and assess BZ adherence in resource-limited settings.