Thesis (MScMedSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Background: HIV-positive patients have a significantly weakened immune system which
makes them highly susceptible for opportunistic infections, requiring additional treatment.
Cryptococcal meningitis and oropharyngeal candidiasis are treated with oral fluconazole. A
great potential for drug-drug interactions (DDIs) between fluconazole and antiretrovirals
(ARVs), efavirenz, nevirapine, and lopinavir/ritonavir, exists due to interference in common
metabolic pathways. The outcome may result in the development of adverse drug reactions
or drug resistance and treatment failure.
Aim: The primary aim of this thesis was to evaluate the effect of fluconazole on the
pharmacokinetics of efavirenz, nevirapine and lopinavir/ritonavir in HIV-infected patients
diagnosed with cryptococcal meningitis or oropharyngeal candidiasis.
Methods: A prospective study was conducted in 80 HIV-positive, treatment experienced
adults (≥18 years old) treated in three different outpatient clinics in the Western Cape region.
Patients were subdivided according to ARV regimen and the use of fluconazole. A sparse
sampling design was used and corresponding ARV serum concentrations were determined by
established HPLC and GC methods. Fluconazole serum concentrations were determined by a
newly developed HPLC method. Patient characteristics, concomitant medications, clinical
test data and ARV serum concentrations were included in a NONMEM generated, onecompartment,
open pharmacometric model with first order elimination to detect any drugdrug
interactions between fluconazole and the studied ARVs. The secondary outcome was to
establish which patient characteristics influence ARV pharmacokinetics.
Results: From 80 outpatients, a total of 276 ARV serum samples (137 efavirenz, 67
nevirapine and 72 lopinavir) were collected for pharmacokinetic evaluation. Efavirenz
clearance was correlated with race and concomitant use of rifampicin. No significant
covariates were established in the nevirapine model. In the lopinavir model, concomitant use
of clotrimazole and the antituberculosis combination isoniazid, pyrazinamide and rifampicin
were identified as significant covariates.
Discussion: No significant effects of fluconazole on the pharmacokinetics of any of the
studied ARVs were observed. Varying efavirenz plasma concentrations in different ethnic
populations may be due to differences in gene expression particularly CYP2B6. Coloured patients had significantly lower efavirenz serum concentrations (56.8% decrease in
clearance), which has not been previously described in the South African context. Although
gender was not a significant covariate in the nevirapine model, female patients tended to have
higher nevirapine serum concentrations. TB treatment in all patients receiving lopinavir
consisted of a combination of isoniazid, pyrazinamide and rifampicin, each with different
effects on CYP isoenzymes. The exact contributing factor of each drug in the ultimate
decrease in lopinavir clearance (46.4%) can therefore not be established.
Conclusions: Given the limitations of the sample size in the present study, no statistical
significant effect of fluconazole on the pharmacokinetics of the investigated ARVs could be
demonstrated. A retrospective analysis of the data showed various co-factors that influence
the pharmacokinetics of the investigated ARVs. This data needs to be confirmed in a
prospective study as the identified covariates are appropriate in the management of HIVinfected
patients in the South African context. / AFRIKAANSE OPSOMMING: Agtergrond: HIV-positief pasiënte het ‘n aansienlike verswakte immuunstelsel, wat hul
hoogs vatbaar tot opportunistiese infeksies maak, en dus, addisionele behandeling benodig.
Cryptococcal meningitis en orofaringeale kandidiase word met orale flukonasool behandel.
As gevolg van middeling in algemene metaboliese paaie is daar ‘n groot moontlikheid van
middel-middel interaksies tussen flukonasool en die antiretrovirale (ARV) middels,
efavirenz, nevirapine, en lopinavir/ritonavir. Die uitkomste hiervan mag tot die ontwikkeling
van nadelige middel-middel interaksies of middelweerstandigheid en mislukte behandeling
lei.
