Antitubercular Agent Delamanid and Metabolites as Substrates and Inhibitors of ABC and Solute Carrier Transporters

Abstract

b Delamanid (Deltyba, OPC-67683) is the first approved drug in a novel class of nitro-dihydro-imidazooxazoles developed for the treatment of multidrug-resistant tuberculosis. Patients with tuberculosis require treatment with multiple drugs, several of which have known drug-drug interactions. Transporters regulate drug absorption, distribution, and excretion; therefore, the inhibition of transport by one agent may alter the pharmacokinetics of another, leading to unexpected adverse events. Therefore, it is important to understand how delamanid affects transport activity. In the present study, the potencies of delamanid and its main metabolites as the substrates and inhibitors of various transporters were evaluated in vitro. Delamanid was not transported by the efflux ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp; MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), solute carrier (SLC) transporters, organic anion-transporting polypeptides, or organic cation transporter 1. Similarly, metabolite 1 (M1) was not a substrate for any of these transporters except P-gp. Delamanid showed no inhibitory effect on ABC transporters MDR1, BCRP, and bile salt export pump (BSEP; ABCB11), SLC transporters, or organic anion transporters. M1 and M2 inhibited P-gp-and BCRP-mediated transport but did so only at the 50% inhibitory concentrations (M1, 4.65 and 5.71 mol/liter, respectively; M2, 7.80 and 6.02 mol/liter, respectively), well above the corresponding maximum concentration in plasma values observed following the administration of multiple doses in clinical trials. M3 and M4 did not affect the activities of any of the transporters tested. These in vitro data suggest that delamanid is unlikely to have clinically relevant interactions with drugs for which absorption and disposition are mediated by this group of transporters.

Combining enabling formulation strategies to generate supersaturated solutions of delamanid: In situ salt formation during amorphous solid dispersion fabrication for more robust release profiles

“…DLM is a weakly basic compound with a reported pKa of 4.3 [2] , and hence exhibits pH-dependent solubility like other weak bases [3] , [4] . The drug is slightly soluble at low pH and undergoes a substantial decrease in solubility when the solution pH increases above the pKa [5] . Despite a fairly long half-life, DLM requires twice daily dosing and must be taken with food to ensure adequate bioavailability [6] .…”

A Pilot Study To Assess the Suitability of Riboflavin As a Surrogate Marker of Breast Cancer Resistance Protein in Healthy Participants

“…(Ibaraki, Japan) following the protocol described previously (Sasabe et al, 2016, Sasabe et al, 2021. The inhibition potential of BMS-986371 towards P-gp and BCRP was assessed using transporter-overexpressing Lewis-lung cancer porcine kidney 1 (LLC-PK1) cells whereas that towards OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2-K was evaluated using transporter-overexpressing HEK-293 cells.…”

“…To assess the potential for BMS-986371 to inhibit the major human intestinal (P-gp and BCRP), hepatic (OATP1B1, OATP1B3, and OCT1), and renal drug transporters (OAT1, OAT3, OCT2, MATE1 and MATE2-K) in vitro, a transporter inhibition study was performed using stably transfected LLC-PK1 and HEK-293 cells that individually overexpressed the transporters (Supplementary Tables). The experiments were performed using the methods described in the previous publications by Sekisui Medical Co., Ltd. (Ibaraki, Japan) (Sasabe et al, 2016, Sasabe et al, 2021. The assessments showed that BMS-986371 was a potent inhibitor of intestinal efflux transporters P-gp and BCRP.…”

Management of drug-resistant tuberculosis in special sub-populations including those with HIV co-infection, pregnancy, diabetes, organ-specific dysfunction, and in the critically ill

“…The WHO has recently endorsed the use of dolutegravir as part of a first-line ART regimen (31). This agent is not only more effective and better tolerated, but is also expected to be safe for co-administration with newer agents such as bedaquiline and delamanid (32,33).…”