A pharmacometric multistate model for predicting long-term treatment outcomes of patients with pulmonary TB.

BACKGROUND: Studying long-term treatment outcomes of TB is time-consuming and impractical. Early and reliable biomarkers reflecting treatment response and capable of predicting long-term outcomes are urgently needed. OBJECTIVES: To develop a pharmacometric multistate model to evaluate the link between potential predictors and long-term outcomes. METHODS: Data were obtained from two Phase II clinical trials (TMC207-C208 and TMC207-C209) with bedaquiline on top of a multidrug background regimen. Patients were typically followed throughout a 24 week investigational treatment period plus a 96 week follow-up period. A five-state multistate model (active TB, converted, recurrent TB, dropout, and death) was developed to describe observed transitions. Evaluated predictors included patient characteristics, baseline TB disease severity and on-treatment biomarkers. RESULTS: A fast bacterial clearance in the first 2 weeks and low TB bacterial burden at baseline increased probability to achieve conversion, whereas patients with XDR-TB were less likely to reach conversion. Higher estimated mycobacterial load at the end of 24 week treatment increased the probability of recurrence. At 120 weeks, the model predicted 55% (95% prediction interval, 50%-60%), 6.5% (4.2%-9.0%) and 7.5% (5.2%-10%) of patients in converted, recurrent TB and death states, respectively. Simulations predicted a substantial increase of recurrence after 24 weeks in patients with slow bacterial clearance regardless of baseline bacterial burden. CONCLUSIONS: The developed multistate model successfully described TB treatment outcomes. The multistate modelling framework enables prediction of several outcomes simultaneously, and allows mechanistically sound investigation of novel promising predictors. This may help support future biomarker evaluation, clinical trial design and analysis.

Relative bioavailability of delamanid 50 mg tablets dispersed in water in healthy adult volunteers.

AIM: Delamanid is a novel drug for the treatment of drug-resistant tuberculosis, manufactured as 50-mg solid and 25-mg dispersible tablets. We evaluated the effects of dispersing the 50-mg tablet, focusing on the relative bioavailability. METHODS: Delamanid, 50-mg tablets administered dispersed vs swallowed whole, was investigated in a phase I, four-period, crossover study. Two of three dose strengths of delamanid (25, 50 or 100 mg) were given to healthy adult participants, in both whole and dispersed forms, with a 7-day washout period. Blood samples were collected over 168 h after each dose. Delamanid and its metabolite DM-6705 were analysed with a validated liquid chromatography tandem mass spectrometry assay. The pharmacokinetics of both analytes were analysed using nonlinear mixed-effect modelling. Palatability and acceptability were determined using a standardized questionnaire. RESULTS: Twenty-four participants completed the study. The bioavailability of dispersed tablets was estimated to be 107% of whole tablets, with a 90% confidence interval of 99.7-114%, fulfilling bioequivalence criteria. The two formulations were not significantly different regarding either bioavailability or its variability. Bioavailability increased at lower doses, by 34% (26-42%) at 50 mg and by 74% (64-86%) at 25 mg, relative to 100 mg. The majority of participants (93%) found the dispersed formulation acceptable in palatability across all delamanid doses. CONCLUSIONS: Dispersed 50-mg delamanid tablets have similar bioavailability to tablets swallowed whole in adult volunteers. This can be an option for children and other patients who cannot swallow whole tablets, improving access to treatment.

Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling.

BACKGROUND AND INTRODUCTION: The dispersible tablet formulation (DTF) of pretomanid has been developed to facilitate future use in children. This work aimed to assess the pharmacokinetics (PK) and relative bioavailability of the DTF compared to the marketed formulation (MF) and the potential influence of dose. METHODS: Pretomanid DTF was investigated in a single-dose, randomized, four-period, cross-over study, with 7 days of washout between doses. Forty-eight healthy volunteers were enrolled and randomized into one of two panels to receive doses either in the fasted state or after a high-fat meal. Each volunteer received doses of 10, 50, and 200 mg DTF, and 200 mg MF pretomanid. Blood samples for pharmacokinetic assessment were drawn following a rich schedule up to 96 h after each single dose. The study data from the panel receiving the high-fat meal were analyzed using a nonlinear mixed-effects modeling approach, and all data were characterized with noncompartmental methods. RESULTS: A one-compartment model with first-order elimination and absorption through a transit compartment captured the mean and variability of the observed pretomanid concentrations with acceptable precision. No significant difference in bioavailability was found between formulations. The mean absorption time for the DTF was typically 137% (86-171%) of that for the MF. The bioavailability was found to be dose dependent with a small positive and larger negative correlation under fed and fasted conditions, respectively. CONCLUSION: Using data from a relative bioavailability study in healthy adult volunteers, a mathematical model has been developed to inform dose selection for the investigation of pretomanid in children using the new dispersible tablet formulation. Under fed conditions and at the currently marketed adult dose of 200 mg, the formulation type was found to influence the absorption rate, but not the bioavailability. The bioavailability of the DTF was slightly positively correlated with doses when administered with food. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04309656, first posted on 16 March 2020.