Elin M. Svensson (1), Mats O. Karlsson (1)
(1) Uppsala University, Uppsala, Sweden
Objectives: To characterize changes in albumin and body weight in patients treated for multidrug-resistant tuberculosis (MDR-TB) with bedaquiline (BDQ) and to investigate the potential impact of these changes on BDQ PK.
Methods: Data were obtained from two phase II studies of BDQ, a highly protein bound drug (unbound fraction fu<0.1% [1]), in MDR-TB patients [2-3]. Observations of albumin, body weight, BDQ and metabolite M2 plasma concentrations were available from the treatment period with BDQ plus optimized background therapy OBT (24 weeks) and following period with only OBT (up to week 120). Mechanistically plausible relationships of albumin, BDQ and its M2 metabolite, including effects of fu (inversely proportional to albumin concentration) were tested in population PK models. Clinical research was approved by institutional review boards and all subjects provided written informed consent.
Results: 4684 albumin observations and 5438 body weight observations from 335 patients were included. Albumin at screening was typically lower than the reference value for healthy individuals and increased over time on treatment. A logistic growth model described the time-course of albumin best. Estimated parameters were A0 (albumin at start of treatment) 3.65 g/dl (RSE 0.9%), Ass (albumin at steady state [SS]) 4.05 g/dl (RSE 0.6%) and T½ (half-life to reach albumin SS) 22.3 weeks (RSE 13%). The IIV in A0, Ass and T½ were 16%, 10% and 118%, respectively. Body weight typically increased during treatment and could be described with a linear model; typical body weight at start of treatment (WT0) and end of follow up (WT120) were 56.7 (RSE 1.1%) and 62.5 (RSE 1.3%) kg, with IIVs of 21% and 22%. RSE in all IIVs were <10%. Correlations A0-WT0 and Ass-WT120 were 35% and 33%. Time varying albumin was used to predict changes in fu and hepatic capacity (i.e. clearance of BDQ and M2). The relationships improved the description of BDQ/M2 data significantly. Allometric scaling with time varying weight instead of weight at baseline improved the fit. The coefficients were 1 for volumes (fixed) and 0.18 for clearances (estimated, p<0.05).
Conclusions: Models describing typical and individual albumin concentrations and body weight were developed. Time-varying albumin and body weight were found to impact BDQ and M2 PK. Incorporating both effects simultaneously and accounting for changes over time aided the characterization of influence of body weight and albumin on BDQ patient PK which has not previously been described.
Acknowledgement
The research leading to these results has received funding from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement n°115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution
References
[1] van Heeswijk RPG, Dannemann B and Hoetelmans RMW. Bedaquiline: a review of human pharmacokinetics and drug–drug interactions, J Antimicrob Chemother 2014; 69(9)
[2] Diacon A, Pym A, Grobusch MP, et al. Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline, New England J Medicin 2014; 371
[3] Janssen Infectious Diseases BVBA. To Evaluate the Safety, Tolerability, and Efficacy of TMC207 as Part of an Individualized Multi-drug Resistant Tuberculosis (MDR-TB) Treatment Regimen in Participants With Sputum Smear-positive Pulmonary MDR-TB. https://clinicaltrials.gov/ct2/show/NCT00910871, 2009- (Accessed April 2015)
Reference: PAGE 24 (2015) Abstr 3390 [www.page-meeting.org/?abstract=3390]
Poster: Drug/Disease modeling - Infection