OC 8510 BIOTRANSFORMATION OF PRAZIQUANTEL FOR THE PHARMACOKINETIC OPTIMISATION OF PRAZIQUANTEL USE IN MASS DRUG ADMINISTRATION AND DEVELOPMENT OF NEW PAEDIATRIC FORMULATIONS

BackgroundPraziquantel (PZQ) is the only drug available for the treatment of all forms of schistosomiasis. New paediatric formulations for the active enantiomer R-PZQ and the racemate PZQ are currently under development. There is however limited drug metabolism and pharmacokinetic data on PZQ available to support these initiatives. Detailed knowledge of PZQ metabolism will enable the use of PBPK modelling to determine appropriate doses for the new formulations in paediatric patients and to predict risks for drug-drug interactions in mass drug administration.MethodsBiotransformation studies on PZQ were conducted in human liver microsomes and recombinant Cytochrome P450s (CYPs). Structure elucidation was inferred from mass spectra. Enzyme kinetic studies to determine the Michaelis-Menten kinetics, Km and Vmax, of the formation of the main metabolites and analysis of clinical samples were determined by LC-MS/MS.ResultsCYP reaction phenotyping studies with HLM and r-CYPs indicate major involvement of CYP1A2, 2 C19, 2D6 and 3A4/5 in the metabolism of R- and S-PZQ. Biotransformation studies showed that PZQ is metabolised to cis-4-OH-PZQ mainly by CYP1A2 and CYP2C19. CYP3A4/5 metabolises PZQ to a mono-hydroxyl metabolite (X-OH-PZQ) whilst CYP2D6 metabolises PZQ to minor novel mono-hydroxyl metabolite (Y-OH-PZQ) both pending structural elucidation by nuclear magnetic resonance. R-PZQ was more rapidly cleared than S–PZQ with variable interindividual AUC and Cmax.Discussion and conclusionThe differential role of CYP1A2 and CYP2C19 and of CYP3A4 and CYP3A5 in the formation the 4-OH-PZQ and the novel X-OH-PZQ respectively are intriguing findings as this has not been reported before in humans. In vitro, cis and not trans 4-OH-PZQ formation has been observed contrary in vivo reports in humans which indicate trans 4-OH-PZQ as the main metabolite. The data will enable us to understand the rapid clearance of PZQ and predict potential drug-drug-gene interactions which mayexplain the inter-individual variability of PZQ pharmacokinetics

Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on child stunting and anaemia in rural Zimbabwe: a cluster-randomised trial.

BACKGROUND: Child stunting reduces survival and impairs neurodevelopment. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on stunting and anaemia in in Zimbabwe. METHODS: We did a cluster-randomised, community-based, 2 × 2 factorial trial in two rural districts in Zimbabwe. Clusters were defined as the catchment area of between one and four village health workers employed by the Zimbabwe Ministry of Health and Child Care. Women were eligible for inclusion if they permanently lived in clusters and were confirmed pregnant. Clusters were randomly assigned (1:1:1:1) to standard of care (52 clusters), IYCF (20 g of a small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counselling; 53 clusters), WASH (construction of a ventilated improved pit latrine, provision of two handwashing stations, liquid soap, chlorine, and play space plus hygiene counselling; 53 clusters), or IYCF plus WASH (53 clusters). A constrained randomisation technique was used to achieve balance across the groups for 14 variables related to geography, demography, water access, and community-level sanitation coverage. Masking of participants and fieldworkers was not possible. The primary outcomes were infant length-for-age Z score and haemoglobin concentrations at 18 months of age among children born to mothers who were HIV negative during pregnancy. These outcomes were analysed in the intention-to-treat population. We estimated the effects of the interventions by comparing the two IYCF groups with the two non-IYCF groups and the two WASH groups with the two non-WASH groups, except for outcomes that had an important statistical interaction between the interventions. This trial is registered with ClinicalTrials.gov, number NCT01824940. FINDINGS: Between Nov 22, 2012, and March 27, 2015, 5280 pregnant women were enrolled from 211 clusters. 3686 children born to HIV-negative mothers were assessed at age 18 months (884 in the standard of care group from 52 clusters, 893 in the IYCF group from 53 clusters, 918 in the WASH group from 53 clusters, and 991 in the IYCF plus WASH group from 51 clusters). In the IYCF intervention groups, the mean length-for-age Z score was 0·16 (95% CI 0·08-0·23) higher and the mean haemoglobin concentration was 2·03 g/L (1·28-2·79) higher than those in the non-IYCF intervention groups. The IYCF intervention reduced the number of stunted children from 620 (35%) of 1792 to 514 (27%) of 1879, and the number of children with anaemia from 245 (13·9%) of 1759 to 193 (10·5%) of 1845. The WASH intervention had no effect on either primary outcome. Neither intervention reduced the prevalence of diarrhoea at 12 or 18 months. No trial-related serious adverse events, and only three trial-related adverse events, were reported. INTERPRETATION: Household-level elementary WASH interventions implemented in rural areas in low-income countries are unlikely to reduce stunting or anaemia and might not reduce diarrhoea. Implementation of these WASH interventions in combination with IYCF interventions is unlikely to reduce stunting or anaemia more than implementation of IYCF alone. FUNDING: Bill & Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Development Cooperation, UNICEF, and US National Institutes of Health.The SHINE trial is funded by the Bill & Melinda Gates Foundation (OPP1021542 and OPP113707); UK Department for International Development; Wellcome Trust, UK (093768/Z/10/Z, 108065/Z/15/Z and 203905/Z/16/Z); Swiss Agency for Development and Cooperation; US National Institutes of Health (2R01HD060338-06); and UNICEF (PCA-2017-0002)

