Population pharmacokinetics of moxifloxacin, cycloserine, p-aminosalicylic acid and kanamycin for the treatment of multi-drug-resistant tuberculosis

- Population pharmacokinetic models of second-line anti-tuberculosis (TB) drugs in multi-drug-resistant TB were developed.
- Dosages of second-line anti-TB drugs were slightly different from previous studies.
- Pharmacokinetic parameters of moxifloxacin were influenced by patients' weight.

Control of multi-drug-resistant tuberculosis (MDR-TB) requires extensive, supervised chemotherapy because second-line anti-TB drugs have a narrower therapeutic range than first-line drugs. This study aimed to develop population pharmacokinetic (PK) models for second-line drugs in patients with MDR-TB, evaluate the recommended dosage regimens and, if necessary, suggest new dosage regimens.A prospective, single-centre PK study was performed on second-line anti-TB drugs in patients with MDR-TB. Moxifloxacin, cycloserine, p-aminosalicylic acid (PAS), kanamycin and other second-line drugs were administered to the patients. Plasma concentrations were analysed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Population PK models were developed using non-linear mixed effect modelling (NONMEM, Version 7.30; ICON Development Solutions, Ellicott City, MD, USA). Simulations were performed using the calculated PK parameters.The respective absorption rate constant, apparent clearance and apparent volume of distribution values were as follows: 0.305/h, 9.37 L/h and 56.7 L for moxifloxacin; 0.135/h, 1.38 L/h and 10.5 L for cycloserine; 0.510/h, 30.8 L/h and 79.4 L for PAS; and 1.67/h, 3.75 L/h and 15.2 L for kanamycin. The simulations showed that the following dosage regimens were more likely to be within the recommended concentration ranges than the raw data in this study: 200 mg of moxifloxacin once daily (QD) (patient weight <50 kg) and 400 mg of moxifloxacin QD (patient weight ≥50 kg), 500-750 mg of cycloserine QD, 4.95-6.6 g of PAS twice daily and 750-1000 mg of intramuscular kanamycin QD. These findings indicate that the recommended doses should be revised to improve the clinical outcomes of MDR-TB treatment.