Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV–1–infected patients dramatically since it was launched in 1996, but there are still many challenges in the provision of HAART, especially to children in resource limited countries. Efavirenz (EFV), a non–nucleoside reverse transcriptase inhibitor (NNRTI) forms part of the recommended national first line antiretroviral treatment regimen for children older than 3 years and weighing more than 10 kg in South Africa. Limited pharmacokinetic information on EFV plasma concentrations in sub–Saharan HIV–1– infected children is available. EFV is primarily metabolised by hepatic CYP2B6 isoenzymes. The CYP2B6 gene is characterised by extensive inter–individual variability in hepatic expression and activity. The single nucleotide change, 516G>T, on the CYP2B6 gene has consistently been associated with elevated EFV plasma levels in different ethnic populations and these are more frequently observed in populations of African descent. The recommended therapeutic range of EFV plasma levels is 1–4 ug/ml and the Cmin should be above 1 ug/ml. In this prospective study (PK/PD.EFV.07) cohort, 60 black children, both genders, with no prior exposure to antiretroviral therapy and eligible for antiretroviral therapy (ART) were enrolled and followed up at 1, 3, 6, 12, 18 and 24 months post HAART initiation. They all attended the outpatient clinic at Harriet Shezi Children’s Clinic, Chris Hani Baragwanath Hospital, Soweto, South Africa. The required ethics approval was obtained to conduct this study. The objectives of this investigation were to: develop and validate a suitable LCMS/ MS method to accurately determine plasma EFV levels from this study population, determine the prevalence and effect of CYP2B6 516G>T polymorphism on EFV plasma levels, determine the population pharmacokinetic clearance (CL/F) value of EFV, identify covariates that influence the clearance of EFV in HIV–1– infected children, and investigate specific pharmacodynamic effects and therapeutic outcomes of this EFV–based regimen within this paediatric population over the 24 months post–HAART initiation. The main findings of the measured mid–dose EFV plasma concentrations showed that sub–therapeutic concentrations (<1 ug/ml) accounted for 18% (116/649), within therapeutic range (1–4 ug/ml) represented 52.5% (341/649), and concentrations above the therapeutic range (>4 ug/ml) represented 29.5% (192/649). A significant number of the samples (47.5%) were outside the accepted therapeutic range during this 24 month follow–up period. Possible reasons contributing to this include genetic variation in drug metabolism and non–adherence. Genotype results on all 60 study participants were: 23% 516 T/T homozygotes, 42% 516 G/G homozygotes and 35% 516 G/T heterozygotes. The 516 T–allelic variant frequency was relatively high at 41%. This also supports and explains why such a large number (29.5%) of the mid–dose interval plasma samples were above (>4 ug/ml) the accepted therapeutic range. Repeated measures ANOVA confirmed that CYP2B6 516 G/G, G/T and T/T genotypes were consistently predictive of the log EFV concentrations at all times (P = 0.0001). The total median (IQR) EFV plasma concentrations over the 24 months post–HAART when pooled, were 6.36 (3.47 - 7.28) for T/T, 2.55 (1.62 - 3.59) for G/T, and 1.41 (1.02 - 1.74) ug/ml for G/G groups respectively (P<0.00001). Multiple comparisons by groups revealed that the EFV plasma concentrations between the T/T and G/G (P=0.000002) and between G/T and G/G (P=0.009) were statistically significant. However, the differences between the EFV plasma concentrations of the T/T and G/T groups were not significantly different (P=0.074). This supports previous results that the presence of the 516 T–allelic variant is responsible for the higher EFV plasma concentrations within individuals presenting with this single nucleotide mutation on the CYP2B6 gene. This EFV–based treatment was well tolerated even at plasma concentrations above the therapeutic range (>4 ug/ml) and most side effects subsided spontaneously. 89% of the participants were virally suppressed at 24 months post–HAART. The efficacy of this EFV–based treatment did not affect the three genotype groups differently and they showed similar improvement in their immunological (CD4–cell count and CD4%) markers and reduction in viral load over the 24 months post– HAART initiation. We found no association of the CYP2B6 516G>T polymorphism and side effects reported after 1 month of treatment within this study population. The final population pharmacokinetic (PK) estimates for EFV clearance (CL/F) were, 2.46, 4.60, and 7.33 l/h for the T/T, G/T, and G/G respective genotype groups. The volume of distribution (V/F) estimate was 89.52 l. The importance of interoccasion variability (IOV) in a PK model for a longitudinal study was again highlighted by this investigation. To our knowledge, this is the first study in black South African HIV–1–infected children with measured sequential EFV plasma concentrations which also investigated the influence of the CYP2B6 516G>T polymorphism on EFV plasma concentrations and the population clearance (CL/F) value of EFV in a longitudinal study over a period of 24 months post–HAART initiation. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2011.

Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV–1–infected patients dramatically since it was launched in 1996, but there are still many challenges in the provision of HAART, especially to children in resource limited countries. Efavirenz (EFV), a non–nucleoside reverse transcriptase inhibitor (NNRTI) forms part of the recommended national first line antiretroviral treatment regimen for children older than 3 years and weighing more than 10 kg in South Africa. Limited pharmacokinetic information on EFV plasma concentrations in sub–Saharan HIV–1– infected children is available. EFV is primarily metabolised by hepatic CYP2B6 isoenzymes. The CYP2B6 gene is characterised by extensive inter–individual variability in hepatic expression and activity. The single nucleotide change, 516G>T, on the CYP2B6 gene has consistently been associated with elevated EFV plasma levels in different ethnic populations and these are more frequently observed in populations of African descent. The recommended therapeutic range of EFV plasma levels is 1–4 ug/ml and the Cmin should be above 1 ug/ml. In this prospective study (PK/PD.EFV.07) cohort, 60 black children, both genders, with no prior exposure to antiretroviral therapy and eligible for antiretroviral therapy (ART) were enrolled and followed up at 1, 3, 6, 12, 18 and 24 months post HAART initiation. They all attended the outpatient clinic at Harriet Shezi Children’s Clinic, Chris Hani Baragwanath Hospital, Soweto, South Africa. The required ethics approval was obtained to conduct this study. The objectives of this investigation were to: develop and validate a suitable LCMS/ MS method to accurately determine plasma EFV levels from this study population, determine the prevalence and effect of CYP2B6 516G>T polymorphism on EFV plasma levels, determine the population pharmacokinetic clearance (CL/F) value of EFV, identify covariates that influence the clearance of EFV in HIV–1– infected children, and investigate specific pharmacodynamic effects and therapeutic outcomes of this EFV–based regimen within this paediatric population over the 24 months post–HAART initiation. The main findings of the measured mid–dose EFV plasma concentrations showed that sub–therapeutic concentrations (<1 ug/ml) accounted for 18% (116/649), within therapeutic range (1–4 ug/ml) represented 52.5% (341/649), and concentrations above the therapeutic range (>4 ug/ml) represented 29.5% (192/649). A significant number of the samples (47.5%) were outside the accepted therapeutic range during this 24 month follow–up period. Possible reasons contributing to this include genetic variation in drug metabolism and non–adherence. Genotype results on all 60 study participants were: 23% 516 T/T homozygotes, 42% 516 G/G homozygotes and 35% 516 G/T heterozygotes. The 516 T–allelic variant frequency was relatively high at 41%. This also supports and explains why such a large number (29.5%) of the mid–dose interval plasma samples were above (>4 ug/ml) the accepted therapeutic range. Repeated measures ANOVA confirmed that CYP2B6 516 G/G, G/T and T/T genotypes were consistently predictive of the log EFV concentrations at all times (P = 0.0001). The total median (IQR) EFV plasma concentrations over the 24 months post–HAART when pooled, were 6.36 (3.47 - 7.28) for T/T, 2.55 (1.62 - 3.59) for G/T, and 1.41 (1.02 - 1.74) ug/ml for G/G groups respectively (P<0.00001). Multiple comparisons by groups revealed that the EFV plasma concentrations between the T/T and G/G (P=0.000002) and between G/T and G/G (P=0.009) were statistically significant. However, the differences between the EFV plasma concentrations of the T/T and G/T groups were not significantly different (P=0.074). This supports previous results that the presence of the 516 T–allelic variant is responsible for the higher EFV plasma concentrations within individuals presenting with this single nucleotide mutation on the CYP2B6 gene. This EFV–based treatment was well tolerated even at plasma concentrations above the therapeutic range (>4 ug/ml) and most side effects subsided spontaneously. 