Thesis (MSc in Medical Science)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Background: Para-aminosalicylic acid (PAS) is one of the first effective anti-tuberculosis agents and has become one of the principal second-line drugs to treat patients with an extended resistance spectrum. Despite being one of the oldest anti-tuberculosis drugs, little data is available regarding its pharmacokinetics, drug interactions, genetic factors and dosing regimens, especially for the relative new granular slow release PAS (GSR-PAS) preparation.
Objectives
The aim of the study was to investigate the pharmacokinetics, tolerability and safety of a single 8 g once- or 4 g twice-daily GSR-PAS dose in a multidrug- or extensively drug resistant tuberculosis (M/XDR-TB) population, in which some subjects were also co-infected with the human immunodeficiency virus (HIV). An additional objective was to investigate the potential covariates (i.e. genetic factors and drug interactions) that can alter the pharmacokinetics of PAS.
Study design and methodology
A randomised, two-period, open-label cross-over study was conducted in 32 adults (≥18 years old) with M/XDR-TB admitted at Brooklyn Chest Hospital, Cape Town, South Africa and treated for drug resistant tuberculosis with a multidrug regimen containing GSR-PAS. The subjects were randomised to follow a single 8 g once-daily GSR-PAS regimen or a 4 g twice-daily GSR-PAS regimen for 8 days. On the eighth day blood samples were obtained at 0, 1, 2, 3, 4, 6, 8, 12 and 24 hours. After the 24-hour sample (Day 9) the regimens were crossed-over. The tolerability and safety of the two regimens were determined using Visual Analogue Scales and interviews. PAS plasma concentrations were determined by a developed HPLC-MS/MS method. N-acetyltransferase (NAT1 and NAT2) genotyping was performed. The data of this study together with unpublished data of a previous study in a very similar population were used in a pharmacometric analysis to determine the PK parameters and any subject covariates.
Results and Discussion
In comparison to the 4 g twice-daily GSR-PAS dose, the single 8 g once-daily GSR-PAS dose generated a pharmacokinetic profile with a significantly higher maximum concentration (Cmax), concentration at 12 hours (C12) and area under the curve 0 to 12 hours (AUC12). The concentrations of all subjects on the twice-daily regimen were maintained above a minimum inhibitory concentration (MIC) throughout a 12-hour interval, while the single 8 g dose was able to sustain the PAS plasma concentrations above the MIC in 18 out of 29 subjects (62.1%) for the entire 24-hour dosing interval. Both regimens were reasonably well tolerated but most subjects preferred the twice-daily dosing. The clearance of PAS was increased by 45% in HIV positive subjects prescribed antiretroviral treatment (ART), possibly due to interaction with efavirenz (EFV). No significant associations were found for any of the individual NAT1 or NAT2 genotypes, but a difference between mean concentrations of the different genotypic groups was reported.
Conclusions
The 8 g once-daily dose has the potential to be included in future regimens. The higher peak concentrations achieved can be expected to increase the bactericidal effect of GSR-PAS without significant loss of bacteriostatic effect, i.e. time over MIC. The 8 g once-daily dose has a reasonable tolerability and is potentially easier to supervise in an outpatient setting. Since antiretrovirals (ARVs) increase PAS clearance and decrease PAS exposure in HIV co-infected subjects on ART, the 8 g once-daily dose will be less suitable for maintaining bacteriostasis in these patients (inadequate PAS exposure). Therefore, PAS and ARV interactions need to be clarified before the 8 g once-daily dose can be recommended for the HIV co-infected patients on ART. / AFRIKAANSE OPSOMMING: Agtergrond
Para-aminosalisielsuur (PAS) is een van die eerste effektiewe anti-tuberkulose middels en het een van die hoof tweede-lyn middels geword om pasiënte met 'n uitgebreide weerstand spektrum te behandel. Ondanks die feit dat PAS die oudste anti-tuberkulose middel is, is daar baie min data beskikbaar met betrekking tot die farmakokinetika, middel interaksies, genetiese faktore en dosering, veral in die geval van die relatiewe nuwe granulêre stadige vrystelbare PAS voorbereiding (GSV-PAS).
