scholarly journals Steady‐state population pharmacokinetics of terizidone and its metabolite cycloserine in patients with drug‐resistant tuberculosis

2019 ◽  
Vol 85 (9) ◽  
pp. 1946-1956 ◽  
Author(s):  
Mwila Mulubwa ◽  
Pierre Mugabo
Keyword(s):  
Steady State ◽  
Population Pharmacokinetics ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
State Population ◽  
Resistant Tuberculosis

scholarly journals Linezolid population pharmacokinetics in South African adults with drug-resistant tuberculosis.

2021 ◽  
Author(s):  
Mahmoud Tareq Abdelwahab ◽  
Sean Wasserman ◽  
James C.M. Brust ◽  
Keertan Dheda ◽  
Lubbe Wiesner ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
South African ◽  
Drug Exposure ◽  
Controlled Trial ◽  
Therapeutic Index ◽  
Drug Resistant ◽  
Concentration Data ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Daily Dose

BACKGROUND Linezolid is widely used for drug-resistant tuberculosis (DR-TB) but has a narrow therapeutic index. To inform dose optimisation, we aimed to characterise the population pharmacokinetics of linezolid in South African participants with DR-TB and explore the effect of covariates, including HIV-co-infection, on drug exposure. METHODS Data were obtained from pharmacokinetic sub-studies in a randomised controlled trial and an observational cohort study, both of which enrolled adults with drug-resistant pulmonary tuberculosis. Participants underwent intensive and sparse plasma sampling. We analyzed linezolid concentration data using non-linear mixed-effects modelling and performed simulations to estimate attainment of putative efficacy and toxicity targets. RESULTS 124 participants provided 444 plasma samples; 116 were on the standard daily dose of 600 mg, while 19 had dose reduction to 300 mg due to adverse events. Sixty-one participants were female, 71 were HIV-positive, and median weight was 56 kg (IQR 50 - 63). In the final model, typical values for clearance and central volume were 3.57 L/h and 40.2 L, respectively. HIV co-infection had no significant effect on linezolid exposure. Simulations showed that 600 mg dosing achieved the efficacy target ( f AUC 0-24h /MIC > 119 at MIC level of 0.5 mg/L) with 96% probability but had 56% probability of exceeding safety target ( trough 24h > 2 mg/L ). The 300 mg dose did not achieve adequate efficacy exposures. CONCLUSION Our model characterised population pharmacokinetics of linezolid in South African patients with DR-TB and supports the 600 mg daily dose with safety monitoring.

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