Browsing by Author "McIlleron, Helen"
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- ItemOpen AccessAssociation of lopinavir concentrations with plasma lipid or glucose concentrations in HIV-infected South Africans: a cross sectional study(BioMed Central Ltd, 2012) Sinxadi, Phumla; McIlleron, Helen; Dave, Joel; Smith, Peter; Levitt, Naomi; Maartens, GaryBACKGROUND: Dyslipidaemia and dysglycaemia have been associated with exposure to ritonavir-boosted protease inhibitors. Lopinavir/ritonavir, the most commonly used protease inhibitor in resource-limited settings, often causes dyslipidaemia. There are contradictory data regarding the association between lopinavir concentrations and changes in lipids.AIM:To investigate associations between plasma lopinavir concentrations and lipid and glucose concentrations in HIV-infected South African adults. METHODS: Participants stable on lopinavir-based antiretroviral therapy were enrolled into a cross-sectional study. After an overnight fast, total cholesterol, triglycerides, and lopinavir concentrations were measured and an oral glucose tolerance test was performed. Regression analyses were used to determine associations between plasma lopinavir concentrations and fasting and 2 hour plasma glucose, fasting cholesterol, and triglycerides concentrations. RESULTS: There were 84 participants (72 women) with a median age of 36 years. The median blood pressure, body mass index and waist: hip ratio were 108/72 mmHg, 26 kg/m2 and 0.89 respectively. The median CD4 count was 478 cells/mm3. Median duration on lopinavir was 18.5 months. The median (interquartile range) lopinavir concentration was 8.0 (5.2 to 12.8) mug/mL. Regression analyses showed no significant association between lopinavir pre-dose concentrations and fasting cholesterol (beta-coefficient 0.04 (95% CI 0.07 to 0.00)), triglycerides (beta-coefficient 0.01 (95% CI 0.04 to 0.02)), fasting glucose (beta-coefficient 0.01 (95% CI 0.04 to 0.02)), or 2-hour glucose concentrations (beta-coefficient 0.02 (95% CI 0.09 to 0.06)). Lopinavir concentrations above the median were not associated with presence of dyslipidaemia or dysglycaemia. CONCLUSIONS: There was no association between lopinavir plasma concentrations and plasma lipid and glucose concentrations.
- ItemOpen AccessCharacterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling(2016) Smythe, Wynand Anton; McIlleron, Helen; Denti, PaoloThis pharmacokinetic sub-study was nested within the phase-III OFLOTUB study investigating the shortening of tuberculosis treatment. A total of 343 adults enrolled in Benin, Guinea, Senegal, and South Africa were randomized to receive rifampicin, isoniazid, pyrazinamide, and ethambutol in the standard 6-month control regimen or the 4-month test regimen where gatifloxacin replaced ethambutol. The pharmacokinetics of all drugs was described at first dose and steady-state using nonlinear mixed-effects modelling, and individual exposures were summarised as area under the concentration-time curve (AUC0-24) and peak concentration. Autoinduction of rifampicin metabolism was characterized with a semi-mechanistic enzyme turn-over model. Gatifloxacin dose was evaluated using Monte Carlo simulations. Lastly, Classification & Regression Tree (CART) analysis techniques were used to identify factors predictive of 2-month culture conversion or 24-month long-term composite outcome. Consistent with literature findings, approximately 73.0, 43.0, 0.3, 6.0 and 0.0% of patients failed to achieve previously reported target concentrations for rifampicin, isoniazid, pyrazinamide, ethambutol, and gatifloxacin, respectively.
- ItemOpen AccessClinical deterioration during antituberculosis treatment in Africa: Incidence, causes and risk factors(BioMed Central Ltd, 2010) Pepper, Dominique; Marais, Suzaan; Wilkinson, Robert; Bhaijee, Feriyl; Maartens, Gary; McIlleron, Helen; De Azevedo, Virginia; Cox, Helen; McDermid, Cheryl; Sokhela, Simiso; Patel, Janisha; Meintjes, GraemeBACKGROUND:HIV-1 and Mycobacterium tuberculosis cause substantial morbidity and mortality. Despite the availability of antiretroviral and antituberculosis treatment in Africa, clinical deterioration during antituberculosis treatment remains a frequent reason for hospital admission. We therefore determined the incidence, causes and risk factors for clinical deterioration. METHODS: Prospective cohort study of 292 adults who initiated antituberculosis treatment during a 3-month period. We evaluated those with clinical deterioration over the following 24 weeks of treatment. RESULTS: Seventy-one percent (209/292) of patients were HIV-1 infected (median CD4+: 129 cells/muL [IQR:62-277]). At tuberculosis diagnosis, 23% (34/145) of HIV-1 infected patients qualifying for antiretroviral treatment (ART) were receiving ART; 6 months later, 75% (109/145) had received ART. Within 24 weeks of initiating antituberculosis treatment, 40% (117/292) of patients experienced clinical deterioration due to co-morbid illness (n = 70), tuberculosis related illness (n = 47), non AIDS-defining HIV-1 related infection (n = 25) and AIDS-defining illness (n = 21). Using HIV-1 uninfected patients as the referent group, HIV-1 infected patients had an increasing risk of clinical deterioration as CD4+ counts decreased [CD4+>350 cells/muL: RR = 1.4, 95% CI = 0.7-2.9; CD4+:200-350 cells/muL: RR = 2.0, 95% CI = 1.1-3.6; CD4+<200 cells/muL: RR = 3.0, 95% CI = 1.9-4.7]. During follow-up, 26% (30/117) of patients with clinical deterioration required hospital admission and 15% (17/117) died. Fifteen deaths were in HIV-1 infected patients with a CD4+<200 cells/muL. CONCLUSIONS: In multivariate analysis, HIV-1 infection and a low CD4+ count at tuberculosis diagnosis were significant risk factors for clinical deterioration and death. The initiation of ART at a CD4+ count of <350 cells/muL will likely reduce the high burden of clinical deterioration.
