Browsing by Author "Denti, Paolo"

Now showing 1 - 11 of 11
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    Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling
    (2016) Smythe, Wynand Anton; McIlleron, Helen; Denti, Paolo
    This 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.
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    Correction to: Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria
    (2021-03-19) Anyorigiya, Thomas A; Castel, Sandra; Mauf, Katya; Atuguba, Frank; Ogutu, Bernhards; Oduro, Abraham; Dosoo, David; Asante, Kwaku-Poku; Owusu-Agyei, Seth; Dodoo, Alexander; Hodgson, Abraham; Binka, Fred; Workman, Lesley J; Allen, Elizabeth N; Denti, Paolo; Wiesner, Lubbe; Barnes, Karen I
    An amendment to this paper has been published and can be accessed via the original article.
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    Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in newly diagnosed pulmonary TB patients in Tanzania
    (Public Library of Science, 2015) Denti, Paolo; Jeremiah, Kidola; Chigutsa, Emmanuel; Faurholt-Jepsen, Daniel; PrayGod, George; Range, Nyagosya; Castel, Sandra; Wiesner, Lubbe; Hagen, Christian Munch; Christiansen, Michael
    Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients.
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    Pharmacokinetics, pharmacogenetics and optimisation of treatment with non-nucleoside reverse transcriptase inhibitors in HIV-infected African children
    (2017) Bienczak, Andrzej Marek; Denti, Paolo; McIlleron, Helen
    Efavirenz 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.
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    Pharmacokinetics, SAfety/tolerability, and EFficacy of high-dose RIFampicin in tuberculosis-HIV co-infected patients on efavirenz- or dolutegravir-based antiretroviral therapy: study protocol for an open-label, phase II clinical trial (SAEFRIF)
    (2020-02-13) Nabisere, Ruth; Musaazi, Joseph; Denti, Paolo; Aber, Florence; Lamorde, Mohammed; Dooley, Kelly E; Aarnoutse, Rob; Sloan, Derek J; Sekaggya-Wiltshire, Christine
    Abstract Background Tuberculosis (TB) is a significant public health problem that causes substantial morbidity and mortality. Current first-line anti-TB chemotherapy, although very effective, has limitations including long-treatment duration with a possibility of non-adherence, drug interactions, and toxicities. Dose escalation of rifampicin, an important drug within the regimen, has been proposed as a potential route to higher treatment efficacy with shorter duration and some studies have suggested that dose escalation is safe; however, these have almost entirely been conducted among human immunodeficiency (HIV)-negative TB patients. TB-HIV co-infected patients on antiretroviral therapy (ART) are at increased risk of drug-drug interactions and drug-related toxicities. This study aims to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz (EFV) and dolutegravir (DTG) in TB-HIV co-infected patients. Methods This study is a randomized, open-label, phase IIb clinical trial among TB-HIV infected adult outpatients attending an HIV clinic in Kampala, Uganda. Patients newly diagnosed with TB will be randomized to either standard-dose or high-dose rifampicin (35 mg/kg) alongside standard TB treatment. ART-naïve patients will be randomly assigned to first-line ART regimens (DTG or EFV). Those who are already on ART (DTG or EFV) at enrollment will be continued on the same ART regimen but with dose adjustment of DTG to twice daily dosing. Participants will be followed every 2 weeks with assessment for toxicities at each visit and measurement of drug concentrations at week 6. At the end of intensive-phase therapy (8 weeks), all participants will be initiated on continuation-phase treatment using standard-dose rifampicin and isoniazid. Discussion This study should avail us with evidence about the effect of higher doses of rifampicin on the pharmacokinetics of EFV and DTG among TB-HIV co-infected patients. The trial should also help us to understand safety concerns of high-dose rifampicin among this vulnerable cohort. Trial registration ClinicalTrials.gov, ID: NCT03982277. Registered retrospectively on 11 June 2019.
