Thesis (MScMedSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: BACKGROUND: The emergence of mycobacterium tuberculosis resistance to first line
drugs has renewed interest in second-line anti-tuberculosis drugs. Generally, Paraaminosalicylic
acid (PAS) is less potent and frequently more toxic than the first line
drugs. Furthermore, the pharmacokinetics of PAS in children has not been well
characterized.
AIMS: The aims of the present study were (1) to determine the pharmacokinetics of
PAS in pediatric patients, (2) to describe the discrepancy between children and adult
pharmacokinetics and the appropriate dosing regimen of PAS and (3) to investigate the
potential of the second-line anti-tuberculosis drugs PAS, terizidone and ethionamide
(often used as first-line drug in children) to inhibit the catalytic activities of CYP450 1A2
and 2C9.
PATIENTS: Twenty two patients with drug resistant tuberculosis were included in the
study. Ten patients were children with mean age of 4.2 years (range: 1 to 12 years).
Twelve patients were adults with mean age of 31.3 years (range: 18 to 53). 4 children
(40%) and 4 adults (33.3%) were HIV positive and were on ART.
METHODS: Children received 75 mg/kg twice daily on the first visit and after two weeks
they received 150 mg/kg once. Adults received a standard 4 g twice daily. Blood
samples were taken at different time points after the dose. In the additional study, the
inhibitory effects of PAS, ethionamide and terizidone on phenacetin O-deethylation, a
marker substrate of CYP1A2 and diclofenac 4’-hydroxylation, a marker substrate of
CYP2C9, were studied using human liver microsomes.
RESULTS: For the 75 mg/kg dose, the mean AUC was 233.3 =g•h/ml and the mean CL
was 10.4 l/h/kg. The mean of the observed Cmax of the drug was 45.4 =g/ml and the
mean Tmax was 4.8 hrs. For the 150 mg/kg dose, the mean AUC of PAS was 277.9
=g•h/ml and the mean CL was 47.1 l/h/kg. The mean of the observed Cmax of the drug
was 56.5 =g/ml and the mean Tmax was 4.8 hrs. On the first visit the mean AUC was 368
=g•h/ml and the mean CL was 13.2 l/h/kg. The mean of the observed Cmax of PAS was
51.3 =g/ml and the mean Tmax was 5.2 hrs. On the second visit the mean AUC was 230 =g•h/ml and the mean CL was 23.9 l/h/kg. The mean of the observed Cmax of PAS was
37.6 =g/ml and the mean Tmax was 5.2 hrs. The comparisons between pharmacokinetics
profile of PAS and patients characteristics e.g. age, indicated no statistically significant
differences between children (both treatment regimens) and adult patients as well as
HIV positive and negative patients. In the in vitro study, all drugs demonstrated no
inhibition potency towards the investigated CYP450 enzymes.
CONCLUSIONS:The dose of 75 mg/kg twice daily in children appears to be appropriate
to achieve serum concentration above the PAS minimum inhibitory concentration of
approximately 1 =g/ml. PAS, ethionamide and terizidone are unlikely to affect the
metabolism of concomitantly administered medications that are metabolized by either
CYP450 1A2 and/or 2C9 isoenzymes. / AFRIKAANSE OPSOMMING: AGTERGROND: Die opkoming van eersteliniemiddel-weerstandige mycobacterium
tuberculosis het opnuut belangstelling in tweedelinie-antituberkulosemiddels
aangewakker. Oor die algemeen is para-aminosalisielsuur (PAS) minder kragtig en
dikwels ook meer toksies. Verder is die farmakokinetika van PAS in kinders nog nie
goed vasgestel nie.
DOELSTELLINGS: Die doelstellings van hierdie studie was (1) om die farmakokinetika
van PAS in pediatriese pasiënte vas te stel, (2) om die diskrepansie tussen kinder- en
volwasse-farmakokinetika, sowel as die toepaslike doseringskedule, van PAS te beskryf
en (3) om die potensiaal van die tweedeline-antituberkulosemiddels PAS, terisidoon en
etioonamied (gereeld gebruik as eerste linie middels in kinders) te ondersoek wat betref
hul vermoë om die katalitiese werking van CYP450 1A2 en 2C9 te inhibeer.
