Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis

The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of >/= 95% and relapse rates of 8.2 mug/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of >/= 8 microg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax >/= 22 mug/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC6) >/= 70 mug.h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC

Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial

OBJECTIVE To evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-eclampsia. DESIGN Randomised, double blind, placebo controlled trial. SETTING Referral hospital in Cape Town, South Africa. PARTICIPANTS 180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks’ gestation undergoing expectant management: 90 were randomised to extended release metformin and 90 to placebo. INTERVENTION 3 g of oral extended release metformin or placebo daily, in divided doses, until delivery. MAIN OUTCOME MEASURE The primary outcome was prolongation of gestation. RESULTS Of 180 participants, one woman delivered before taking any trial drug. The median time from randomisation to delivery was 17.7 days (interquartile range 5.4-29.4 days; n=89) in the metformin arm and 10.1 (3.7-24.1; n=90) days in the placebo arm, a median difference of 7.6 days (geometric mean ratio 1.39, 95% confidence interval 0.99 to 1.95; P=0.057). Among those who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 (interquartile range 5.4-28.7; n=76) days compared with 7.9 (3.0-22.2; n=74) days in the placebo arm, a median difference of 9.6 days (geometric mean ratio 1.67, 95% confidence interval 1.16 to 2.42). Among those who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 (interquartile range 4.8-28.8; n=40) days compared with 4.8 (2.5-15.4; n=61) days in the placebo arm, a median difference of 11.5 days (geometric mean ratio 1.85, 95% confidence interval 1.14 to 2.88). Composite maternal, fetal, and neonatal outcomes and circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin did not differ. In the metformin arm, birth weight increased non-significantly and length of stay decreased in the neonatal nursery. No serious adverse events related to trial drugs were observed, although diarrhoea was more common in the metformin arm. CONCLUSIONS This trial suggests that extended release metformin can prolong gestation in women with preterm preeclampsia, although further trials are needed. It provides proof of concept that treatment of preterm pre-eclampsia is possible. TRIAL REGISTRATION Pan African Clinical Trial Registry PACTR201608001752102 https://pactr.samrc.ac.za/.Catherine A Cluver, Richard Hiscock, Eric H Decloedt, David R Hall, Sonja Schell, Ben W Mol, Fiona Brownfoot, Tu, uhevaha J Kaitu, u-Lino, Susan P Walker, Stephen Ton