Pharmacokinetics of Pyrazinamide: optimising dosing regimens for drug-sensitive and -resistant tuberculosis [PublishAheadOfPrint]

Pyrazinamide is used in the treatment of tuberculosis(TB) because its sterilising effect against tubercle bacilli allows treatment shortening. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multi-drug resistant tuberculosis(MDR-TB). Pyrazinamide pharmacokinetic(PK) data from 61 HIV/TB co-infected patients in South Africa was used in the analysis. They were administered weight adjusted doses of pyrazinamide, rifampicin, isoniazid, and ethambutol in fixed-dose combination tablets according to WHO guidelines and underwent intensive PK sampling on day 1, 8, 15, and 29. The data was interpreted using nonlinear mixed-effects modelling. PK profiles were best described using a one-compartment model with first-order elimination. Allometric scaling was applied to disposition parameters using fat-free mass. Clearance increased by 14% from the 1st day to the 29th day of treatment. More than 50% of patients with weight less than 55 kg achieved lower pyrazinamide exposures at steady state than the targeted AUC0-24 of 363 mg⋅h/L. Among patients with drug susceptible TB, adding 400 mg to the dose for those weighing 30-54 kg improved exposure. Average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1500 mg, 1750 mg and 2000 mg to patients in the 33-50 kg, 51-70 kg and greater than 70 kg weight-bands respectively.

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