- ItemOpen AccessDeterminants and consequences of the pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in a cohort of tuberculosis patients(2004) McIlleron, Helen; Folb, Peter I; Little, Francesca; Smith, PeteA prospectlve pharmacokinetic study was conducted amongst a cohort of 142 patients with tuberculosis (TB) susceptible to rifampicin and isoniazid at Brewelsleloof Hospital, Worcester, in the Western Cape.
- ItemOpen AccessDevelopment and validation of liquid chromatography mass spectrometry (L/C/MS/MS) assay for the determination of plasma 4betahydroxycholestrol and cholesterol in HIV infected children in Africa(2015) Ngwalero, Precious; Wiesner, Lubbe; McIlleron, Helen4β-hydroxycholesterol (4β-OHC) is a metabolite of cholesterol formed by Cytochrome (CYP) 3A4/5/7 enzymes. It has recently been proposed as an endogenous biomarker forCYP3A4/5/7 activity. This may be useful in prediction of drug-drug interactions and other metabolic processes affected by regulators of CYP3A activity. The aim of this study was to develop and validate an LC/MS/MS assay for the determination of 4β-OHC in human plasma and use 4β-OHC as a biomarker of CYP3A4/5/7 metabolism in HIV-infected children with and without treatment in Africa. Determination of 4β-OHC from plasma was performed by saponification and derivatisation reaction processes followed by high performance liquid chromatography with MS/MS detection on an AB Sciex Qtrap 5500 mass spectrometer. Since 4β-OHC is an endogenous metabolite in human plasma, a stable isotope labelled (SIL) analogue, 4β-OHC-D7, was used as a surrogate analyte for the preparation of calibration standards and quality controls. A second SIL analogue, 4β-OHC-D4 was used as the internal standard. The transitions of the protonated derivatised products were monitored atm/z 613, 620 and 617 to the product ions m/z 490, 497 and 494 for 4β-OHC, 4β-OHC-D7and 4β-OHC-D4 respectively. The calibration curve fitted a quadratic (weighted by1/concentration2) regression over the range 2-500 ng/ml. Validation accuracy and precision statistics summary for three consecutive runs were between 98.9% and 103%, and 3.5%and 12% respectively of all quality controls. The assay's recovery, selectivity and analyte stability were established. The validated assay was successfully applied on clinical samples, where 4β-OHC was used as a biomarker to investigate the levels of CYP3A induction in HIV-infected children with and without treatment containing non-nucleoside reverse transcriptase inhibitors (NNRI).It was found that plasma 4β-OHC concentrations at baseline were significantly lower in children belonging to the naïve group compared to nevirapine (NVP) and efavirenz (EFV)groups. When NVP and EFV groups were compared at non-baseline treatment weeks, the median 4β-OHC concentrations were significantly higher in EFV group than the NVP group. Regarding the effect of time on treatment, a significant increase in 4β-OHC concentrations was observed from baseline to each of the non-baseline weeks in naïve group. Conversely, in the NVP group, there was a significant decrease in 4β-OHC concentrations from baseline to each of the non-baseline weeks. Time did not show any significant effect on 4β-OHC concentrations in EFV group. Furthermore, at baseline, age, sex and weight did not affect 4β-OHC concentrations in all the three groups. This study has provided a method that would be utilised to determine plasma 4β-OHC concentrations using relatively small volumes - typical of samples taken from children. The results of this study suggest that children on antiretroviral therapy (ART) are at risk of effects of CYP3A induction, as indicated by the increase of 4β-OHC concentrations in the NVP and EFV groups. Additionally, prolonged use of the ART may activate some nuclear receptors that regulate CYP3A enzyme activity thereby negatively affecting, for example, the regulation of lipid and glucose metabolism. The developed method may therefore be useful in predicting drug-drug interactions in the context of multiple therapy and may also be used in predicting other metabolic processes affected by regulators of CYP3A activity. Further prospective studies with larger sample sizes are required to confirm and build on the evidence shown in this study.
- ItemOpen AccessThe development, implementation and validation of a plasma-based high performance liquid chromatographic assay for Isoniazid and N-Acetylisoniazid: an acetylator status population study at Brewelskloof Hospital(2001) Cockcroft, Jennifer Jean; Smith, Peter; McIlleron, HelenA novel high performance liquid chromatographic assay has been developed for the simultaneous determination of isoniazid and N-acetylisoniazid in plasma. Solid phase extraction involving C18 columns is used to extract the drug and the metabolite from 0.5 ml plasma. The analyte peaks are resolved using a CB Spherisorb analytical column and ultraviolet detection at 270 nm. The assay is specific to the compounds, with consistent recovery of greater than 75% for isoniazid and over 90% for N-acetylisoniazid. The limits of detection in plasma are 300 ng/ml and 150 ng/ml for isoniazid and N-acetylisoniazid respectively. Linearity was conserved down to these concentrations. This assay was used to generate pharmacokinetic data on 114 tuberculosis patients recruited for this study at Brewelskloof hospital, Worcester, South Africa. Using these data, various markers were investigated for the determination of acetylator phenotype, namely isoniazid half-life, isoniazid plasma level at three hours, and the ratio of metabolite to drug at three hours. The ratio of metabolite to drug at three hours proved to be the most reliable method for phenotype classification, this being confirmed during the genotypic portion of the study. Trimodality was evident, although the nondiscrete separation of intermediate and rapid acetylators made this tentative. The mean values of area under the concentration-time curve for each acetylator type were found to be significantly different, with rapid acetylators being potentially compromised in terms of exposure to isoniazid (slow 32.39 mg. l⁻¹.hr, intermediate 21.25 mg. l⁻¹.hr and rapid 16.04 mg. l⁻¹.hr). Other pharmacokinetic parameters were bimodally distributed, homozygous and heterozygous rapid acetylators forming a single acetylator group. Codominance of the rapid and slow alleles was confirmed, the estimation of a mean intermediate elimination rate constant being within 7% of the observed mean. The correlation of genotype to phenotype was found to be 88.2% and the allelic distribution was determined to be acceptable using the Hardy Weinberg equation. The incidence of raised liver enzyme levels was low in the study population with no relation to acetylator phenotype. Age and weight gain after two months of daily therapy did not correlate with phenotype. The slow acetylator population comprised of a greater proportion of men, while women exhibited twice the number of rapid acetylators. No patient factors could be implicated in the apparent discordance of phenotype with genotype, and this suggests that there may be new allelic variants in this population. This report provides validation and proves the usefulness of a novel HPLC plasma-based assay for determining isoniazid and N-acetylisoniazid levels in patients with tuberculosis.