Doel
Die doel van die studie was om navorsing te doen oor die farmakokinetika, verdraagsaamheid en veiligheid van ʼn enkele 8 g een keer daaglikse en 4 g twee keer daaglikse GSV-PAS dosering in ʼn multi- of uitgebreide weerstandige tuberkulose (M/XDR-TB) populasie, waar sommige proefpersone ook met die Menslike Immuniteitsgebreksvirus (MIV) geko-infekteer is. ʼn Verdere doel van die studie was om te bepaal of potensiële kovariate soos genetika en medisyne interaksies die farmakokinetika van PAS verander.
Metodes
ʼn Onwillekeurige, twee-periode, oop-etiket oorkruisingstudie was op 32 M/XDR-TB volwassenes (≥ 18 jaar oud) uitgevoer terwyl hulle vir middel weerstandige tuberkulose in Brooklyn Chest hospitaal (Kaapstad, Suid-Afrika) behandel is. Die deelnemers was onwillekeurig ingedeel om ʼn 8 g eenkeer daaglikse GSV-PAS dosering of ʼn 4 g twee keer daaglikse GSV-PAS dosering vir agt dae te volg. Op die agste dag was bloedmonsters op die volgende ure 0, 1, 2, 3, 4, 6, 8, 12, en 24 geneem. Na die 24-uur monster (Dag 9) was die doserings omgekeer. Die verdraagsaamheid en veiligheid van die twee doserings is bepaal deur gebruik te maak van Visueel Analogiese Skale en onderhoude. PAS plasma konsentrasies is bepaal deur 'n ontwikkelde HPLC-MS/MS metode. N-asetieltransferase (NAT1 en NAT2) genotipering is uitgevoer. Die data van hierdie studie saam met ongepubliseerde data van 'n vorige studie is gebruik in farmakometriese analise om die farmakokinetiese parameters en enige kovariate te bepaal.
Resultate en Bespreking
In vergelyking met die 4 g GSV-PAS twee keer daaglikse dosis, het die enkele 8 g daaglikse dosis, ‘n pharmakokinetiese profiel met ‘n beduidende hoër maksimum konsentrasie (Cmax), 12-uur konsentrasie (C12) en area onder die kurwe van 0 tot 12 uur (AUC12), gegenereer.
Die PAS plasma konsentrasies van alle proefpersone, wat op die twee keer daaglikse dosis was, was tydens die 12-uur interval bo die die minimum inhiberende konsentrasie (MIK) gehou. Terwyl die enkele 8 g dosis die PAS plasma konsentrasies vir die duur van die 24 uur interval bo die MIK in 18 van 29 (62%) proefpersone gehandhaaf het. Die meeste proefpersone het die twee-daaglikse dosering verkies, maar beide doserings was redelik goed verdra. Die verwydering van PAS het met 45% toegeneem in HIV positiewe proefpersone wat antiretrovirale behandeling ontvang het, moontlik weens interaksies met efavirenz. Geen beduidende assosiasies vir enige van die individuele NAT1 of NAT2 genotiepes was gevind nie, maar ‘n verskil tussen die gemiddelde konsentrasies van die verskillende genotiepes is gerapporteer.
Gevolgtrekking
Die 8 g een keer daaglikse dosis het die potensiaal om in toekomstige doserings ingesluit te word. Die hoër piek konsentrasies van die 8 g daaglikse dosis, kan moontlik die bakterisidiese (kiem-dodende) effek van GSV-PAS verhoog, sonder om die beduidende bakteriostatiese (kiem-inhiberende) effek (o.a. tyd oor MIK), te verloor. Die 8 g een keer daaglikse dosis is redelik verdraagsaam en kan potensieël makliker gekontrolleer word in die geval van buite-pasiënte. Serdert antiretrovirale middels (ARVs) PAS verwydering verhoog en gevolglik die PAS plasma konsentrasies verlaag in die MIV ko-infekteerde proefpersone wat op ARVs is, sal die 8 g een keer daaglikse dosis minder geskik wees vir die handhawing van bakteriostasis in hierdie pasiënte (onvoldoende PAS blootstelling). Dus moet daar klarigheid verkry word oor PAS en ARV interaksies voordat die 8 g een keer daaglikse dosis vir MIV ko-infekteerde pasiënte op ARVs aanbeveel kan word.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/85726 |
| Date | 12 1900 |
| Creators | De Kock, Lizanne |
| Contributors | Rosenkranz, B., Diacon, A. H., Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Clinical Pharmacology. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | 257 p. : ill. |
| Rights | Stellenbosch University |
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