Stable, compounded bedaquiline suspensions to support practical implementation of pediatric dosing in the field

Abstract

BACKGROUND: Bedaquiline (BDQ) tablets are indicated as part of a combination regimen for the treatment of multidrug-resistant TB in adults, adolescents and children. A dispersible tablet formulation is now approved but is not currently available in all settings. The aim of this study was to develop stable extemporaneous liquid formulations of BDQ that can be stored at room temperature or 30°C for several weeks, to support pragmatic pediatric dosing in the field and reduce wastage.METHODS: BDQ tablets were suspended in simple syrup and a sugar-free vehicle. Each 20 mg/mL formulation was stored at room temperature or 30°C for 30 days in amber dispensing bottles. Appearance, BDQ potency, pH and microbial counts were determined on Days 0, 15 and 30.RESULTS: The BDQ potency in both formulations remained at 98–101% of the theoretical concentration for 30 days. The appearance, pH and microbial count of sugar-free formulation did not change during the 30-day storage. The simple syrup formulation was stable for 15 days as microbial growth was observed on Day 30.CONCLUSIONS: BDQ may be prepared in syrup or sugar-free suspensions: syrup suspensions can be stored for 15 days at room temperature and 30C, whereas sugar-free suspensions can be stored for 30 days at room temperature and 30C. This information will support practical BDQ dosing for children in the field.

A novel home-based method for preparing suspensions of anti-TB drugs

“…We recently described the methodology for the preparation of extemporaneous formulations of BDQ, CFZ, DLM, and Pa in a pharmacy/dispensary setting. 11 – 14 However, access to a pharmacy may be limited in many situations. We have therefore developed a device and methodology that permits extemporaneous formulation preparation at home by the caregiver or patient.…”

“…We follow previously described preparation procedures for compounded formulations of these drugs in simple syrup. 11 – 14 The concentrations selected for the four drugs were BDQ 20 mg/mL, CFZ 10 mg/mL, DLM 5 mg/mL, and Pa 20 mg/mL, based on discussions with clinicians and pharmacists in the field and the age-appropriate doses provided in the Field Guide by the Sentinel Project. 2 Within these concentrations, it is possible to accurately measure dosing volumes at home using oral syringes, spanning from half a teaspoon (2.5 mL) to 4 teaspoons (20 mL).…”

“…Stability-indicating high-performance liquid chromatographic (HPLC) methods were developed for each drug and verified using forced degradation studies, as previously described. 11 – 14 Details of the analytical methods are given in Table 1 ( Supplementary Data ).…”

“…In a series of recently published papers, we have described the process for preparing extemporaneous formulations of key second-line TB drugs – bedaquiline (BDQ), clofazimine (CFZ), delamanid (DLM), and pretomanid (Pa) – in a pharmacy or a dispensary setting under the supervision of a pharmacist. 11 – 14 In this paper, we describe a novel simple device and the methodology of using this device to convert BDQ, CFZ, DLM, and Pa tablets into liquid suspensions at home. This is especially beneficial for patients who do not have access to child-friendly or dysphagia-friendly formulations, or easy access to compounding pharmacies.…”

Advances of new drugs bedaquiline and delamanid in the treatment of multi-drug resistant tuberculosis in children

“…Janssen is developing a child-friendly version of bedaquiline, but it may not be available for some time ( Garcia-Prats et al., 2018 ). The practical dose of bedaquiline for children may be supported by the suspension or syrup forms of bedaquiline that are proven to be available ( Taneja et al., 2023 ). Meanwhile, a trial (NCT03032367) sponsored by the IMPAACT Network is comparing the effectiveness of using whole tablets and dissolved bedaquiline for children who cannot swallow whole tablets ( Garcia-Prats et al., 2018 ).…”