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Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets.

ABSTRACT: BACKGROUND:Nevirapine is the only nonnucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose-combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression in African children is limited, and the predictive power of the current therapeutic range was never evaluated in this population, thereby limiting treatment optimization. METHODS:We analysed data from 322 African children (aged 0.3-13 years) treated with nevirapine, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 144 weeks. Nevirapine trough concentration (Cmin) and other factors were tested for associations with viral load more than 100 copies/ml and transaminase increases more than grade 1 using proportional hazard and logistic models in 219 initially antiretroviral treatment (ART)-naive children. RESULTS:Pre-ART viral load, adherence, and nevirapine Cmin were associated with viral load nonsuppression [hazard ratio?=?2.08 (95% confidence interval (CI): 1.50-2.90, P?12.4?mg/l), hazard ratio?=?5.18 (95% CI 1.95-13.80, P?

SUBMITTER: Bienczak A

PROVIDER: S-EPMC5572624 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets.

Bienczak Andrzej A Denti Paolo P Cook Adrian A Wiesner Lubbe L Mulenga Veronica V Kityo Cissy C Kekitiinwa Addy A Gibb Diana M DM Burger David D Walker Ann S AS McIlleron Helen H

AIDS (London, England) 20170401 7

<h4>Background</h4>Nevirapine is the only nonnucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose-combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression in African children is limited, and the predictive power of the current therapeutic range was never evaluated in this population, thereby limiting treatment optimization.<h4>Methods</h4>We analysed data ...[more]

PMID: 28060017

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Project description:BackgroundLimited data are available on adverse events among children admitted to hospital. The Canadian Paediatric Adverse Events Study was done to describe the epidemiology of adverse events among children in hospital in Canada.MethodsWe performed a 2-stage medical record review at 8 academic pediatric centres and 14 community hospitals in Canada. We reviewed charts from patients admitted from April 2008 through March 2009, evenly distributed across 4 age groups (0 to 28 d; 29 to 365 d; > 1 to 5 yr and > 5 to 18 yr). In stage 1, nurses and health records personnel who had received training in the use of the Canadian Paediatric Trigger Tool reviewed medical records to detect triggers for possible adverse events. In stage 2, physicians reviewed the charts identified as having triggers and described the adverse events.ResultsA total of 3669 children were admitted to hospital during the study period. The weighted rate of adverse events was 9.2%. Adverse events were more frequent in academic pediatric centres than in community hospitals (adjusted odds ratio [OR] 2.98, 95% confidence interval [CI] 1.65-5.39). The incidence of preventable adverse events was not significantly different between types of hospital, but nonpreventable adverse events were more common in academic pediatric centres (adjusted OR 4.39, 95% CI 2.08-9.27). Surgical events predominated overall and occurred more frequently in academic pediatric centres than in community hospitals (37.2% v. 21.5%, relative risk [RR] 1.7, 95% CI 1.0-3.1), whereas events associated with diagnostic errors were significantly less frequent (11.1% v. 23.1%, RR 0.5, 95% CI 0.2-0.9).InterpretationMore children have adverse events in academic pediatric centres than in community hospitals; however, adverse events in the former are less likely to be preventable. There are many opportunities to reduce harm affecting children in hospital in Canada, particularly related to surgery, intensive care and diagnostic error.

Project description:Purpose: The aims of this study was to investigate the mutual pharmacokinetic interactions between steady-state atorvastatin and metformin and the effect of food on the fixed-dose combined (FDC) tablet of atorvastatin and metformin extended release (XR). Subjects and methods: Study 1, an open-labeled, fixed sequence, multiple-dose pharmacokinetic drug-drug interaction study, was divided into 2 parts. Atorvastatin (40 mg) or metformin (1,000 mg) XR tablets were administered once daily via mono- or co-therapy for 7 days. Plasma levels of atorvastatin and 2-OH-atorvastatin, were quantitatively determined for 36 h in part A (n=50) while metformin plasma concentration was measured up to 24 h in part B (n=16) after the last dosing. Study 2, a randomized, open-labeled, single-dose, two-treatment, two-period, two-sequence crossover study, involved 27 healthy subjects to investigate the impact of food intake on the pharmacokinetics of a combined atorvastatin/metformin XR 20/500 mg (CJ-30056 20/500 mg) tablet. Results: After multiple doses of mono- or co-therapy of atorvastatin (40 mg) and metformin (1,000 mg) XR, the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for the peak plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve during the dosing interval at steady state (AUCτ,ss) were 1.07 (0.94-1.22) and 1.05 (0.99-1.10) for atorvastatin, 1.06 (0.96-1.16) and 1.16 (1.10-1.21) for 2-OH-atorvastatin, and 1.00 (0.86-1.18) and 0.99 (0.87-1.13) for metformin, respectively. Food delayed time to reach maximum concentration (tmax), decreased atorvastatin Cmax by 32% with a GMR (90% CI) of 0.68 (0.59-0.78), and increased metformin AUCt by 56% with a GMR (90% CI) of 1.56 (1.43-1.69). Conclusion: No clinically relevant pharmacokinetic interaction was seen when atorvastatin was co-administered with metformin. Food appeared to change the absorption of atorvastatin and metformin from an FDC formulation. These alterations were in accordance with those described with the single reference drugs when ingested with food.

Dataset Information

Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets.

Publications

Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets.

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