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Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children.

ABSTRACT: AIMS:Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets. METHODS:A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 h was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability. RESULTS:There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell. CONCLUSIONS:The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug-resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

SUBMITTER: Svensson EM

PROVIDER: S-EPMC6138504 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children.

Svensson Elin M EM du Bois Jeannine J Kitshoff Rene R de Jager Veronique R VR Wiesner Lubbe L Norman Jennifer J Nachman Sharon S Smith Betsy B Diacon Andreas H AH Hesseling Anneke C AC Garcia-Prats Anthony J AJ

British journal of clinical pharmacology 20180627

<h4>Aims</h4>Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets.<h4>Methods</h4>A randomized, open-label, two-period cross-over study was conducted in 24 healthy ad ...[more]

PMID: 29952141

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Project description:BackgroundOral solution N-acetylcysteine (NAC) is an antidote for acetaminophen overdose, but its unpleasant taste and aroma can impede delivery even after the coadministration of antiemetic medications. Flavored effervescent NAC tablets dissolved in water might be a more palatable formulation than oral solution NAC diluted with soft drink.ObjectivesTo evaluate the relative bioavailability of these 2 formulations and assess subjective preferences between them.MethodsThirty healthy adult volunteers (mean [SD] = 35.2 [9.14] years) were enrolled in this open-label, randomized, single-dose, crossover study, with a 7-day washout period. Volunteers were randomized to receive 11 g effervescent test formulation or the reference product under fasting conditions, after which 19 serial blood samples were collected over 48 hours. Total plasma NAC concentrations were evaluated by LC-MS, and pharmacokinetic parameters were calculated. The 2 formulations were considered bioequivalent if the 90% CIs of log-transformed ratios of pharmacokinetic parameters were within the predetermined bioequivalence range (80%-125%) established by the US Food and Drug Administration. Within 15 minutes of dosing, subjects were also asked to rank formulation attributes on a 5-point hedonic scale, with mean group differences analyzed by Wilcoxon signed rank test. Safety-profile assessment included treatment-emergent adverse events, physical examination, chemistry, and hematology parameters.ResultsThe concentration-versus-time profiles were similar for the 2 formulations, with mean Cmax of 26.5 μg/mL for effervescent NAC tablets and 28.4 μg/mL for oral solution NAC. The 90% CIs for the pharmacokinetic parameters met the criteria for concluding bioequivalence, and subjects preferred effervescent NAC tablets in terms of taste (P = 0.0247), flavor (P = 0.0082), texture (P = 0.009), and overall likeability (P = 0.0012), but there was no difference for smell (P = 0.0533). All treatment-emergent adverse events were mild, with no differences between the treatment groups.ConclusionsData from this study of a single dose of 11 g oral NAC demonstrated that effervescent NAC tablets and oral solution NAC met the regulatory criteria for bioequivalence in fasting healthy adult subjects. Effervescent NAC tablets appear to be a more palatable alternative for treatment of acetaminophen overdose. ClinicalTrials.gov identifier: NCT02723669. (Curr Ther Res Clin Exp. 2016; 83C:1-7) © 2016 Elsevier HS Journals, Inc.

Project description:Medication adherence can be challenging for persons with difficulty swallowing tablets. We investigated the bioequivalence of a dissolved tablet when compared with that of a whole tablet of the fixed-dose combination elvitegravir (EVG)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir (TFV) alafenamide fumarate (TAF). A within-subject fixed-order two-period open-label study was conducted in 12 HIV-negative research participants after obtaining informed consent. Participants took a single dose each of the whole tablet and dissolved tablet under direct observation, separated by a 14-day washout period. The dissolved tablet was prepared by adding one whole EVG/COBI/FTC/TAF tablet to 120 mL tap water and stirring. Both dosage types were taken with a standardized meal. Plasma samples were obtained for 72 h postdose. Plasma EVG, FTC, TAF, and TFV were analyzed with liquid chromatographic-tandem mass spectrometric methods. Peak plasma concentration (Cmax) and the area under the concentration-time curve extrapolated to infinity (AUC0-∞) were estimated using WinNonlin software (v.8.3). The primary outcome was bioequivalence consistent with FDA guidance using the 90% confidence interval or the geometric mean ratio. Of 12 participants, 7 were black (58%) and 5 were white (42%), 4 were women (33%), 8 were men (67%), and the mean age was 43.6 years (23-54). There were no complaints about taste with the dissolved tablet. Bioequivalence was established only for FTC. EVG Cmax and AUC0-∞ were higher by 18% and 12%, respectively, when taking the dissolved compared with the whole tablet. TAF AUC0-∞ and Cmax were both 8% lower, whereas TFV Cmax and AUC0-∞ were 8% and 5% lower, respectively, when taken after dissolution. EVG/COBI/FTC/TAF dissolved rapidly in water and had no unpleasant taste. Increases in EVG and decreases in TAF and TFV concentrations were observed when taking dissolved EVG/COBI/FTC/TAF. These changes were judged to be clinically insignificant. Dissolving EVG/COBI/FTC/TAF in water may be suitable for those with pill swallowing challenges. The trial was registered on (//clinicaltrials.gov NCT03717129).

Project description:ObjectiveFeasibility study to investigate the acceptability of different-sized placebo tablets in children aged 4-12 years.Design and settingClinical Research Facilities, inpatient wards and outpatient clinics within a Regional Paediatric Hospital and/or District General Hospital. Healthy children and National Health Service (NHS) patients were asked to swallow three placebo tablets: 6 mm, 8 mm and 10 mm, smallest to largest. The researcher observed children's facial expressions and behaviours on swallowing and measured the volume of water consumed. Participants completed a questionnaire about the overall acceptability; including swallowability, taste and volume of water consumed. For analysis, participants were stratified by age: 4-8 years and 9-12 years.ResultsThe feasibility study led to an estimated recruitment rate of 0.8% for NHS inpatients and 211 healthy children over a 1-year period. In total, 55 participants were recruited, 30 to the younger group, of which 77% had never taken a tablet before. 84% of the 25 older children had previously taken a tablet. All participants attempted to swallow the smallest sized tablet. The children aged 4-8 years found the larger tablets easier to swallow, however the older children found little difference between the tablet sizes. The younger children required more water to swallow each tablet size compared with the older children where an increasing volume of water was consumed as tablet size increased. Taste was rated highly for both age groups. The 8 mm tablets were deemed the most acceptable tablet size by all participants.ConclusionTablets are potentially an acceptable formulation for children aged 4-12 years. Most children aged 4-8 years who attempted to swallow tablets successfully did so. Recruitment of NHS inpatients to medicine acceptability studies is challenging, however, recruitment of children of staff proved an effective strategy. Valuable lessons have been learnt from this feasibility study which will inform the design of a larger definitive trial.

Dataset Information

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children.

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Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children.

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