- ItemOpen AccessEffect of rifampicin-based antitubercular therapy on nevirapine plasma concentrations in South African adults with HIV-associated tuberculosis(2013) Cohen, Karen; Maartens, Gary; McIlleron, HelenSub-Saharan Africa is overwhelmed by dual epidemics of human immunodeficiency virus (HIV) and tuberculosis (TB) infection. Non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) is recommended for first-line treatment in adult HIV treatment programmes in resource-limited settings [1]. Many South African HIV-infected patients initiate ART while on TB treatment, 38 percent in one local study [2]. In addition, although ART reduces the incidence of TB, incidence in patients on ART is higher than in the HIV uninfected population [3], therefore incident TB on ART requiring concomitant treatment is very common. Efavirenz is regarded as the NNRTI of choice for TB co-infected patients [1] as outcomes are superior compared to those achieved with nevirapine-based ART [4] and concomitant TB treatment does not significantly reduce efavirenz concentrations [5]. However nevirapine is cheaper than efavirenz and is used extensively used in lower income countries with limited access to efavirenz [1]. Data characterising the extent to which concomitant rifampicin-based TB treatment decreases nevirapine plasma concentration therefore remain important.
- ItemOpen AccessIsoniazid and acetylisoniazid urine concentrations as a maker of adherence to isoniazid preventative therapy in children(2013) Amlabu, Veronica Asibi; McIlleron, Helen; Smith, PeteThe World Health Organization recommends the use of isoniazid preventive therapy to reduce the incidence of tuberculosis disease in populations at risk for developing the disease. Adherence to isoniazid preventive therapy is needful for efficacy. A urine assay known as the Arkansas test is widely used to monitor the ingestion of isoniazid. However, this test is limited by a drop in sensitivity with increasing time post isoniazid dose. Furthermore, results from the test can be affected by observer variation in colour changes, concomitant medications, urinary dilution, and presence of other substances in urine. Moreover, the Arkansas test results have not been evaluated against objective measurement of isoniazid and acetylisoniazid urine concentrations. This study seeks to measure the urine concentrations of isoniazid and acetylisoniazid at different time points after a dose in children, in order to establish reference ranges for liquid chromatography tandem mass spectrometry measurements of urine isoniazid and acetylisoniazid, as well as the Arkansas method. The reference ranges would provide a standard which can be used to estimate the probability of adherence to prior doses.
- ItemOpen AccessLack of association between stavudine exposure and lipoatrophy, dysglycaemia, hyperlactataemia and hypertriglyceridaemia: a prospective cross sectional study(BioMed Central Ltd, 2010) Sinxadi, Phumla; van der Walt, Jan-Stefan; McIlleron, Helen; Badri, Motasim; Smith, Peter; Dave, Joel; Levitt, Naomi; Maartens, GaryBACKGROUND: Stavudine continues to be widely used in resource poor settings despite its toxicity. Our objective was to determine association between plasma stavudine concentrations and lipoatrophy, concentrations of glucose, lactate and triglycerides. METHODS: Participants were enrolled in a cross-sectional study with lipoatrophy assessment, oral glucose tolerance test, fasting triglycerides, finger prick lactate, and stavudine concentrations. Individual predictions of the area under the concentration curve (AUC) were obtained using a population pharmacokinetic approach. Logistic regression models were fitted to assess the association between stavudine geometric mean ratio > 1 and impaired fasting glucose, impaired glucose tolerance, hyperlactataemia, hypertriglyceridaemia, and lipoatrophy. RESULTS: There were 47 study participants with a median age of 34 years and 83% were women. The median body mass index and waist:hip ratio was 24.5 kg/m2 and 0.85 respectively. The median duration on stavudine treatment was 14.5 months. The prevalence of lipoatrophy, impaired fasting glucose, impaired glucose tolerance, hyperlactataemia, and hypertriglyceridaemia were 34%, 19%, 4%, 32%, and 23% respectively. Estimated median (interquartile range) stavudine AUC was 2191 (1957 to 2712) ng*h/mL. Twenty two participants had stavudine geometric mean ratio >1. Univariate logistic regression analysis showed no association between stavudine geometric mean ratio >1 and impaired fasting glucose (odds ratio (OR) 2.00, 95% CI 0.44 to 9.19), impaired glucose tolerance (OR 1.14, 95% CI 0.07 to 19.42), hyperlactataemia (OR 2.19, 95%CI 0.63 to 7.66), hypertriglyceridaemia (OR 1.75, 95%CI 0.44 to 7.04), and lipoatrophy (OR 0.83, 95% CI 0.25 to 2.79). CONCLUSIONS: There was a high prevalence of metabolic complications of stavudine, but these were not associated with plasma stavudine concentrations. Until there is universal access to safer antiretroviral drugs, there is a need for further studies examining the pathogenesis of stavudine-associated toxicities.
