An analytical investigation of the impact of crushing of first-line antituberculosis medication and administration via a nasogastric tube

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dc.contributor.advisorKellermann, Tracyen_ZA
dc.contributor.authorPhogole, Cassiusen_ZA
dc.contributor.otherFaculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology.en_ZA
dc.date.accessioned2022-11-15T13:55:08Zen_ZA
dc.date.accessioned2023-01-16T12:47:30Zen_ZA
dc.date.available2022-11-15T13:55:08Zen_ZA
dc.date.available2023-01-16T12:47:30Zen_ZA
dc.date.issued2022-11en_ZA
dc.descriptionThesis (MSc) -- Stellenbosch University, 2022.en_ZA
dc.description.abstractENGLISH ABSTRACT: Background Currently, the treatment of TB patients admitted to an intensive care unit (ICU) in South African Hospitals is performed by the off-label practice of crushing the first-line antituberculosis drugs isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB) and administration to the patients through a nasogastric (NG) tube as the majority of these patients are often sedated or intubated and therefore cannot swallow the whole tablets. This has, however, been associated with low drug exposure insufficient to effectively treat the Mycobacterial infection. Additionally, there is a paucity of alternative intravenous (IV) formulations of first-line antituberculosis drugs, especially in developing countries. The stability and solubility of these crushed drugs dissolved in water are questionable. Furthermore, the impact of the removal of the protective outer tablet coating and its effect on absorption and subsequent bioavailability has not been elucidated in the literature. Moreover, drug loss of crushed first-line antituberculosis drugs by adsorption to the surface materials used during medication preparation and administration via NG tube has also not been documented. Therefore, the present study aimed to investigate the root cause of the poor plasma drug exposure observed when crushing the first-line antituberculosis drugs and administration through an NG tube using laboratory-based techniques with possible translational interventions that can be applied in clinical settings to ameliorate their bioavailability. Methods The aqueous solubility of crushed drugs under the inversion mixing method was evaluated against easily implementable mixing methods (sonication and vortexing) with/without ascorbic acid (Asc). Moreover, the aqueous stability assessment of these crushed first-line antituberculosis drugs in mono-suspensions with/without Asc and co-suspensions at room and low temperatures was executed as well. The stability of the whole/crushed tablets in fasted-state simulated gastrointestinal fluids (FSSGIFs) was evaluated with/without Asc. Lastly, the drug loss by adsorption to the surface materials used during medication preparation and in vitro administration through an NG tube was quantitatively determined. Results Rifampicin (RIF) was the only drug showing poor aqueous solubility and instability in the simulated-gastric fluid. However, the addition of Asc has been shown to significantly (P<0.001) improve RIF solubility in both water and FSSGIFs with no detrimental effects. A minimum recommended volume of water (10 ml) to rinse the NG tube after administration of medication was shown to be inadequate to clear off all the residues of crushed antituberculosis medication. However, when an additional rinsing step with another 10 mL of water (total volume of 20 mL) was employed in the current study the amount of APIs of crushed first-line antituberculosis drugs adsorbed to these surface materials was significantly (p<0.001) reduced. Conclusion Co-administration of first-line antituberculosis medication with Asc when off-label crushing practice is used may improve RIF bioavailability. Furthermore, rinsing the NG tube with 20 mL of water after administering TB medication was shown to ensure adequate drug delivery, which may improve the bioavailability of nonpolar drugs that adhere to the surface of an NG tube.en_ZA
