L’emtricitabine est une molécule centrale dans la stratégie de lutte contre l’infection à VIH. En effet, elle est recommandée en première intention pour le traitement de l’infection chez l’adulte, ainsi que pour la prévention de la transmission de l’infection. Bien que l’emtricitabine soit une molécule clé, elle reste jusqu’à présent peu étudiée. Il est donc primordial d’analyser et de caractériser la pharmacocinétique de l’emtricitabine dans les différentes populations susceptibles d’être exposées à cette molécule. Une approche de population a été utilisée pour réaliser les analyses pharmacocinétiques, nous permettant de décrire la pharmacocinétique avec peu de prélèvements par individu (contraintes éthiques, difficulté de recueil des prélèvements…) et nous permettant d’expliquer la variabilité observée. L’étude rapportant la pharmacocinétique de l’emtricitabine chez l’adulte a mis en évidence une modification du profil cinétique selon l’état de la fonction rénale. Le modèle développé nous a permis d’évaluer les recommandations posologiques actuelles. Afin d’optimiser l’efficacité, la simulation de schémas thérapeutiques alternatifs chez les patients avec une insuffisance rénale modérée a été réalisée. Dans le cadre de la prévention de la transmission mère-enfant, l’étude décrivant la pharmacocinétique de l’emtricitabine chez les femmes enceintes a mis en évidence une modification de la pharmacocinétique au cours de la période gestationnelle. Toutefois, il ne semblait pas nécessaire d’adapter la posologie au cours de la grossesse. La dernière étude a permis d’étudier la pharmacocinétique de l’emtricitabine dans le tractus génital masculin. L’étude de la pénétration dans le compartiment génital est d’un intérêt capital pour le traitement mais aussi pour la prévention de la transmission de l’infection à VIH dans le cadre de la prophylaxie pré-exposition. Notre étude a rapporté une distribution importante de l’emtricitabine dans le tractus génital, avec des concentrations séminales supérieures aux concentrations plasmatiques. / Emtricitabine is a key antiretroviral drug in the strategy to fight against HIV infection. Indeed, emtricitabine is recommended in first-line treatment for HIV infection in adults, as well as for the prevention of HIV transmission. Although emtricitabine is a key molecule, it remains poorly studied until now. It is therefore essential to analyze and characterize the pharmacokinetics of emtricitabine in the different populations that may be exposed to this drug. A population approach was used to perform pharmacokinetic analyses, allowing us to describe the pharmacokinetics with few samples per individual (ethical constraints, difficulty of samples collection...) and allowing us to explain the observed variability. The study reporting emtricitabine pharmacokinetics in adults highlighted a change in emtricitabine kinetic profile depending on the state of renal function. The developed model allowed us to evaluate the current dosing recommendations. To optimize efficiency, simulations of alternative regimens in patients with moderate renal impairment were performed. As part of the prevention of mother to child transmission, the study describing emtricitabine pharmacokinetics in pregnant women showed a change in pharmacokinetics during the gestational period. However, it did not seem necessary to adjust the dosage during pregnancy. The latest work focused on emtricitabine pharmacokinetics in the male genital tract. Studying the penetration in the genital tract is of major interest for treatment but also for prevention of HIV transmission in the context of pre-exposure prophylaxis. Our study reported a significant distribution of emtricitabine in the genital compartment, with concentrations in seminal plasma higher than concentrations in blood plasma.