- ItemOpen AccessManagement of HIV-associated tuberculosis in resource-limited settings: a state-of-the-art review(BioMed Central Ltd, 2013) Lawn, Stephen; Meintjes, Graeme; McIlleron, Helen; Harries, Anthony; Wood, RobinThe HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited settings. Reducing the nearly 0.5 million deaths that result each year has been identified as a key priority. Major progress has been made over the past 10 years in defining appropriate strategies and policy guidelines for early diagnosis and effective case management. Ascertainment of cases has been improved through a twofold strategy of provider-initiated HIV testing and counseling in TB patients and intensified TB case finding among those living with HIV. Outcomes of rifampicin-based TB treatment are greatly enhanced by concurrent co-trimoxazole prophylaxis and antiretroviral therapy (ART). ART reduces mortality across a spectrum of CD4 counts and randomized controlled trials have defined the optimum time to start ART. Good outcomes can be achieved when combining TB treatment with first-line ART, but use with second-line ART remains challenging due to pharmacokinetic drug interactions and cotoxicity. We review the frequency and spectrum of adverse drug reactions and immune reconstitution inflammatory syndrome (IRIS) resulting from combined treatment, and highlight the challenges of managing HIV-associated drug-resistant TB.
- ItemOpen AccessManagement of HIV-associated tuberculosis in resource-limited settings: a state-of-the-art review(BioMed Central, 2013-12-02) Lawn, Stephen D; Meintjes, Graeme; McIlleron, Helen; Harries, Anthony D; Wood, RobinThe HIV-associated tuberculosis (TB) epidemic remains a huge challenge to public health in resource-limited settings. Reducing the nearly 0.5 million deaths that result each year has been identified as a key priority. Major progress has been made over the past 10 years in defining appropriate strategies and policy guidelines for early diagnosis and effective case management. Ascertainment of cases has been improved through a twofold strategy of provider-initiated HIV testing and counseling in TB patients and intensified TB case finding among those living with HIV. Outcomes of rifampicin-based TB treatment are greatly enhanced by concurrent co-trimoxazole prophylaxis and antiretroviral therapy (ART). ART reduces mortality across a spectrum of CD4 counts and randomized controlled trials have defined the optimum time to start ART. Good outcomes can be achieved when combining TB treatment with first-line ART, but use with second-line ART remains challenging due to pharmacokinetic drug interactions and cotoxicity. We review the frequency and spectrum of adverse drug reactions and immune reconstitution inflammatory syndrome (IRIS) resulting from combined treatment, and highlight the challenges of managing HIV-associated drug-resistant TB.
- ItemOpen AccessOptimization of 1st-line antituberculosis dosing regimens using a population pharmacokinetic approach: food effects, drug combinations and pharmacological effects(2014) Zvada, Simbarashe Peter; McIlleron, Helen; Simonsson, USHThe aim of this thesis was to evaluate optimal doses of 1st-line antituberculosis dosing regimens using a population pharmacokinetic approach, quantify food effects, drug combinations and pharmacological effects. The population pharmacokinetics of rifampicin, isoniazid and pyrazinamide in 76 children with tuberculosis were described using a population pharmacokinetic approach, and then Monte Carlo simulation were performed to evaluate adequacy of newly recommended weight band based doses in World Health Organisation (WHO) guidelines. Food effect (breakfast) was evaluated on rifapentine pharmacokinetic data in 35 healthy male volunteers. Effect of co-administered intermittent rifapentine on the pharmacokinetics of moxifloxacin was evaluated in 28 patients with pulmonary tuberculosis, who participated in a multicenter controlled clinical trial evaluating high dose rifapentine in combination with moxifloxacin. The moxifloxacin pharmacokinetic model, together with a previously published ofloxacin pharmacokinetic model, was used to evaluate the efficacy between moxifloxacin and ofloxacin. Furthermore, pharmacokinetic summary variables of rifapentine and moxifloxacin were evaluated as predictors of treatment outcome. Simulations based on the final models suggested that with the new guidelines, and utilizing available paediatric fixed dose combinations, children will receive adequate rifampicin exposures when compared to adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. For food effect, all meals compared with the fasting state, high fat meal had the greatest effect on rifapentine oral bioavailability, increasing it by 86%; bulky low-fat, bulky-high-fat, and chicken soup resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for the metabolite 25-desacetyl rifapentine. For drug-resistant tuberculosis, using a target ratio of ≥100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the cumulative fraction of response (CFR) was 88% for moxifloxacin and only 43% for ofloxacin. The higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of ≥90%. In terms of drug-interaction, rifapentine increased the clearance of moxifloxacin by 8% during antituberculosis treatment compared to that after treatment completion without rifapentine. Also, the effect moxifloxacin and rifapentine pharmacokinetics indices on outcome treatment outcome support that combined effect of longer treatment duration and higher rifapentine exposures are associated with better treatment response. In summary, the newer WHO doses for children may give lower pyrazinamide and isoniazid exposures in many children than in adults. Meals have a substantial impact on rifapentine exposure. Rifapentine did not result in a clinically significant change in moxifloxacin exposure. Moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. The combined effect of longer treatment duration, higher rifapentine exposures are associated with better treatment outcome, but could not differentiate which major factor needed for favourable outcome.