dc.description.abstractAFRIKAANS OPSOMMING: Aangesien die meerderheid van TB-pasiënte wat in 'n intensiewesorgeenheid (ICU) in Suid-Afrikaanse Hospitale opgeneem is, dikwels verdoof of geïntubeer word, kan hulle dus nie die hele tablet sluk nie. Daarom word die behandeling van hierdie pasiënte uitgevoer deur die “buite-etiket” praktyk. Dit behels die fynmaak van die eerste-lyn antituberkulose middels, Isoniazid (INH), Rifampisien (RIF), Pirazinamied (PZA) en Etambutol (EMB) en die toediening hiervan aan die pasiënte deur 'n nasogastriese (NG) buis. Dit is egter geassosieer met lae middelblootstelling en dus oneffektiewe behandeling van die Mikobakteriese infeksie. Daarbenewens is daar 'n gebrek aan alternatiewe binneaarse (IV) formulerings van eerste-lyn antituberkulose middels, veral in ontwikkelende lande. Die stabiliteit en oplosbaarheid van hierdie fyngemaakte medikasie wat in water opgelos is, is betwyfelbaar. Verder is die impak van die verwydering van die beskermende buitenste tabletbedekking en die effek daarvan op absorpsie en daaropvolgende biobeskikbaarheid nie in die literatuur toegelig nie. Die verlies aan die fyngemaakte eerste-lyn antituberkulose middels veroorsaak deur die adsorpsie aan die oppervlak materiaal wat gebruik word tydens medikasie voorbereiding en toediening via NG buis is ook nie gedokumenteer nie. Daarom was die doel van hierdie huidige studie om die hoofoorsaak van die lae plasma bloodstelling van hierdie medikasie te ondersoek, wanneer die eerste-lyn antituberkulose middels fyngemaak en deur ‘n NG buis toegedien word. Dit was uitgevoer met moontlike translasie-intervensies wat in kliniese omgewings toegepas kan word om hul biobeskikbaarheid te verbeter. Metodes Die wateroplosbaarheid van gebreekte middels onder die inversiemengmetode is geëvalueer teenoor maklik implementeerbare mengmetodes met/sonder askorbiensuur (Asc). Verder is die waterige stabiliteit assessering van hierdie fyngemaakte eerste-lyn antituberkulose middels in mono- en ko-suspensies met/sonder Asc by kamer en lae temperature ook uitgevoer. Die stabiliteit van die heel/gebreekte tablette in vas-toestand gesimuleerde gastroïntestinale vloeistowwe (FSSGIFs) is geëvalueer met/sonder Asc. Laastens is die geneesmiddelverlies deur adsorpsie aan die oppervlakmateriaal wat tydens medikasievoorbereiding en in vitro toediening deur 'n NG-buis gebruik is, kwantitatief bepaal. Resultate RIF was die enigste middel wat swak wateroplosbaarheid en onstabiliteit in die gesimuleerde maagvloeistof getoon het. Daar is egter getoon dat die byvoeging van Asc aansienlik (P<0.001) RIF-oplosbaarheid in beide water en FSSGIF's verbeter met geen nadelige effekte nie. 'n Minimum aanbevole volume water (10 ml) om die NG-buis na toediening van medikasie te spoel, het getoon dat dit onvoldoende was om al die oorblyfsels van gebreekte antituberkulose-medikasie uit te vee. Wanneer 'n bykomende spoelstap met nog 10 ml water (totale volume van 20 ml) egter in die huidige studie gebruik is, is die hoeveelheid API's van gebreekte eerstelyn-antituberkulosemiddels wat aan hierdie oppervlakmateriale geadsorbeer is, aansienlik verminder (p<0.001). Afsluiting Gesamentlike toediening van eerste-lyn antituberkulose medikasie met Asc wanneer buite-etiket fynmaak praktyk gebruik word, kan RIF biobeskikbaarheid verbeter. Verder is getoon dat die spoel van die NG-buis met 20 ml water na die toediening van TB-medikasie voldoende geneesmiddellewering verseker, wat die biobeskikbaarheid van nie-polêre middels wat aan die oppervlak van 'n NG-buis kleef, kan verbeter.af_ZA
dc.description.versionMastersen_ZA
dc.format.extentxxi, 173 pages : illustrationsen_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/126050en_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subjectAntitubercular agents – South Africaen_ZA
dc.subjectTuberculosis – Patients – South Africaen_ZA
dc.subjectIntensive care units – South Africaen_ZA
dc.subjectTuberculosis -- Treatment – South Africaen_ZA
dc.subjectUCTDen_ZA
dc.titleAn analytical investigation of the impact of crushing of first-line antituberculosis medication and administration via a nasogastric tubeen_ZA
dc.typeThesisen_ZA
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