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- Title
Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling.
- Authors
Litjens, Carlijn H. C.; Verscheijden, Laurens F. M.; Bolwerk, Celine; Greupink, Rick; Koenderink, Jan B.; van den Broek, Petra H. H.; van den Heuvel, Jeroen J. M. W.; Svensson, Elin M.; Boeree, Martin J.; Magis-Escurra, Cecile; Hoefsloot, Wouter; van Crevel, Reinout; van Laarhoven, Arjan; van Ingen, Jakko; Kuipers, Saskia; Ruslami, Rovina; Burger, David M.; Russel, Frans G. M.; Aarnoutse, Rob E.; te Brake, Lindsey H. M.
- Abstract
Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed [P/O] ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement.
- Subjects
DRUG therapy for tuberculosis; QUINOLINE; IN vitro studies; IN vivo studies; CONCEPTUAL structures; DRUG interactions; DOSE-effect relationship in pharmacology; RIFAMPIN; ANTIBIOTICS
- Publication
Journal of Clinical Pharmacology, 2022, Vol 62, Issue 3, p385
- ISSN
0091-2700
- Publication type
Article
- DOI
10.1002/jcph.1972