- ItemOpen AccessPharmacokinetic-Pharmacogenetic-and-Pharmacodynamic Adherence Relationships in Cohort South African HIV Infected Children on Lopinavir-and Nevirapine-Based Regimens(2019) Moholisa, Retsilisitsoe R; McIlleron, Helen; Maartens, Gary; Sinxadi, PhumlaBackground: Antiretroviral therapy (ART), notably lopinavir and nevirapine substantially reduces Human immune-deficiency virus (HIV) associated morbidity and mortality in HIVinfected children. Low concentrations of nevirapine and lopinavir have been linked to inferior virological outcomes; it is recommended that lopinavir and nevirapine concentrations are maintained above 1 mg/L and 3 mg/L, respectively, in order to maintain viral suppression. Adherence to both lopinavir and nevirapine ART, respectively has long known to be a crucial contributor to HIV treatment success. Lopinavir and nevirapine pharmacokinetics demonstrate considerable inter-individual variability, which may affect treatment outcomes. At least part of this variability may be explained by host genetic factors. Associations between human genetic variants and exposure to lopinavir and nevirapine are incompletely understood, and have not been studied in a South African paediatric population. Data in this thesis were from a clinical trial conducted at Rahima Moosa Mother and Child Hospital in Johannesburg to assess whether NVP can be re-used (Post-randomization Phase) among 323 children exposed to NVP for PMTCT if they are first suppressed on ritonavir-boosted lopinavir based regimen (Pre-randomization Phase). This thesis assessed the relationship between serial clinic visits lopinavir (Pre-and-Post-randomization) and nevirapine (Postrandomization) concentrations and/or percentage adherence(Pre-and-Post-randomization) and virological outcomes in children. Moreover, population pharmacokinetics models were used to characterise lopinavir and nevirapine parameters. From the final models parameters were derived and were used to assess the relationship between lopinavir and nevirapine pharmacokinetics and genetic polymorphism relevant to both drugs Methods: Cox proportional hazard regression modelling for multiple failure events was used to estimate the crude and adjusted hazard effect of lopinavir (Pre-and Post-randomization) and nevirapine(Post-randomization) concentrations and/or percent adherence(Pre-and Post-randomization) of viral load>400 copies/mL (Pre-randomization) and >50 copies/mL (Post-randomization), respectively. The population means and variances of lopinavir and nevirapine pharmacokinetic parameters at steady state were estimated using non-linear mixed-effects regression. The final models of lopinavir and nevirapine were used to derive individual clearances (CL/F), minimum concentrations (Cmin) and area under the concentration time curves (AUC). The associations between model-derived pharmacokinetic parameters and genotypes in selected genes relevant to lopinavir or nevirapine were explored. Results: In 237 children pre-randomization with viral loads and lopinavir concentrations, the crude and adjusted Cox models revealed significant associations between virologic failure (viral load>400 copies/mL) and both lopinavir plasma concentrations (<1/mg/L) and pretreatment height-for-age z-scores but not percent adherence. In 99 children postrandomization, lopinavir concentrations >1 mg/L reduced the risk of viremia (viral load >50 copies/mL) with about 40%, compared to children with LPV <1 mg/L. No association was found with percent adherence in this group. In 95 children on nevirapine post-randomization, nevirapine concentrations were not significantly associated with increased hazard of viremia (viral load >50 copies/mL). Similarly, there was no significant association with percent adherence in this group. Lopinavir and nevirapine pharmacokinetics were both separately best described with a one compartment models with absorption lag time and transit compartment absorption models, respectively. There was an age driven effect on lopinavir and nevirapine relative bioavailability, respectively. After adjusting for multiple testing, there was no significant association between lopinavir CL/F, Cmin and AUC and genetic polymorphisms in the ABCB1, CYP3A4, CYP3A5 and SLCO1B1. CYP2B6 516G→T and CYP2B6 983T→C were associated with NVP CL/F. CYP2B6 983T→C was associated with NVP Cmin and AUC. Additionally, polymorphisms in the ABCB1 and CYP3A5 were independently associated with NVP CL/F, Cmin and AUC. Conclusions: Lopinavir concentrations <1mg/L were associated with the increased hazard of viremia (viral load >400 copies/mL or >50 copies/mL). The results suggest that lopinavir plasma concentration monitoring at a routine clinic visit may be a useful tool in identifying sub-therapeutic antiretroviral concentrations in children, and this could be used as a guide to therapeutic drug monitoring in children. There was no statistically significant association between polymorphisms in the ABCB1, CYP3A4, CYP3A5 and SLCO1B1 and lopinavir pharmacokinetics. Polymorphisms in the ABCB1, CYP2B6 CYP3A4 and CYP3A5 predicted nevirapine pharmacokinetics.
- ItemOpen AccessPharmacokinetics, pharmacogenetics and optimisation of treatment with non-nucleoside reverse transcriptase inhibitors in HIV-infected African children(2017) Bienczak, Andrzej Marek; Denti, Paolo; McIlleron, HelenEfavirenz and nevirapine are the most widely used agents for treatment of HIV in children. Sources of variability in their pharmacokinetics and its association with virological outcome and adverse events in African children are poorly characterised, thereby limiting treatment optimisation. To fill this gap we studied population pharmacokinetics (PK) of efavirenz and nevirapine in 478 children from CHAPAS-3 (aged 0.3-1.5 years) using non-linear mixed effects modelling and identified predictors of treatment outcome and PK thresholds most predictive of increased risk of nonsuppression using Cox proportional hazards regression models and likelihood profiling. Efavirenz PK was described by 2-compartment disposition model with 1st-order elimination and transit-compartment absorption and nevirapine by 1-compartment model with elimination through a well-stirred liver model and transit-compartment absorption. Combined effect of SNPs 516GT and 983TC was the strongest predictor of between-subject variability in clearance (89% and 68% decrease between fastest/slowest CYP2B6 metabolic subgroups for efavirenz and nevirapine, respectively). PK was affected by weight, described with allometric scaling. Nevirapine intrinsic clearance displayed diurnal variations (oscillations of amplitude 29%, maximum at 12 noon), while age affected pre-hepatic bioavailability (31.7% lower at birth and increasing exponentially). In antiretroviral treatment (ART)-naïve children (n=325) increased exposures were associated with decreased risk of non-suppression for both drugs. In efavirenz, risk further increased for children>8 years and for younger boys; in nevirapine for high pre-ART VL, low pre-ART CD4% and low adherence. Thresholds most predictive of non-suppression in efavirenz were: Cmid-dose=1.12 mg/L, Cmin=0.65 mg/L and AUC0-24=28 mg∙h/L, while nevirapine had no clear threshold. Adverse events were infrequent in efavirenz, whereas in nevirapine transient transaminase elevations >grade 1 were associated with Cmin>12.4 mg/L. Non-nucleoside reverse transcriptase inhibitors dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C, in particular for efavirenz where we observe 10-fold differences in exposures between metabolic subgroups. Moreover the target Cmin and AUC0-24 could be lowered in children for efavirenz. Treatment initiation at lower pre-ART VL and higher pre-ART CD4%, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity.
