Rifampicin Resistant Tuberculosis in Lesotho: Diagnosis, Treatment Initiation and Outcomes.

The Lesotho guidelines for the management of drug-resistant tuberculosis (TB) recommend initiation of patients diagnosed with rifampicin resistant (RR)-TB on a standardized drug resistant regimen while awaiting confirmation of rifampicin resistant TB (RR-TB) and complete drug susceptibility test results. Review of diagnostic records between 2014 and 2016 identified 518 patients with RR-TB. Only 314 (60.6%) patients could be linked to treatment records at the Lesotho MDR hospital. The median delay in treatment initiation from the availability of Xpert MTB/RIF assay result was 12 days (IQR 7-19). Only 32% (101) of patients had a documented first-line drug resistant test. MDR-TB was detected in 56.4% of patients while 33.7% of patients had rifampicin mono-resistance. Only 7.4% of patients assessed for second-line resistance had a positive result (resistance to fluoroquinolone). Treatment success was 69.8%, death rate was 28.8%, loss to follow up was 1.0%, and 0.4% failed treatment. Death was associated with positive or unavailable sputum smear at the end of first month of treatment (Fisher exact p < 0.001) and older age (p = 0.007). Urgent attention needs to be given to link patients with RR-TB to care worldwide. The association of death rate with positive sputum smear at the end of the first month of treatment should trigger early individualization of treatment.

Bioavailability of two licensed paediatric rifampicin suspensions: implications for quality control programmes.

SETTING: To assess the revised World Health Organization-recommended dose of 10-20 mg/kg rifampicin (RMP), we studied the steady state pharmacokinetics of RMP in South African children who received standard treatment for drug-susceptible tuberculosis (TB). OBJECTIVE: To determine the formulation effect on the pharmacokinetics of RMP. DESIGN: RMP plasma concentrations were characterised in 146 children (median age 1.4 years, range 0.2-10.2). The morning dose on the day of the pharmacokinetic evaluation was administered as one of two RMP single-drug oral suspensions. RESULTS: While one formulation achieved 2 h concentrations in the range of those observed in adults (median 6.54 mg/l, interquartile range [IQR] 4.47-8.84), the other attained a median bioavailability of only 25% of this, with a median 2 h concentration of 1.59 mg/l (IQR 0.89-2.38). CONCLUSION: RMP is a key drug for the treatment of TB. It is critical that the quality of RMP suspensions used to treat childhood TB is ensured.

Simultaneous determination of efavirenz, rifampicin and its metabolite desacetyl rifampicin levels in human plasma.

A simple and rapid isocratic, high performance liquid chromatography (HPLC) assay employing solid phase extraction (SPE) for the simultaneous determination of the anti HIV drug, efavirenz, the anti-tuberculosis drug, rifampicin and the desacetyl metabolite of rifampicin in plasma from HIV/tuberculosis infected patients has been developed. Using a Zorbax SB-Phenyl reverse-phase analytical column with UV detection, good separation and detection of the drugs was attained within a 10min run time. Intra- and inter-assay precision RSD values were found to be less than 15% at the concentrations examined (0.1-20µg/mL). The LOQ was found to be 0.1µg/mL for each agent and the assay was found to generate a linear response up to 20µg/mL. This low cost assay can accurately detect efavirenz and rifampicin concentrations within a clinically relevant concentration range using standard chromatography equipment, making it particularly applicable to resource-limited settings.

Quality control of anti-tuberculosis FDC formulations in the global market: part II-accelerated stability studies.