Les femmes enceintes sont exposées à de nombreux médicaments et les essais cliniques sont difficilement réalisables dans cette population, c'est pourquoi avoir une méthode qui permet d'estimer l'ampleur des modifications de pharmacocinétique chez la femme enceinte et le passage transplacentaire est essentiel. En effet les modifications physiologiques prennent place durant cette période clé. Nous avons développé des modèles pharmacocinétiques basé sur la physiologie (PBPK) et intégré les modifications physiologiques connues survenant durant la grossesse. Ils décrivent bien la pharmacocinétique de 3 antirétroviraux éliminés par le rein, le ténofovir (TFV), l'emtricitabine (FTC) et la lamivudine (3TC) et d'une molécule métabolisée par le CYP3A4, 2D6 et 2B6, la névirapine (NVP) et ceci pour différentes voies d'administration et pour des populations enceintes et non enceintes. De plus les clairances individuelles disponibles pour le TFV, le FTC et le 3TC tout au long de la grossesse ont permis d'explorer l'évolution de la sécrétion rénale. Celle-ci évoluerait proportionnellement au débit plasmatique rénal. L'intégration dans les modèles PBPK, des paramètres estimés à partir de l'expérience ex-vivo de cotylédon humain perfusé, a permis la prédiction de la cinétique foetale en fin de grossesse du TFV, FTC et NVP. Les prédictions ont été validées en les comparants aux concentrations mesurées au sang de cordon à l'accouchement. De plus, pour la névirapine nous avons exploré le métabolisme foetal et en avons conclu que même si celui-ci existe et est proche voir un peu supérieur à celui du nouveau-né, il n'influence pas la cinétique foetale. / Pregnant women are exposed to numerous drugs and for obvious ethical reasons studies in this sensitive population arelimited. Information about the maternal pharmacokinetic (PK) changes and transplacental transfer of drugs prior to theiradministration to pregnant women would be highly useful. Indeed is it known that physiological changes during pregnancycan affect drug disposition. Time-varying pregnancy-related physiological parameters changes were implemented in fullPBPK models. They successfully predicted the disposition of 3 renally excreted drugs tenofovir (TFV), emtricitabine (FTC)and lamivudine (3TC) and one metabolized drug, nevirapine (NVP) for non-pregnant and pregnant populations. We foundthat both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related tochanges in renal plasma flow. Transplacental parameters estimated from ex vivo human placenta perfusion experiments implemented in PBPK models allowed good prediction of foetal TFV, FTC and NVP PK. Predictions were compared to observed cord blood concentrations to validate these models. Moreover, we have explored nevirapine foetal metabolism and concluded that even if the foetal metabolism is the same than the newborn one or a little more important, it is notlikely to impact foetal PK.

BACKGROUND: Numerous methods have been devised to combat human immunodeficiency virus (HIV) replication and disease progression. Composed of an integrase strand transfer inhibitor, a pharmacoenhancer, and two reverse transcriptase inhibitors, Stribild is a relatively new combination HIV drug formulated for once-a-day dosing. METHODS: Relevant information, original research articles and reviews, were gathered primarily through the use of the PubMed database. The search was conducted without date restrictions in order to collect both historical and recent information concerning HIV, individual drugs, and combinations for a thorough overview. RESULTS: Stribild, when taken with food, provides therapeutic drug concentrations as seen through comparison with the respective individual or boosted individual drugs. Stribild non-inferiority has been shown when compared to other HIV drug combinations, ritonavir-boosted atazanavir or efavirenz each with a tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) backbone. The co-formulation also retained high viral suppression in patients switching from other regimens, such as efavirenz/TDF/FTC, raltegravir/TDF/FTC, or various ritonavir-boosted protease inhibitors with TDF/FTC. The elvitegravir and cobicistat combination was unaffected by moderate hepatic impairment; however, hepatic and renal function along with changes in bone mineral density should be monitored closely. Stribild presented with relatively few side effect occurrences, but drug interactions may pose a larger problem for continuous therapy. CONCLUSIONS: Stribild provides viral suppression, comparable to other combination HIV drugs through review of non-inferiority and regimen simplification studies, with minimal adverse effects. Although the breadth of Stribild effectiveness has begun to unfold, studies are lacking in older patients as well as adolescents.

Magister Scientiae - MSc (Pharmaceutical Chemistry) / The rapid increase in access to new antiretrovirals (ARVs) worldwide and, especially in sub-Saharan Africa, coupled with the well-documented problem of poor quality ARVs in developing countries has underscored the need for quality assessment of these medicines. South Africa has the worst human immunodeficiency virus (HIV) epidemic profile in the world; consequently, it has rolled out the world's largest antiretroviral ARV programme. With increasing market penetration of generic medicine in South Africa and especially ARVs, there is a call for stringent quality control mechanisms following the marketing approval (post-market quality control) of these medications. Unfortunately, evidence suggests that the World Health Organisation (WHO) recommendations for this aspect of quality assurance is not met by most Medicine Regulatory Authorities. In South Africa and many other countries this is attributed to a lack of physical and financial resources to enforce effective post-marketing surveillance (PMS) of all pharmaceuticals available in the country.