- ItemOpen AccessThe Plasma, Whole Blood and Intracellular Concentrations of Antiretroviral Agents in South African Children Receiving Combination Antiretroviral Therapy with and without Concomitant Antitubercular Treatment(2009) Ren, Yuan; McIlleron, Helen; Smith, PJBackground: Tuberculosis (TB) is the most common opportunistic infection in children with human immunodeficiency virus (HIV) infection in developing countries, and co-treatment for HIV infection and TB is frequently indicated. Efavirenz and lopinavir/ritonavir (ratio 1:1) as part of antiretroviral therapy are used in combination with rifampicin-based antitubercular treatment in South African TB/HIV co-infected children. Adult studies show that concomitant rifampicin significantly reduces efavirenz and lopinavir plasma concentrations. However, the pharmacokinetics (PK) of efavirenz and lopinavir/ritonavir are poorly characterized in children, especially African children and no study has evaluated the effect of rifampicin-based antitubercular treatment on efavirenz and lopinavir/ritonavir plasma concentrations in children. Although therapeutic drug monitoring (TDM) is recommended in selected patients (including young children and patients receiving concomitant antitubercular treatment), TDM is seldom available in resource-constrained countries. There is an urgent need to develop a field friendly method which requires small volumes of blood, and inexpensive processing and storage conditions. Furthermore, because HIV replicates in the cells, efavirenz and lopinavir need to penetrate into these infected cells to inhibit viral replication. Therefore, directly measurement of intracellular concentrations of these drugs in HIV-infected children could provide better understanding of drug exposure at the action site. It is also important to evaluate the effects of frequently co-administered drugs on intracellular accumulation of efavirenz and lopinavir. Objectives: 1) To evaluate efavirenz and lopinavir/ritonavir plasma concentrations and determine the effects of rifampicin on efavirenz and lopinavir/ritonavir PK in HIV-infected African children with and without rifampicin-based antitubercular treatment. 2) To develop and validate the dried blood spot (DBS) method as an alternative to conventional plasma methods of drug concentration measurement in TDM. 3) To evaluate in vivo intracellular concentrations of efavirenz and lopinavir/ritonavir in HIV-infected children with and without concomitant antitubercular treatment. 4) To determine the in vitro modulation effects on the intracellular accumulation of efavirenz IV and lopinavir in human peripheral blood mononuclear cells (PBMCs) by drug efflux protein inhibitors, as well as frequently co-administered rifampicin and ritonavir (at low dose; as pharmacoenhancer). Methods: 1) Plasma efavirenz and lopinavir/ritonavir concentrations were measured by validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method in TB/HIV co-infected children during and after rifampicin-based antitubercular treatment as well as in a group of controls (HIV-infected children without TB). Children in the efavirenz study (n= 30) were receiving standard doses of efavirenz as part of antiretroviral treatment. Trough concentrations (Cmin) of efavirenz were estimated by extrapolation of the log-linear concentration-time line to 24 hours after the previous dose. Children in the lopinavir/ritonavir study were receiving additional ritonavir (lopinavir: ritonavir ratio 1:1) during antitubercular treatment (n= 15), and standard doses of lopinavir/ritonavir (LPV/r; ratio 4:1) after antitubercular treatment, and in controls (n= 15). The PK of lopinavir and ritonavir were characterized from concentration-time curves using WinNonlin version 4.1 by non-compartmental analysis. 2) Aliquots of 50 μ L of whole blood from the efavirenz and lopinavir/ritonavir studies were dried onto filter paper. The drug concentrations were analyzed using validated LC/MS/MS method. The effects of high temperature and direct sunlight on the stabilities of these antiretroviral drugs in DBS samples were tested. 3) Intracellular concentrations of efavirenz, lopinavir and ritonavir were measured in trough concentrations of 11 TB/HIV co-infected children using a validated LC/MS/MS method. Six children were receiving double dose of LPV/r (4:1) with concomitant rifampicin; 5 children were receiving standard doses of efavirenz with rifampicin-based antitubercular treatment, 3 of them had intracellular concentrations measured again after completing rifampicin-based antitubercular treatment. 4) in vitro intracellular accumulation of efavirenz and lopinavir were measured in human PBMCs in the absence and presence of P-glycoprotein inhibitors (verapamil at 50 μ M, V furosemide at 50 μ M and cyclosporine A at 20 μ M) and frequently co-administered drugs at levels representing the average concentrations found in patients (ritonavir at 5 mg/L and rifampicin at 4 mg/L). The concentrations of efavirenz and lopinavir in PBMCs were determined by LC/MS/MS. Results and Conclusions: 1) The co-administration of rifampicin did not significantly reduce efavirenz estimated Cmin concentrations. A high proportion of children with and without concomitant antitubercular treatment had sub-therapeutic efavirenz concentrations despite being correctly dosed according to the manufacturer's instructions, raising concerns about the adequacy of current efavirenz dosing recommendations in children. The lopinavir key PK parameter, Cmin, was not significantly different in same group of children during and after rifampicin-based antitubercular treatment or compared to HIV-infected children without tuberculosis. The recommended minimum therapeutic concentration was achieved in 87% of children during antitubercular treatment and in 92% without concomitant antitubercular treatment. Therefore, in the context of limited options, LPV/r with additional ritonavir (ratio 1:1) is an acceptable approach to treat young children receiving concomitant rifampicin-based antitubercular treatment, although safety remains a concern and hepatic alanine transaminase levels should be monitored regularly. 