Browsing by Author "Burger, David M."

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    Pediatric Underdosing of Efavirenz: A Pharmacokinetic Study in Uganda
    (JAIDS Journal of Acquired Immune Deficiency Syndromes, 2011) Fillekes, Quirine; Natukunda, Eva; Balungi, Jackie; Kendall, Lindsay; Bwakura-Dangarembizi, Mutsa; Keishanyu, Rosette; Ferrier, Alex; Lutakome, Joseph; Gibb, Diana M.; Burger, David M.; Walker, A. Sarah
    Objectives: To evaluate international pediatric efavirenz dosing recommendations using full pharmacokinetic (PK) information. Design: Open-label, multicenter, PK study. Methods: Forty-one HIV-infected Ugandan children (3–12 years) on efavirenz + lamivudine + abacavir were enrolled in a study of twice-daily to once-daily lamivudine + abacavir 36 weeks after antiretroviral therapy initiation in the ARROW trial. Once-daily efavirenz doses were 200, 250, 300, 350 mg for children weighing 10 to ,15, 15 to ,20, 20 to ,25, 25 to ,30 kg, respectively, using 200/50 mg capsules or halved 600 mg tablets in case of 300 and 350 mg doses. Intensive plasma PK sampling (t = 0, 1, 2, 4, 6, 8, 12 hours postobserved ingestion) was performed at steady state (PK1) and repeated 4 weeks later (PK2, including a further 24-hour sample). Results: Forty-one and 39 children had evaluable efavirenz profiles at PK1 and PK2, respectively. Seventeen (41%) were boys. Five, 16, 17, 3 were in the 10 to ,15, 15 to ,20, 20 to ,25, 25 to ,30 kg weight bands. The geometric mean (%CV) the area under the concentration– time curve 0–24 hours postdose was 50.8 (90.8%) and 55.5 (82.7%) h$mg$L-1 at PK1 and PK2, respectively. Six children at PK1 and 7 at PK2 had subtherapeutic C8h and/or C12h (,1.0 mg/L), 7 of 41 (17%) at either visit. At PK2, 15 of 39 (38%) children had C24h ,1.0 mg/L (median (interquartile range) [range] 1.1 (0.7–2.9) [0.3–18.4]). Ten children at PK1 and 11 at PK2 had C8h and/or C12h .4.0 mg/L; 12 of 41 (29%) at either visit. Conclusions: African children aged 3–12 years, on efavirenz dosed according to 2006 WHO/manufacturer’s recommendations, had lower and highly variable efavirenz PK parameters compared with adult data from manufacturer’s leaflet. There were no differences across weight bands, suggesting no major effect of using half tablets. Higher pediatric efavirenz doses, as per WHO 2010 recommendations, should be used and investigated further but may risk increasing the proportion of children with potentially toxic levels.
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    Pharmacokinetics And Pharmacodynamics Of Azithromycin In Severe Malaria Bacterial Co-Infection In African Children (TABS-PKPD): A Protocol For A Phase II Randomised Controlled Trial
    (Wellcome Open Research, 2021) Olupot, Peter Olupot; Okiror, William; Mnjalla, Hellen; Muhindo, Rita; Uyoga, Sophie; Mpoya, Ayub; Williams, Thomas N.; terHeine, Rob; Burger, David M.; Urban, Britta; Connon, Roisin; George, Elizabeth C.; Gibb, Diana M.; Walker, A. Sarah; Maitland, Kathryn
    African children with severe malaria are susceptible to Gram-negative bacterial co-infection, largely non-typhoidal Salmonellae, leading to a substantially higher rates of in-hospital and post-discharge mortality than those without bacteraemia. Current evidence for treating co-infection is lacking, and there is no consensus on the dosage or length of treatment required. We therefore aimed to establish the appropriate dose of oral dispersible azithromycin as an antimicrobial treatment for children with severe malaria and to investigate whether antibiotics can be targeted to those at greatest risk of bacterial co-infection using clinical criteria alone or in combination with rapid diagnostic biomarker tests. A Phase I/II open-label trial comparing three doses of azithromycin: 10, 15 and 20 mg/kg spanning the lowest to highest mg/kg doses previously demonstrated to be equally effective as parenteral treatment for other salmonellae infection. Children with the highest risk of bacterial infection will receive five days of azithromycin and followed for 90 days. We will generate relevant pharmacokinetic data by sparse sampling during dosing intervals. We will use population pharmacokinetic modelling to determine the optimal azithromycin dose in severe malaria and investigate azithromycin exposure to change in C-reactive protein, a putative marker of sepsis at 72 hours, and microbiological cure (seven-day), alone and as a composite with seven-day survival. We will also evaluate whether a combination of clinical, point-of-care diagnostic tests, and/or biomarkers can accurately identify the sub-group of severe malaria with culture-proven bacteraemia by comparison with a control cohort of children hospitalized with severe malaria at low risk of bacterial co-infection.