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    Pharmacometric modelling to inform and improve TB and HIV treatment: Focus on drug-drug interactions and neglected populations
    (2022) Gausi, Kamunkhwala; Denti, Paolo
    The global scale-up of tuberculosis treatment administered with antiretroviral therapy (ART) is the primary contributor to the 11 million averted deaths among individuals living with HIV observed between 2000 and 2019 in adults and children. Unfortunately, not all patients in need could fully benefit from these recent improvements in treatment because neglected populations are often excluded from clinical trials, including pregnant and breastfeeding women, children, adolescents, those with co-morbidities requiring additional drug treatments, and those with drug-resistant strains. This leaves many unanswered questions surrounding the management of TB, HIV, and TB/HIV in these vulnerable subpopulations. In this thesis, we utilise population pharmacokinetics and pharmacodynamic modelling to improve TB and HIV treatment in neglected populations using data from patients with TB or/and HIV. We analyse the pharmacogenomics, pharmacokinetics, and drug-drug interaction of efavirenz, isoniazid, and bedaquiline in pregnant women and characterise the pharmacokinetics and pharmacodynamics of high dose isoniazid in adults with multidrugresistant tuberculosis. We found that isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were N-acetyltransferase 2 and CYP2B6 genotypes, which resulted in a 5-fold difference for both drugs between rapid and slow metabolisers. Bedaquiline exposures were lower during both postpartum and antepartum compared to historical data in non-pregnant patients. For high dose isoniazid, we observed markedly lower isoniazid exposures in participants on combination MDR-TB treatment compared to monotherapy and identified saturable kinetics at doses >10 mg/kg. We suggest that dosing isoniazid based on N-acetyltransferase 2 acetylator status might help patients attain effective exposures against inhA-mutated isolates.
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    Pharmacometrics of dolutegravir and tenofovir: a quantitative approach to characterise drug-drug interactions, pharmacogenetics and optimise treatment
    (2023) Kawuma, Aida; Denti, Paolo; Maartens Gary
    Africa houses more than 50% of the 37 million people estimated to be living with HIV (PLWH). Although great strides have been made in increasing access to antiretroviral therapy, the number of new HIV infections remains high. In sub-Saharan Africa, co-infections of HIV, tuberculosis, and malaria are common because the three pandemics overlap considerably. Treatment of these co-infections is often challenging because of the potential for drug-drug interactions. Dolutegravir-based regimens are now the preferred first-line option for the management of HIV. Therefore, many African countries have transitioned most PLWH from efavirenz- to dolutegravir-based regimens. A fixed-dose combination containing dolutegravir, tenofovir, and lamivudine taken daily constitutes one of the most widely used regimens in Africa. In this thesis, we employ population pharmacokinetic modelling to optimise HIV treatment using data from healthy volunteers or PLWH, some of whom also have tuberculosis. We characterise dolutegravir pharmacokinetics, pharmacogenetics, and its drug-drug interaction with the antituberculosis drugs rifampicin and rifabutin and with the antimalarial drugs artemether-lumefantrine and artesunate-amodiaquine. We also describe the pharmacokinetics of tenofovir when dosed as either tenofovir disoproxil fumarate or tenofovir alafenamide in South Africans living with HIV. We found that rifampicin increases dolutegravir clearance more than twofold, leading to a reduction in its exposure. We confirmed that this interaction can be overcome with twice-daily dosing of 50-mg dolutegravir. We also demonstrate that a simpler regimen of 100 mg once daily may be sufficient. We also found that rifabutin decreases dolutegravir volume of distribution, but without an overall change in exposure. The interaction between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine was not clinically significant, and no dose adjustment is required when these are co-administered. Lastly, we demonstrate that polymorphisms within the UGT1A locus affect dolutegravir exposure among Africans. For tenofovir, we created a joint model that describes its disposition when given either as tenofovir disoproxil fumarate or tenofovir alafenamide. In conclusion, by employing pharmacometric techniques, we were able to analyze and pool data from different studies, including sparsely sampled data, and run simulations to test and inform alternative dosing scenarios.