89% of the participants were virally suppressed at 24 months post–HAART. The efficacy of this EFV–based treatment did not affect the three genotype groups differently and they showed similar improvement in their immunological (CD4–cell count and CD4%) markers and reduction in viral load over the 24 months post– HAART initiation. We found no association of the CYP2B6 516G>T polymorphism and side effects reported after 1 month of treatment within this study population. The final population pharmacokinetic (PK) estimates for EFV clearance (CL/F) were, 2.46, 4.60, and 7.33 l/h for the T/T, G/T, and G/G respective genotype groups. The volume of distribution (V/F) estimate was 89.52 l. The importance of interoccasion variability (IOV) in a PK model for a longitudinal study was again highlighted by this investigation. To our knowledge, this is the first study in black South African HIV–1–infected children with measured sequential EFV plasma concentrations which also investigated the influence of the CYP2B6 516G>T polymorphism on EFV plasma concentrations and the population clearance (CL/F) value of EFV in a longitudinal study over a period of 24 months post–HAART initiation. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2011.

Chemotherapy plays an important role in the treatment of cancer. However, these drugs also cause death of non-malignant cells, resulting in severe side-effects. In addition, drug resistance may exist. Predictive tools for dose and drug selection are therefore warranted. In this thesis predictive pharmacometric models were developed for the main dose-limiting side-effect, neutropenia, and for treatment response following chemotherapy. Neutropenia is associated with a high risk for life-threatening infections and leads frequently to reduced dose delivery and thereby suboptimal treatment of the tumor. A better characterization of the dynamics of docetaxel induced neutropenia was obtained by simultaneous analysis of neutrophils and leukocytes. The fraction of neutrophils was shown to change over the time-course, hence leukocytes and neutrophil counts are not interchangeable biomarkers. Sometimes neutrophil count is reported as categorical severity of neutropenia (Grade 0-4). A method was developed that allowed analysis of these data closer to its true continuous nature. The main regulatory hormone of neutrophils is granulocyte colony stimulating factor (G-CSF). Although recombinant G-CSF is used as supportive therapy to prevent neutropenia, little is known of how the endogenous G-CSF concentrations vary in patients following chemotherapy. A prospective study was carried out and simultaneous analysis of endogenous G-CSF and neutrophils following chemotherapy enabled a more mechanistic model to be developed that also could verify the self-regulatory properties of the physiological system. Patient characteristics were investigated using a pharmacokinetic-myelosuppression model for docetaxel in patients with normal and impaired liver function. The model was a useful tool in evaluating different dosing strategies and a reduced dosing scheme was suggested in patients with poor liver function, thereby enabling docetaxel treatment in this patient population which has previously been excluded. Treatment of acute myeloid leukemia with daunorubicin and cytarabine is associated with drug resistance and high variability in pharmacokinetics, which was partly explained for daunorubicin by peripheral leukocyte count. An integrated model of the in vitro drug sensitivity and treatment response showed that in vitro drug sensitivity was predictive for treatment outcome in this patient population and may therefore be used for choice of drug. The developed pharmacometric models in this thesis may be useful in the optimization of treatments schedules for existing and new drugs as well as to assist in drug and dose selection to improve therapy in an individual patient. The models and methods presented may also facilitate pooled analysis of data and demonstrate principles which could be useful for the pharmacometric community.