PASIËNTE: Twee-en-twintig pasiënte met middelweerstandige tuberkulose is in hierdie
studie ingesluit. Tien pasiënte was kinders met ‘n gemiddelde ouderdom van 4.2 jaar
(reeks: 1 tot 12 jaar). Twaalf pasiënte was volwassenes met ‘n gemiddelde ouderdom
van 31.3 jaar (reeks: 18 tot 53 jaar). 4 kinders (40%) en 4 volwassenes (33.3%) was
MIV positief en was op TRM’s.
METODES: Kinders het 75 mg/kg twee maal daaliks gedurende die eerste besoek
ontvang en 150 mg/kg een maal ná twee weke ontvang. Volwassenes het ‘n
standaarddosis van 4 g twee maal daagliks ontvang. Bloedmonsters is op verskillende
tye ná die dosering geneem. In die addisionele studie is in die inhiberende effekte van
PAS, etioonamied en terisidoon op fenasetien-O-deëtilering, ‘n merkersubstraat van
CYP1A2 en diklofenak-4’-hidroksilasie, ‘n merkersubstraat van CYP2C9, ondersoek
deur gebruik te maak van menslike lewermikrosome.
RESULTATE: Vir die 75 mg/kg dosis was die gemiddelde area-onder-die-kurwe (AOK)
233.3 =g•h/ml en die gemiddelde middelopruiming (CL) 10.4 l/h/kg. Die gemiddelde
geobserveerde Cmaks van die middel was 45.4 =g/ml en die gemiddelde Tmaks was 4.8 h.
Vir die 150 mg/kg dosering was die gemiddelde AOK van PAS 277.9 =g•h/ml en die
gemiddelde CL 47.1 l/h/kg. Die gemiddelde geobserveerde Cmaks van die middel was 56.5 =g/ml en die gemiddelde Tmaks was 4.8 h. Gedurende die eerste besoek was die
AOK 368 =g•h/ml en die gemiddelde CL was 13.2 l/h/kg. Die gemiddelde
geobserveerde Cmaks van PAS was 51.3 =g/ml en die gemiddelde Tmaks was 5.2 h.
Gedurende die tweede besoek was die gemiddelde AOK 230 =g•h/ml en die
gemiddelde CL 23.9 l/h/kg. Die gemiddelde geobserveerde Cmaks van PAS was 37.6
=g/ml en die gemiddelde Tmaks was 5.2 h. Die vergelyking van PAS-farmakokinetika en
eienskappe van die pasiënte het geen statisties beduidende verskille in die gemiddelde
AOK tussen kinders (op albei doserings) en volwassenes getoon nie. Met die in vitrostudie
het geen van die middels inhibisie-werking teenoor die CYP450-ensieme wat
ondersoek is, getoon nie.
GEVOLGTREKKINGS: Die gevolgtrekking kan gemaak word dat die dosering van 75
mg/kg twee maal daagliks voldoende is om serumkonsentrasies wat bo PAS se
minimum inhiberende konsentrasie van 1 =g/ml te bereik. Dit is onwaarskynlik dat PAS,
etioonamied en terisidoon die metabolisme van gelyktydig-toegediende medikasies, wat
op hul beurt deur die CYP240-isoënsieme 1A2 en/of 2C9 gemetaboliseer word, sal
affekteer. / Division of Pharmacology, Stellenbosch
University / National Research Foundation (NRF) grant generously offered by Professor Donald Grant
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/20165 |
| Date | 03 1900 |
| Creators | Liwa, Anthony Cuthbert |
| Contributors | Bouic, Patrick, Stellenbosch University. Faculty of Health Sciences. Dept. of Medicine. Pharmacology. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | Unknown |
| Type | Thesis |
| Format | xvii, 159 p. : ill. , some col. |
| Rights | Stellenbosch University |
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