2) Plasma and DBS concentrations of efavirenz, lopinavir and ritonavir were strongly correlated. The median (interquartile range, IQR) DBS/plasma concentration ratios for efavirenz, lopinavir and ritonavir were 0.93 (IQR 0.83, 1.08), 0.73 (IQR 0.61, 0.90) and 1.05 (IQR 0.74, 1.21), respectively. PK parameters of efavirenz and ritonavir were closely similar between DBS and plasma; whereas lopinavir pre-dose and Cmin (at 12 hours after lopinavir intake) concentrations were 16% lower in DBS samples. The 3 antiretroviral drugs in DBS samples were stable at 37 deg C for 7 days and with exposure to direct sunlight for 2 hours. DBS can be used as an alternative field-friendly method for efavirenz, lopinavir and ritonavir concentration monitoring. However, pre-dose and Cmin concentrations of lopinavir in DBS samples need to be increased by 16% when used to predict plasma concentrations. VI 3) In vivo median intracellular/plasma concentration ratios for efavirenz, lopinavir and ritonavir amongst 11 TB/HIV co-infected children during antitubercular treatment were 0.91 (IQR 0.54, 1.19), 0.22 (IQR 0.09, 0.31) and 4.17 (IQR 1.30, 7.33), respectively. Two children had efavirenz intracellular/plasma concentration ratios during vs. after antitubercular treatment: 1.00 vs. 0.61 and 0.27 vs. 0.79. 4) Furosemide significantly increased efavirenz and lopinavir accumulation in healthy human PBMC samples by 1.2- 1.5 fold. Whereas, neither verapamil nor cyclosporin A had significant effects on efavirenz or lopinavir intracellular accumulation. Despite being an inducer of P-glycoprotein, rifampicin increased the accumulation of both efavirenz and lopinavir to different extents in all 3 PBMC samples. The low-dose ritonavir (at the concentration found in HIV-infected patients) had no effect on intracellular accumulation of efavirenz and lopinavir at therapeutic concentrations.
- ItemOpen AccessPopulation pharmacokinetic models describing drug-drug interactions and variability in HIV infected South Africans on protease inhibitor-based antiretroviral regimens with and without tuberculosis(2012) Chao, Zhang; McIlleron, HelenLopinavir/ritonavir is an important component of the first-line and second-line antiretroviral treatment for young children and adults respectively in the current World Health Organization guidelines. Rifampicin, a key component of antituberculosis treatment, profoundly reduces lopinavir concentrations. Therefore, investigation of the optimal dosage regimens of lopinavir/ritonavir when co-administered with rifampicin-based antituberculosis treatment is needed urgently. Moreover, treatment adherence is associated with virological and clinical responses to antiretroviral treatment, and reduced adherence leads to the development of drug resistance. The projects in this thesis were designed to characterize the population pharmacokinetic parameters of lopinavir and ritonavir in HIV infected South Africans, to account for the drug-drug interactions between lopinavir, ritonavir and rifampicin, to investigate optimal dose regimens of lopinavir/ritonavir when administered with rifampicin, and to investigate new approach to evaluate adherence.
- ItemOpen AccessPopulation pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs(2013) Chigutsa, Emmanuel; McIlleron, Helen; Kirkpatrick, CarlThe pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in 78 patients with tuberculosis were described using non-linear mixed effects modeling. Pharmacodynamic data was comprised of weekly sputum liquid culture (using mycobacterial growth indicator tubes) time to detection results from 144 patients during the first 2 months of treatment. The effect of drug exposure on patient outcomes was investigated. To determine the adequacy of ofloxacin drug exposure, the probability of attaining the required area-under-the-curve to minimum inhibitory concentration ratio (AUC/MIC) of ofloxacin was determined in 65 patients on treatment for multidrug resistant tuberculosis. To improve efficiency in the clinical development of new drug regimens, clinical trial simulation was used to determine the optimal study design for a study investigating the efficacy of a new antitubercular drug regimen. The SLCO1B1 rs4149032 polymorphism existed at a high frequency of 0.70 in South Africans and resulted in a 28% decrease in bioavailability of rifampicin. The rifampicin peak concentration was a significant predictor of the 2 month treatment outcomes. A semimechanistic time to event model was developed to analyze days to positivity (time to detection) data. The model was comprised of a biexponential decay model describing bacillary decline in sputum from patients, followed by a logistic model with a lag time for growth of the mycobacteria in liquid culture. For the current 800 mg daily dose of ofloxacin, the probability of attaining an AUC/MIC target ratio of at least 100 was only 0.45. Based on clinical trial simulation, the optimum parallel study design was comprised of 125 study participants in each of 2 arms to achieve a study power of at least 80%. Increasing the study length beyond 42 days reduced study power perhaps due to increased amounts of censored data. Higher doses of rifampicin are required in the majority of South African patients with tuberculosis. A novel pharmacodynamic model of tuberculosis treatment is presented, which can be used for investigation of covariates such as drug exposure. Ofloxacin should be replaced with a more potent fluoroquinolone for treatment of multidrug resistant tuberculosis. Clinical trials should not be unduly long otherwise this may compromise study power.