OBJECTIVE: To determine the quality and performance of rifampicin (RMP) containing fixed-dose combination (FDC) formulations of anti-tuberculosis drugs sourced from the international market with respect to physical, chemical and dissolution properties after storage at accelerated stability conditions (40 degrees C/75% relative humidity) and to identify appropriate storage specifications. METHODS: Formulations across different companies and combinations were subjected to 6-month accelerated stability testing in packaging conditions recommended by the manufacturer. Various pharmacopeial and nonpharmacopeial tests for tablets were performed for 3- and 6-month samples. RESULTS: All the formulations were found to be stable, where extent of dissolution was within +/- 10% of that of the initial value, and all formulations passed the pharmacopeial limits for assay and content uniformity of 90-110% and +/- 15% of average drug content, respectively. CONCLUSIONS: Good quality RMP-containing FDCs that remain stable after 6-month accelerated stability testing are available in the marketplace.

Minimum sample size and sampling time requirements for assessment of rifampicin bioequivalence from FDC formulations.

SETTING: The WHO- and IUATLD-recommended protocol for rifampicin (RMP) bioequivalence utilises 20-22 volunteers and 8 h, whereas the requirement of other regulatory authorities is 12 volunteers with a 24 h sampling schedule. Differing sampling size and time requirements may change the outcome of RMP bioequivalence. OBJECTIVE: To determine the minimal sample size and time required to assess RMP bioequivalence from FDC formulations. DESIGN: Bioequivalence studies were conducted that fulfilled the criteria of the WHO and Indian regulatory protocols. From earlier studies, retrospective pharmacokinetic evaluation, power of the test and bioequivalence limits were also calculated using 8-22 volunteers and sampling points of 8-24 h. Pharmacokinetic and statistical evaluations from three representative studies showing low, moderate and high intra-subject variability are given to determine minimum requirements for RMP bioequivalence. RESULT: It was found that a sampling schedule up to 8 h was sufficient to compare the absorption process of RMP. There was no influence of reduced sample size on bioequivalence estimates of RMP that showed low or moderate variability. However, in a study showing higher variation, a sample size of 14-16 subjects was found to be optimal. CONCLUSION: It is possible to reduce the sample size requirement for determination of RMP bioequivalence using the WHO protocol.

Quality control of anti-tuberculosis fixed-dose combination formulations in the global market: an in vitro study.

OBJECTIVE: To determine the quality, and especially the dissolution properties of rifampicin, of fixed-dose combination (FDC) formulations of anti-tuberculosis agents manufactured by major market holders in the anti-tuberculosis sector and supplied for use in national tuberculosis control programmes. METHODS: Dissolution studies were performed for four formulations supplied by four different manufacturers in four dissolution media (0.1N and 0.01N HCl, phosphate buffer [PB] and 20% vegetable oil in PB), at four different agitation rates using USP apparatus II. The formulations were subjected to 4-week accelerated stability studies (40 degrees C / 75% RH) and evaluated for physical, chemical and dissolution stability. RESULTS: The formulations tested complied with pharmacopeial quality control (QC) tests. The extent of rifampicin release was independent of dissolution medium; however, a slight decrease in the dissolution rate was observed in two products. More than 75% of drug was released in 45 min at all agitation intensities except 30 rpm, and 20% oil in the medium reflected fed state. Formulations were stable in the packaging conditions recommended by the manufacturer for at least 4 weeks. CONCLUSIONS: The formulations tested passed the QC tests and were found to be stable. A decrease in the rate, although not the extent, of dissolution necessitated multiple point dissolution in gastric and intestinal pH conditions to ensure consistency in in vivo bioavailability.

Evaluation of rifampicin bioequivalence in fixed-dose combinations using the WHO/IUATLD recommended protocol.

For an accurate assessment of rifampicin bioequivalence from fixed-dose combinations (FDCs), and to reduce the time and cost constraints associated with bioequivalence studies, the World Health Organization and the International Union Against Tuberculosis and Lung Disease have developed a simplified screening protocol. This study was undertaken with the objective of testing the applicability of this protocol for all types of FDCs. Data were obtained for volunteers common to three studies, and pharmacokinetic parameters were evaluated by different statistical tests. From the results, it has been demonstrated that the simplified screening protocol is suitable for evaluating the bioequivalence of rifampicin in all the types of FDCs available on the market.