Masters Degrees (Clinical Pharmacology)
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Browsing Masters Degrees (Clinical Pharmacology) by Author "Fouche, Desire"
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- ItemDrug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients(Stellenbosch : Stellenbosch University, 2012-03) Fouche, Desire; Rosenkranz, Bernd; Stellenbosch University. Faculty of Health Sciences. Dept. of Medicine. Pharmacology.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.