Doel: Die primêre doel van hierdie tesis was om die effek van flukonasool op die
farmakokinetika van efavirenz, nevirapine en lopinavir/ritonavir in HIV geïnfekteerde
pasiënte met gediagnoseerde cryptococcal meningitis en orofaringeale kandidiase te evalueer.
Metodes: Die studie was met 80 HIV-positief, behandeling-ervare volwassenes (≥18 jaar)
onderneem. Voorafgenoemde was in drie verskillende buitepasiëntklinieke in die Wes-Kaap
behandel. Pasiënte was volgens ARV regimen en die gebruik van flukonasool, of dan nie,
verder verdeel. ‘n Beperkte steekproef ontwerp was gebruik, en ooreenstemmende ARV
serum konsentrasies is deurgevestigde HPLC en GC metodes vasgestel. Flukonasool serum
konsentrasies was deur ‘n nuutontwikkelde HPLC metode vasgestel. Pasiëntkenmerke,
gepaardgaande medikasie, kliniesetoets data en ARV serum konsentrasies was by ‘n
NONMEM genereerde, een-kompartement, oop farmakometriese model met eerste orde
eliminasie ingesluit om enige middel interaksies tussen flukonasool en die bestudeerde ARVs
op te tel. Die sekondêre uitkomste was om vas te stel watter pasiënt kenmerke ARV
farmakokinetika beïnvloed.
Resultate:Uit 80 buitepasïente was ‘n totaal van 276 ARV serum monsters (137 efavirenz,
67 nevirapine en 72 lopinavir) vir farmakokinetiese evaluasie gekollekteer. Efavirenz
opruiming was met ras gekorreleer asook gepaardgaande gebruik van rifampisien. Geen
betekenisvolle ko-variante was in die nevirapine model vasgestel nie. In die lopinavir model
het die gepaardgaande gebruik van clotrimazole en die anti-tuberkulose kombinasie
isoniazied, pyrazinamied en rifampisien, lopinavir opruiming verminder.
Bespreking: In hierdie studie is geen betekenisvolle effekte van flukanosool op die
farmakokinetika van enige van die bestudeerde ARVs waargeneem nie. Afwisselende
efavirenz plasma konsentrasies in verskillende etniese populasies mag aan verskille in
geenuitdrukking, veral CYP2B6, toegeskryf word. Kleurling pasïente het betekenisvolle
verlaagde efavirenz serum konsentrasies getoon (56.8% verlaging in opruiming). Hierdie
bevinding is nog nooit voorheen in die Suid-Afrikaanse konteks beskryf nie. Alhoewel geslag
nie ‘n beduidende ko-variant in die nevirapine model was nie, het vroulike pasïente geneig
om hoer nevirapine serum konsentrasies te hê. TB behandeling, in alle pasïente wat lopinavir
ontvang het, het uit die volgende kombinasie bestaan: isoniazied, pyrazinamied en
rifampisien, elk met hul eie effekte op CYP isoensieme. Die presiese bydra van elke middel
in die uiteindelike verlaging (46.4%) in lopinavir opruiming kan dus nie vasgestel word nie.
Gevolgtrekking: Gegewe die beperkings van die steekproef in die huidige studie, kon geen
statistiese beduidende effek van flukonazool op die farmakokinetika van die betrokke ARVs
gedemonstreer word nie. ‘n Retrospektiewe analise van die data het gewys dat verskeidene
ko-faktore die farmakokinetika van die betrokke ARVs beïnvloed. Hierdie data moet in ‘n
prospektiewe studie bevestig word omdat die geidentifiseerde covariates die bestuur van
MIV-positiewe pasiente in die Suid-Afrikaanse konteks te verbeter.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/20079 |
| Date | 03 1900 |
| Creators | Fouche, Desire |
| Contributors | Rosenkranz, Bernd, 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 | English |
| Type | Thesis |
| Format | 222 p. : ill. |
| Rights | Stellenbosch University |
Page generated in 0.0025 seconds