Pretomanid can significantly increase plasma rivaroxaban concentrations-a case report

Rivaroxaban, a direct factor Xa inhibitor, is an oral anticoagulant used in the prevention and treatment of thromboembolic disease. The clearance of rivaroxaban involves excretion unchanged via the kidneys where it is subject to active secretion into the renal tubules, involving P-glycoprotein (P-gp) and organic anion transporter 3 (OAT3). Pretomanid, a nitroimidazole antibiotic used for multidrug-resistant tuberculosis (MDR-TB), is an OAT3 inhibitor based on in vitro data. This case report describes a "natural experiment" involving rivaroxaban concentration monitoring. It entails a novel pharmacokinetic interaction between rivaroxaban and pretomanid in a 61-year-old male undergoing MDR-TB treatment.

Following pretomanid initiation, rivaroxaban trough plasma concentration increased more than two-fold, prompting a halving of rivaroxaban dose, and subsequent restoration of trough concentration to pre-pretomanid value.

This interaction appears to be mediated by pretomanid inhibition of OAT3, which reduces renal clearance of rivaroxaban. Other components of MDR-TB regimen and pre-existing medications are unlikely to be contributory based on their pharmacokinetic profiles.

This case highlights the potential impact of drug interactions involving pretomanid and known OAT3 perpetrators on the pharmacokinetics of rivaroxaban and other OAT3 substrates, particularly those of low therapeutic index, such as methotrexate. Given the global rise in MDR-TB, further research into pretomanid as a perpetrator of drug interactions is warranted.