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    Population pharmacokinetic and pharmacodynamic modelling to improve tuberculosis treatment
    (2021) Abdelwahab, Mahmoud Tareq; Denti, Paolo
    Tuberculosis continues to claim millions of lives each year despite enormous efforts to control the epidemic over the past century. It remains the leading cause of death worldwide from a curable infectious disease. Tuberculosis is a significant cause of maternal mortality and morbidity, but little is known about the effect of pregnancy on anti-TB drugs concentrations. A critical challenge to the global efforts to control the tuberculosis epidemic is the spreading of drug resistance to first-line tuberculosis drugs. The treatment of drug-resistant tuberculosis relies on both new anti-tuberculosis agents such as bedaquiline, delamanid, and pretomanid and repurposed drugs, such as linezolid and clofazimine. In this thesis, we employed nonlinear mixed-effects modelling to evaluate the pharmacokinetics of first-line tuberculosis drugs isoniazid, pyrazinamide, and ethambutol in pregnancy. We assessed the pharmacokinetics and pharmacodynamics of pretomanid, clofazimine, and linezolid in African tuberculosis patients. Reassuringly, we found no significant pregnancy effect on the exposure of these antituberculosis agents, thus confirming the suitability of current doses in pregnancy. For pretomanid, we found that in spite of exposure being reduced by 44% with rifampicin coadministration, the drug levels were within the efficacy range observed in previous trials, provided that pretomanid doses are administered with food. Clofazimine exposure was found to accumulate more slowly in women, an effect driven by sex-related differences in the proportion of body fat. We characterised the effect of clofazimine concentration on QT interval prolongation. We investigated alternative dosing regimen to optimise clofazimine treatment and suggested that a 2-week loading dose may support treatment shortening by safely enabling more rapid attainment of efficacy targets. For linezolid model, we characterised population pharmacokinetic parameters in African tuberculosis patients, assessed probability of target attainment and related toxicity following different doses administration. We showed that population modelling could maximize information from collected data, and have a significant impact on advancing patients care especially in places with limited resources.
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    Population pharmacokinetic modelling to address the gaps in knowledge of commonly used HIV and TB drugs in children
    (2021) Tikiso, Tjokosela; Denti, Paolo; Mcilleron, Helen
    The epidemiology of HIV and TB are overlapping, particularly in sub-Saharan Africa, and TB infection remains common in HIV-positive children. The combined administration of anti-tubercular and antiretroviral therapies(ART) may lead to drug-drug interactions potentially needing to be addressed with the adjustment of doses. This thesis assessed the pharmacokinetics of abacavir and ethambutol and evaluated the influence of covariates such as age and concomitant medication on the PK parameters across different studies using nonlinear mixed-effects modelling. The models developed were used to estimate area under the concentration-time curve (AUC) and maximum concentrations (Cmax) achieved with the currently-recommended weight-adjusted doses. A web-based paediatric dosing tool, which is meant to be used as a first step in the design of clinical trials for paediatric dosing was also developed. The model describing the pharmacokinetics of abacavir found: a) abacavir exposure to be 18.4% larger (CI:7.50-32.2) after the first dose of ART compared to abacavir co-treated with standard lopinavir/ritonavir for over 7 days, possibly indicating that clearance is induced with time on ART, b) malnourished HIV infected children had much higher exposures but this effect waned with a half-life of 12.2 (CI: 9.87-16.8) days as children stayed on nutritional rehabilitation and recovered, c). during co-administration of rifampicin-containing antituberculosis treatment and super-boosted lopinavir/ritonavir, abacavir exposure was decreased by 29.4% (CI: 24.3-35.8), d) children receiving efavirenz had 12.1% (CI: 2.57-20.1) increased abacavir clearance compared to standard lopinavir/ritonavir. The effects did not result in abacavir exposures lower or higher than those reported in adults and are not likely to be clinically important. The ethambutol model found lower concentrations than those reported in adults. The predicted ethambutol median (IQR) Cmax was 1.66 (1.21-2.15) mg/L for children on ethambutol with or without ART (excluding super-boosted lopinavir/ritonavir) and 