- ItemOpen AccessRandomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy(2014-11-19) Naiker, Suhashni; Connolly, Cathy; Wiesner, Lubbe; Kellerman, Tracey; Reddy, Tarylee; Harries, Anthony; McIlleron, Helen; Lienhardt, Christian; Pym, AlexanderAbstract Background Pharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV/r. Sub-optimal dosing can lead to acquired rifamycin resistance (ARR). The plasma concentration of 25-O-desacetylrifabutin (d-RBT), the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity. Methods and results Sixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and LPV/r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0–48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio (90% CI) for AUC0–48 and Cmax was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for RBT 150 mg tiw compared with RBT 300 mg and 0.4 (0.4-0.4) and 0.5 (0.5-0.6) for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24 < 4.5 μg.h/mL, which has previously been associated with acquired rifamycin resistance (ARR). Plasma d-RBT concentrations increased 5-fold with tiw rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. One case of uveitis (grade 4), occurred in a patient taking rifabutin 300 mg daily prior to starting ART, and grade 3 neutropenia (asymptomatic) was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations. Conclusions A daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR. Trial registration ClinicalTrials.gov Identifier: NCT00640887
- ItemOpen AccessRifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis(BioMed Central Ltd, 2009) Schaaf, Hendrik S; Willemse, Marianne; Cilliers, Karien; Labadarios, Demetre; Maritz, Johannes S; Hussey, Gregory D; McIlleron, Helen; Smith, Peter; Donald, Peter RBACKGROUND: Rifampin is a key drug in antituberculosis chemotherapy because it rapidly kills the majority of bacilli in tuberculosis lesions, prevents relapse and thus enables 6-month short-course chemotherapy. Little is known about the pharmacokinetics of rifampin in children. The objective of this study was to evaluate the pharmacokinetics of rifampin in children with tuberculosis, both human immunodeficiency virus type-1-infected and human immunodeficiency virus-uninfected. METHODS: Fifty-four children, 21 human immunodeficiency virus-infected and 33 human immunodeficiency virus-uninfected, mean ages 3.73 and 4.05 years (P = 0.68), respectively, admitted to a tuberculosis hospital in Cape Town, South Africa with severe forms of tuberculosis were studied approximately 1 month and 4 months after commencing antituberculosis treatment. Blood specimens for analysis were drawn in the morning, 45 minutes, 1.5, 3.0, 4.0 and 6.0 hours after dosing. Rifampin concentrations were determined by liquid chromatography tandem mass spectrometry. For two sample comparisons of means, the Welch version of the t-test was used; associations between variables were examined by Pearson correlation and by multiple linear regression. RESULTS: The children received a mean rifampin dosage of 9.61 mg/kg (6.47 to 15.58) body weight at 1 month and 9.63 mg/kg (4.63 to 17.8) at 4 months after commencing treatment administered as part of a fixed-dose formulation designed for paediatric use. The mean rifampin area under the curve 0 to 6 hours after dosing was 14.9 and 18.1 mug/hour/ml (P = 0.25) 1 month after starting treatment in human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children, respectively, and 16.52 and 17.94 mug/hour/ml (P = 0.59) after 4 months of treatment. The mean calculated 2-hour rifampin concentrations in these human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children were 3.9 and 4.8 mug/ml (P = 0.20) at 1 month after the start of treatment and 4.0 and 4.6 mug/ml (P = 0.33) after 4 months of treatment. These values are considerably less than the suggested lower limit for 2-hour rifampin concentrations in adults of 8.0 mug/ml and even 4 mug/mlCONCLUSION:Both human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children with tuberculosis have very low rifampin serum concentrations after receiving standard rifampin dosages similar to those used in adults. Pharmacokinetic studies of higher dosages of rifampin are urgently needed in children to assist in placing the dosage of rifampin used in childhood on a more scientific foundation.
- ItemOpen AccessThe safety, effectiveness and concentrations of adjusted lopinavir/ritonavir in HIV-infected adults on rifampicin-based antitubercular therapy(Public Library of Science, 2012) Decloedt, Eric H; Maartens, Gary; Smith, Peter; Merry, Concepta; Bango, Funeka; McIlleron, HelenObjective Rifampicin co-administration dramatically reduces plasma lopinavir concentrations. Studies in healthy volunteers and HIV-infected patients showed that doubling the dose of lopinavir/ritonavir (LPV/r) or adding additional ritonavir offsets this interaction. However, high rates of hepatotoxicity were observed in healthy volunteers. We evaluated the safety, effectiveness and pre-dose concentrations of adjusted doses of LPV/r in HIV infected adults treated with rifampicin-based tuberculosis treatment. METHODS: Adult patients on a LPV/r-based antiretroviral regimen and rifampicin-based tuberculosis therapy were enrolled. Doubled doses of LPV/r or an additional 300 mg of ritonavir were used to overcome the inducing effect of rifampicin. Steady-state lopinavir pre-dose concentrations were evaluated every second month. RESULTS: 18 patients were enrolled with a total of 79 patient months of observation. 11/18 patients were followed up until tuberculosis treatment completion. During tuberculosis treatment, the median (IQR) pre-dose lopinavir concentration was 6.8 (1.1-9.2) mg/L and 36/47 (77%) were above the recommended trough concentration of 1 mg/L. Treatment was generally well tolerated with no grade 3 or 4 toxicity: 8 patients developed grade 1 or 2 transaminase elevation, 1 patient defaulted additional ritonavir due to nausea and 1 patient developed diarrhea requiring dose reduction. Viral loads after tuberculosis treatment were available for 11 patients and 10 were undetectable. CONCLUSION: Once established on treatment, adjusted doses of LPV/r co-administered with rifampicin-based tuberculosis treatment were tolerated and LPV pre-dose concentrations were adequate.