WEPE043 - Poster Exhibition
Absence of clinically relevant drug interaction between delamanid, a new drug for multidrug-resistant tuberculosis (MDR-TB) and tenofovir or lopinavir/ritonavir in healthy subjects
A. Paccaly1, C. Petersen1, S. Patil2, P. Bricmont2, J. Kim3, M. Harlin2, C. Wells1
1Otsuka Pharmaceutical Development and Commercialization, Otsuka Novel Products, Clinical Development, Rockville, United States, 2Otsuka Pharmaceutical Development and Commercialization, Clinical Pharmacology, Rockville, United States, 3Otsuka Pharmaceutical Development and Commercialization, Otsuka Novel Products, Biometrics, Rockville, United States
Background: Delamanid (DLM, OPC-67683), a novel nitro-dihydro-imidazooxazole derivative, is under investigation for the treatment of MDR-TB patients, including those with HIV on ARV (Antiretroviral) therapy. Although tenofovir (TFV) and lopinavir/ritonavir (LPV/RTV) have well documented toxicities in treating HIV patients, they are mainstays of therapy in many regions.. LPV/RTV is associated with severe hepatotoxicity and contra-indicated with drugs metabolized by CYP3A because of potent CYP3A inhibition by RTV, and with potent CYP3A inducers that may reduce LPV efficacy. DLM does not inhibit nor induce CYP enzymes.
Methods: This phase 1, open-label randomized, multiple dose parallel group trial investigated the drug-drug interaction potential of DLM and TFV (Viread) or LPV/RTV (Kaletra). Healthy subjects (18-45 years, similar number M/F) were assigned to treatment groups (n≥10/Group): DLM, TFV, LPV/RTV, DLM+TFV, DLM+LPV/RTV, for 14 days to reach steady-state exposure. Blood was drawn for pharmacokinetic (PK) evaluation on D1 (pre-dose), D12-13 (troughs) and D14 (PK profile). PK parameters and geometric mean ratios for Cmax and AUCt with 90%CI were determined. Safety evaluation included clinical laboratory assessments, physical examination, and vital signs, electrocardiograms and AEs assessment.
Results: DLM did not affect TFV, LPV or RTV drug exposure. TFV had no effect on DLM exposure, while a slightly higher (20%) DLM exposure was observed with LPV/RTV, possibly related to CYP3A inhibition by RTV.
Effect of co-administration of DLM with TFV or LPV/RTV on Exposure
[Effect of DLM with TFV or LPV/RTV]
TEAEs were least frequent in the DLM alone group. The number of subjects with TEAEs was similar for TVR or LRV/RTV alone and in combination with DLM
Conclusions: No clinically relevant changes in drug exposure occurred with combined administration of DLM and TFV or LPV/RTV in healthy subjects. DLM is a promising new agent to treat MDR-TB patients on ARV therapy containing TFV or LPV/RTV.
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