Yes / Emtricitabine (ECB) afforded dimorphic cocrystals (Forms I, II) of benzoic acid (BA), whereas with p-hydroxybenzoic acid (PHBA), p-aminobenzoic acid (PABA) are resulted in as high Z'' cocrystals. Intriguingly, the Z'' of cocrystals are trends from two to fourteen based on the manipulation of functional groups on the para position of BA (where H atom is replaced with that of OH or NH2 group). ECB‒PABA cocrystal consists of six molecules each and two water molecules in the asymmetric unit (Z''=14) with 2D planar sheets represents the rare pharmaceutical cocrystal. The findings suggest that the increment of H bond donor(s) systematically via a suitable coformer are in correspondence with attaining high Z'' cocrystals. Further, solid state NMR spectroscopy in conjunction with single crystal X-ray diffraction are demonstrated as significant tools to enhance the understanding of the number of symmetry independent molecules in the crystalline lattice and provide insights to the mechanistic pathways of crystallization. / Department of Science and Technology (DST) Fund for improvement of S & T Infrastructure (FIST) with grant no. SR/FST/CST-266/2015(c) to PS and VP. AN and VV acknowledge the Government of India under National Overseas Scholarship (2012-13) and High Commission of India, London UK for PhD studentship.

PhD. (Department of Biotechnology, Faculty of Applied and Computer Sciences), Vaal University of Technology. / South Africa utilises more antiretroviral (ARV) compounds per capita than any other nation in the fight against Human Immune Deficiency Virus (HIV) or acquired immunodeficiency syndrome (AIDS). Considering the main entrance pathways of antiviral drugs into the urban water cycle, excretions via urine or faeces from treated individuals play a dominant role. Due to the limited efficiency of conventional biological treatment (activated sludge), ARVs were detected in South African wastewater treatment plant effluents and surface waters. This poses a threat to aquatic environments due to the toxicity of ARVs and can be a potential contributor to ARV resistance due to persistent low level ARV exposure in the general population. This study investigated the efficacy of a moving bed biofilm reactor (MBBR) for ctybtri8nthe elimination of five ARV compounds i.e., tenofovir, emtricitabine, nevirapine, ritonavir and efavirenz from synthetic wastewater. Furthermore, the study also looked at the shift in microbial community compositions of biofilms in the MBBR due to exposure to the ARV compounds. Lastly, the ecotoxicity of the MBBR’s influent and effluent along with the actual ARV compounds were examined. The capacity of ARV degradation by the MBBR was investigated by spiking synthetic wastewater influent with 10 μg/L of five ARV compounds. Actual removal during treatment was assessed by sampling the inlets and outlets of the reactor. A targeted solid phase extraction method with Ultra High Pressure Liquid Chromatography coupled to quadrupole time of flight mass spectrometry (LC-MS/MS) was used to quantify the five ARV compounds. Microbial diversity (alpha-diversity) of seeded sludge from a full-scale municipal WWTP and biofilm samples from a laboratory scale MBBR system during pre- and post-introduction of ARV compounds was investigated by Illumina sequencing of the 16S rRNA gene. Ecological toxicity of the MBBR’s influent and effluent along with the five ARV compounds was determined using the Vibrio fischeri, Daphnia magna and Selenastrum capricornutum toxicity test kits and measured as EC50. After MBBR treatment; Nevirapine, Tenofovir, Efavirenz, Ritonavir and Emtricitabine all showed marked reduction in concentration between the influent and effluent of the MBBR. On average, the percentage removed for Nevirapine, Tenofovir, Efavirenz, Ritonavir and Emtricitabine was 62.31%, 74.18%, 93.62%, 94.18% and 94.87% respectively. Microbial diversity results demonstrated that the introduction of antiretroviral drugs affects the bacterial community composition and diversity considerably. For instance, Nitrosomonas, Nitrospira and Alicycliphilus were found to be higher in post introduction of ARV compounds biofilm samples than in biofilm samples before the introduction of ARV compounds. The EC50 for Tenofovir, Emtricitabine, Nevirapine, Ritonavir and Efavirenz were 82.5, 41.7, 39.3, 60.3 and 0.21 mg/L respectively for S. capricornutum; 81.3, 50.7, 49, 87.1 and 0.43 mg/L respectively for D. magna; and 73.5, 55.1, 41.3, 83.6 and 0.55 mg/L respectively for V. fischeri. The EC50 of the influent and effluent were found to be above 100% concentration, therefore they could not be specifically determined. The ecotoxicity results show that ARV compounds are potentially toxic to the environment, with efavirenz being more toxic than the other four ARV compounds tested. Since there were no toxic effects observed from the effluent, it can be assumed that mineralisation has occurred, or the transformation products are of less or equal toxicity to the influent (because the influent did not show any toxic effects to the model organisms tested).