Submitted by Juliana da Silva Oliveira null (julianaoliveira_enf@yahoo.com.br) on 2016-09-11T21:03:04Z No. of bitstreams: 1 DISSERTACAO JULIANA OLIVEIRA pdf.pdf: 874937 bytes, checksum: e0c74af40cc92b0d03be09da8c3d52d1 (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-09-12T17:21:46Z (GMT) No. of bitstreams: 1 oliveira_js_me_bot.pdf: 874937 bytes, checksum: e0c74af40cc92b0d03be09da8c3d52d1 (MD5) / Made available in DSpace on 2016-09-12T17:21:46Z (GMT). No. of bitstreams: 1 oliveira_js_me_bot.pdf: 874937 bytes, checksum: e0c74af40cc92b0d03be09da8c3d52d1 (MD5) Previous issue date: 2016-08-01 / Objetivos: Questionamentos têm sido lançados sobre a eficácia das formulações genéricas de vancomicina, empregadas com frequência nos países em desenvolvimento. No entanto, a grande disponibilidade de testes para monitorar a concentração de vancomicina no soro tornou possível ajustar as doses, a fim de melhorar os resultados. Nosso estudo teve como objetivo descrever os padrões de prescrição e monitorização de dose sérica de vancomicina genérica em um hospital brasileiro. Estávamos especialmente interessados no impacto desses parâmetros sobre o prognóstico de pacientes. Métodos: Uma coorte retrospectiva de 513 pacientes adultos que foram tratados com vancomicina em 2014 foi estudada. Desfechos de interesse foram: (a) atingir concentrações séricas mínimas sub-ótimas na primeira ocasião de monitoramento e (b) morte dentro de 30 dias da introdução vancomicina. A análise multivariada (regressão logística e de Cox) foi aplicada. Resultados: Menos de 25% dos indivíduos alcançaram concentração sérica mínima ótima (15-20 mg/L), mesmo depois de cinco testes e ajustes posológicos. No entanto, a soma dos indivíduos que apresentaram concentrações ideais e altas foi predominante em cada teste. Doença renal (OR = 4,86, IC95% = 2,05-11,53, P <0,001) e dose diária (OR para mg/kg = 1,04, IC95% = 1,01-1,07, P = 0,01) foram positivamente associada com níveis mais elevados de vancomicina. Além disso, indivíduos mais jovens eram menos propensos a apresentar baixa concentração sérica. Na análise de sobrevivência, as concentrações ideais foram associadas com melhores desfechos, mas apenas aqueles com níveis elevados apresentaram aumento significativo do risco (HR = 1,80, IC95% = 1,05-3,07, P = 0,03). Conclusão: Os resultados alertam para riscos de toxicidade com altas concentrações de vancomicina. O ajuste fino da posologia (por exemplo, com infusão contínua) pode contribuir para melhorar a segurança e eficácia. / Objectives: Concerns have been raised about generic formulations of vancomycin – especially in developing countries – but the wide availability of tests for monitoring serum vancomycin concentration made it possible to adjust doses in order to improve outcomes. We aimed at describing patterns of generic vancomycin prescription and monitoring in a Brazilian hospital and their impact on outcomes. Methods: A cohort of 513 adult patients who were treated with vancomycin in year 2014 was retrospectively studied. Outcomes of interest were achieving suboptimal serum trough concentrations in the first serum monitoring and death within 30 days of vancomycin introduction. Multivariable analysis (logistic and Cox regression was applied) Results: Less than 25% of subjects achieved optimal (15-20 mg/L) trough concentrations, even after five tests and dosing adjustments. However, the sum of subjects presenting optimal and high concentrations was predominant in each and every test. Renal disease (OR=4.86, 95%CI=2.05-11.53, P<0.001) and daily dosing (OR for mg/kg =1.04, IC95%=1.01-1.07, P=0.01) were positively associated with higher vancomycin levels. Additionally, younger subjects were less likely to present lower serum concentration. In survival analysis, optimal concentrations were associated with better outcomes, but only those with high levels presented significantly increased risk (HR=1.80, 95%CI=1.05-3.07, P=0.03). Conclusion: Our results warn about risks of toxicity with high concentrations of vancomycin. Fine adjustment of posology (e.g., with continuous infusion) may contribute to improve safety and efficacy.

The pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in TB/HIV coinfected patients recruited in two phase III clinical trials (61 patients in TB-HAART and 222 patients in RAFA study) were described using nonlinear mixed-effects modelling. Concentration-time data for rifampicin (TB-HAART study) was used to develop a semimechanistic pharmacokinetic model incorporating autoinduction and saturable pharmacokinetics. A model describing the pharmacokinetics of pyrazinamide (TB-HAART study) was developed and used to evaluate the 24-hour area under the concentration-time curve (AUC0–24), and maximum concentrations (Cmax) achieved with the currently recommended weight-adjusted doses for drug-susceptible and -resistant tuberculosis. Concentration-time data from the RAFA study were used to characterise the pharmacokinetics of the four drugs of the fixed dose combination (FDC) therapy including desacetyl-rifampicin, and acetyl-isoniazid. Binary recursive techniques were applied in the conditional inference framework to determine predictors including drug exposure of time-to-stable culture conversion and poor long-term treatment outcomes. The model describing the pharmacokinetics of rifampicin predicted that increasing the dose results in a more than proportional increase in exposure. Clearance of rifampicin increased by 90% from baseline to steady-state due to autoinduction and the process takes up to 21 days. Monte Carlo simulations showed that rifampicin doses of at least 25 mg/kg would be required to achieve an AUC0–24/MIC ratio of at least 271. Based on the model describing the pharmacokinetics of isoniazid, co-administration of isoniazid and efavirenz-based antiretroviral therapy results in a 54% reduction in isoniazid exposure only in fast acetylators. There were disparities in exposure across weight bands for all the four drugs: patients with lower weight had reduced exposure. To match drug exposure across the weight bands, we recommend the addition of one FDC tablet to patients with weight less than 55 kg. There is need to explore the use of fat-free mass-adjusted dosing since cumulative evidence shows its superiority over total body weight in driving exposure via allometric scaling for all first-line antituberculosis drugs. Individual drug exposures were not predictive of either time-to-stable culture conversion or long-term tuberculosis treatment outcomes. Baseline X-ray grading, HIV stage as TB diagnosis, and treatment arm were predictive of time-to-stable culture conversion while the presence of cavities, patient’s level of physical activity and CD4 count were the drivers of long-term treatment outcomes.

Indiana University-Purdue University Indianapolis (IUPUI) / Drug-Drug Interaction (DDI) is one of the major causes of adverse drug reaction (ADR) and has been demonstrated to threat public health. It causes an estimated 195,000 hospitalizations and 74,000 emergency room visits each year in the USA alone. Current DDI research aims to investigate different scopes of drug interactions: molecular level of pharmacogenetics interaction (PG), pharmacokinetics interaction (PK), and clinical pharmacodynamics consequences (PD). All three types of experiments are important, but they are playing different roles for DDI research. As diverse disciplines and varied studies are involved, interaction evidence is often not available cross all three types of evidence, which create knowledge gaps and these gaps hinder both DDI and pharmacogenetics research. In this dissertation, we proposed to distinguish the three types of DDI evidence (in vitro PK, in vivo PK, and clinical PD studies) and identify all knowledge gaps in experimental evidence for them. This is a collective intelligence effort, whereby a text mining tool will be developed for the large-scale mining and analysis of drug-interaction information such that it can be applied to retrieve, categorize, and extract the information of DDI from published literature available on PubMed. To this end, three tasks will be done in this research work: First, the needed lexica, ontology, and corpora for distinguishing three different types of studies were prepared. Despite the lexica prepared in this work, a comprehensive dictionary for drug metabolites or reaction, which is critical to in vitro PK study, is still lacking in pubic databases. Thus, second, a name entity recognition tool will be proposed to identify drug metabolites and reaction in free text. Third, text mining tools for retrieving DDI articles and extracting DDI evidence are developed. In this work, the knowledge gaps cross all three types of DDI evidence can be identified and the gaps between knowledge of molecular mechanisms underlying DDI and their clinical consequences can be closed with the result of DDI prediction using the retrieved drug gene interaction information such that we can exemplify how the tools and methods can advance DDI pharmacogenetics research. / 2 years

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