Effects of genetic polymorphisms of drug metabolizing enzymes and co-medications on tamoxifen metabolism in black South African women with breast cancer

Clinical outcomes of tamoxifen treatment show wide inter-individual variability. Co-medications and genetic polymorphisms of enzymes involved in tamoxifen metabolism contribute to this variability. Drug-drug and drug-gene interactions have seldom been studied in African black populations. We evaluated the effects of commonly co-administered medicines on tamoxifen pharmacokinetics in a cohort of 229 South African black female hormone-receptor positive breast cancer patients. We also investigated the pharmacokinetic effects of genetic polymorphism in enzymes involved in tamoxifen metabolism including the variants CYP2D6*17 and *29 which have been mainly reported in people of African descent. Tamoxifen (TAM) and its major metabolites, N-desmethyltamoxifen (NDM), 4-OH-tamoxifen (4-OHTAM), and endoxifen (ENDO), were quantified in plasma using the liquid chromatography-mass spectrometry (LC/MS/MS). The GenoPharm® open array was used to genotype CYP2D6, CYP3A5, CYP3A4, CYP2B6, CYP2C9, and CYP2C19. Results showed that CYP2D6 diplotype and CYP2D6 phenotype significantly affected endoxifen concentration (p<0.001 and p<0.001). CYP2D6*17 and CYP2D6*29 significantly reduced the metabolism of NDM to ENDO. Antiretroviral therapy (ART) had a significant effect on NDM levels and the TAM/NDM and NDM/ENDO Metabolic Ratios (MRs) but did not result in significant effects on ENDO levels. In conclusion, CYP2D6 polymorphisms affected endoxifen concentration and the variants CYP2D6*17 and CYP2D6*29 significantly contributed to low exposure levels of endoxifen. This study also suggests a low risk of drug-drug interaction in breast cancer patients on tamoxifen

The impact of HIV on non-adherence for tamoxifen among women with breast cancer in South Africa

Purpose Women living with HIV (WLWH) and breast cancer (BC) have worse overall survival than HIV-negative women with BC, and poor adherence to prescribed tamoxifen is known to contribute to poor survival. We therefore investigated the association of HIV infection with adherence to adjuvant tamoxifen among women with localized hormone receptor (HR)-positive breast cancer in South Africa. Methods Among 4,097 women diagnosed with breast cancer at six hospitals in the prospective South African Breast Cancer and HIV Outcomes (SABCHO) cohort study between July 2015 and December 2020, we focused on black women with stages I-III HR-positive breast cancer who were prescribed 20 mg of adjuvant tamoxifen daily. We collected venous blood once from each participant during a routine clinic visit, and analyzed concentrations of tamoxifen and its metabolites using a triple quadruple mass spectrometer. We defined non-adherence as a tamoxifen level 60 years (73.4% vs 52.6%, odds ratio (OR) = 2.49, 95% confidence interval (CI) = 1.26-4.94); likewise, WLWH (70.5% vs 52.6%, OR = 2.16, 95% CI = 1.26-3.70) than HIV-negative women. In an adjusted model WLWH had twice the odds of non-adherence to tamoxifen, compared to HIV-negative women (OR = 2.40, 95% CI = 1.11-5.20). Conclusion High rates of non-adherence to adjuvant tamoxifen may limit the overall survival of black South African women with HR-positive breast cancer, especially among WLWH