Dose- and Time-dependency of the Toxicity and Pharmacokinetic Profiles of Bedaquiline and Its N-desmethyl Metabolite in Dogs.

Abstract

Bedaquiline (BDQ) is an antibiotic to treat pulmonary multidrug-resistant tuberculosis (MDR-TB). Studies up to 39 weeks were conducted orally in dogs to assess the toxicity and pharmacokinetics of BDQ and its N-desmethyl metabolite (D-BDQ). Phospholipidosis (PLD) seen in the monocytic phagocytic system was considered an adaptive change. Skeletal muscle, heart, stomach, liver, and pancreas toxicities with D-BDQ as the main contributor were associated with a less-than-dose-proportional increase in plasma exposure and an overproportional tissue uptake of BDQ and D-BDQ at high-dose levels. Tissue concentrations of BDQ and D-BDQ slowly decreased after lowering the dose, contributing to the recovery of the pathological findings. Treatment was better tolerated at mid-dose levels, characterized by a dose-proportional increase in plasma and tissue exposures. Treatment at a low dose, reaching exposures approximating therapeutic exposures, was without adverse effects and not associated with PLD. There was no evidence of delayed toxicities after treatment cessation. Intermittent dosing was better tolerated at high doses. Since MDR-TB patients are dosed within the linear plasma exposure range and plasma levels of BDQ and D-BDQ are similar or lower than in dogs, PLD and adverse findings related to tissue accumulation that occurred at high doses in dogs are unlikely to occur in humans.

• Authors: Ilham Smyej, Sandra De Jonghe, Adriana Looszova, Geert Mannens, Tom Verhaeghe, Sandy Thijssen, Sofie Starckx, Ann Lampo, Marie-Claude Rouan
• Journal: Toxicologic pathology (Toxicol Pathol) Vol. 45 Issue 5 Pg. 663-675 (07 2017) ISSN: 1533-1601 [Electronic] United States
• PMID: 28789609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antitubercular Agents
• Diarylquinolines
• Phospholipids
• bedaquiline

Topics

• Administration, Oral
• Animals
• Antitubercular Agents (administration & dosage, chemistry, pharmacokinetics, toxicity)
• Diarylquinolines (administration & dosage, chemistry, pharmacokinetics, toxicity)
• Dogs
• Female
• Male
• Muscle, Skeletal (chemistry, metabolism)
• Myocardium (chemistry, metabolism)
• Pancreas (chemistry, metabolism)
• Phospholipids (analysis, chemistry)
• Tissue Distribution