Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling.

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.

Modeling the Accumulation of Degradable Polymer Drug Carriers in the Brain.

The blood-brain barrier (BBB) limits the access of drugs to the brain. Intensive research is being conducted on the development of nanoparticulate drug carriers that mediate transfer across the BBB. A question that has been neglected so far is the potential accumulation of the carrier in the brain upon long-term exposure. Here, we address this question by implementing a kinetic model to relate drug loading, required concentration of drug in the brain, and drug clearance to the degradation half-life of the carrier. As a test case with clinical relevance we chose poly-lactic-co-glycolic-acid (PLGA) as a carrier material and a chemotherapeutic for which the required parameters could be recovered from the literature. For methotrexate with a drug load of 8.5 %, a required concentration of free drug of 1 µm, a release from PLGA of 6 hours, a drug clearance from the brain of 3 hours and a half-life of polymer degradation of 28 days, a steady-state accumulation of 1.3 g polymer would be reached in the brain (1.5 L) after seven months. While this number is surprisingly small, further physiological research is warranted to assess to which degree this will be in a tolerable range.