0.882 (0.669-1.28) mg/L for children on ethambutol with super-boosted lopinavir/ritonavir, these are below the lower limit of the recommended Cmax range of 2 mg/L. During co-administration with super-boosted lopinavir, ethambutol exposure was decreased by 32% (CI: 23.8-38.9), likely due to drug-drug interaction involving absorption, metabolism or elimination. Bioavailability was decreased in children who were administered ethambutol in a crushed form, with an estimate decrease of 30.8% at birth, and an increase of 9.6% for each year of age up to 3.2 years where bioavailability was now similar to children taking EMB full tablet. The developed paediatric dosing tool contains two major sections. a) the ‘generic module’ which uses allometric scaling -based predictions to explore the expected AUC for a generic drug, b) the ‘drug-specific module’ which can simulate entire pharmacokinetic profiles (concentration over time after dose) by using a drug-specific population pharmacokinetic model. In summary, under the current weight-adjusted doses, abacavir exposure remained within the adult recommended levels. Ethambutol dose adjustment would be required in order to achieve adult exposures. A web-based paediatric dosing tool that uses allometric scaling -based predictions as well as drug specific predictions based on published pharmacokinetic models was successfully developed.
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    Population/ Nonlinear mixed-effects modelling of pharmacokinetics and pharmacodynamics of tuberculosis treatment
    (2018) Chirehwa, Maxwell Tawanda; Denti, Paolo; Mcilleron, Helen
    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.
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    The Next Generation Scientist program: capacity-building for future scientific leaders in low- and middle-income countries
    (BioMed Central, 2018-10-10) Pillai, Goonaseelan; Chibale, Kelly; Constable, Edwin C; Keller, Akiko N; Gutierrez, Marcelo M; Mirza, Fareed; Sengstag, Christian; Masimirembwa, Collen; Denti, Paolo; Maartens, Gary; Ramsay, Michèle; Ogutu, Bernhards; Makonnen, Eyasu; Gordon, Richard; Ferreira, Carlos G; Goldbaum, Fernando A; Degrave, Wim M S; Spector, Jonathan; Tadmor, Brigitta; Kaiser, Hedwig J
    Background Scientific and professional development opportunities for early career scientists in low- and middle- income countries (LMICs) are limited and not consistent. There is a disproportionately low number of biomedical and clinical researchers in LMIC’s relative to their high burden of disease, a disparity that is aggravated by emigration of up to 70% of scientists from their countries of birth for education and employment elsewhere. To help address this need, a novel University-accredited, immersive fellowship program was established by a large public-academic-private network. We sought to describe the program and summarize progress and lessons learned over its first 7-years. Methods Hallmarks of the program are a structured learning curriculum and bespoke research activities tailored to the needs of each fellow. Research projects expose the scientists to state-of-the-art methodologies and leading experts in their fields while also ensuring that learnings are implementable within their home infrastructure. Fellows run seminars on drug discovery and development that reinforce themes of scientific leadership and teamwork together with practical modules on addressing healthcare challenges within their local systems. Industry mentors achieve mutual learning to better understand healthcare needs in traditionally underserved settings. We evaluated the impact of the program through an online survey of participants and by assessing research output. Results More than 140 scientists and clinicians from 25 countries participated over the 7-year period. Evaluation revealed strong evidence of knowledge and skills transfer, and beneficial self-reported impact on fellow’s research output and career trajectories. Examples of program impact included completion of post-graduate qualifications; establishment and implementation of good laboratory- and clinical- practice mechanisms; and becoming lead investigators in local programs. There was a high retention of fellows in their home countries (> 75%) and an enduring professional network among the fellows and their mentors. Conclusions Our experience demonstrates an example for how multi-sectoral partners can contribute to scientific and professional development of researchers in LMICs and supports the idea that capacity-building efforts should be tailored to the specific needs of beneficiaries to be maximally effective. Lessons learned may be applied to the design and conduct of other programs to strengthen science ecosystems in LMICs.