Simultaneous quantitation of delamanid (OPC-67683) and its eight metabolites in human plasma using UHPLC–MS/MS

Mei, Meng; Smith, Benjamin D.; Johnston, Brad; Carter, Spencer; Brisson, Jerry; Roth, Sharin E.

doi:10.1016/j.jchromb.2015.07.058

Cited by 12 publications

(10 citation statements)

References 8 publications

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“…Plasma samples were analyzed for delamanid and its metabolites using a specific and validated high performance liquid chromatography assay with a tandem mass spectrophotometric detection (i.e., liquid chromatography-tandem mass spectrometry [LC-MS/MS]) method developed by Tandem Laboratories, Salt Lake City, UT ( 21 ). Delamanid, its metabolites, and the internal standard (OPC-14714) were extracted from plasma using protein precipitation, followed by injection of the supernatant.…”

Section: Methodsmentioning

confidence: 99%

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Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects

Mallikaarjun

Wells

Petersen

et al. 2016

Antimicrob Agents Chemother

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Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of delamanid with tenofovir or efavirenz did not affect the PK characteristics of delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with delamanid resulted in an approximately 25% higher delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCτ). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower delamanid exposures (47 and 42% for the AUCτ and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCτ values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCτ and Cmax values were about 25% higher with delamanid coadministration. The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to decreased delamanid absorption and not to CYP induction.

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Section: Methodsmentioning

confidence: 99%

“…Plasma samples were analyzed for delamanid and metabolite concentration using a specific and validated UPLC-MS/MS method by Tandem Laboratories similar to that described for study 1 ( 21 ). Plasma samples were analyzed for lopinavir and ritonavir concentration using a specific and validated LC-MS/MS method by Tandem Laboratories.…”

Section: Methodsmentioning

confidence: 99%

Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects

Mallikaarjun

Wells

Petersen

et al. 2016

Antimicrob Agents Chemother

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“…Blood samples were collected from all trial 204 patients for determination of delamanid plasma concentrations, and the area under the curve during 24 h (AUC 0 -24 ), minimum concentration (C min ), and maximum concentration (C max ) were determined as described previously (4). Delamanid concentrations in plasma were determined using ultrahigh performance liquid chromatographic-tandem mass spectrometry (11). (The full protocol of trial 204 can be found at http://www.nejm.org/doi/suppl/10.1056/NEJMoa1112433/suppl_file /nejmoa1112433_protocol.pdf.…”

Section: Figmentioning

confidence: 99%

MIC of Delamanid (OPC-67683) against Mycobacterium tuberculosis Clinical Isolates and a Proposed Critical Concentration

Stinson

Kurepina

Venter

et al. 2016

Antimicrob Agents Chemother

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“…The elution steps were as follows: 0 to 1.0 min of a linear gradient of from 25% to 40% solvent B, 1.0 to 9.0 min of a linear gradient of from 40% to 55% solvent B, and 9.0 to 13.0 min of an isocratic elution at 55% solvent B. Equilibration was achieved 8 min after returning to the initial conditions. The column effluent was delivered to the electrospray ionization ion source in positive ion multiple-reaction-monitoring mode to produce product ions of m/z 466.5 ¡ 352.0 for M1 and m/z 458.2 ¡ 295.5 for the internal standard (OPC-14714, a benzoquinolinone analogue compound used in the quantitation method involving human plasma [24]). The calibration of M1 both in 1% BSA-HBSS and in the cell suspension showed good linearity (correlation coefficient [r], 0.9976 to 0.9983 and 0.9958 to 0.9984, respectively) over the M1 concentration range of 1.2 to 1,200 nmol/liter using weighted (1/concentration 2 ) leastsquares regression.…”

Section: Lc-ms/ms Analysis Of M1mentioning

confidence: 99%

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

Sasabe

Shimokawa

Shibata

et al. 2016

Antimicrob Agents Chemother

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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.

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Simultaneous quantitation of delamanid (OPC-67683) and its eight metabolites in human plasma using UHPLC–MS/MS

Cited by 12 publications

References 8 publications

Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects

Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects

MIC of Delamanid (OPC-67683) against Mycobacterium tuberculosis Clinical Isolates and a Proposed Critical Concentration

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

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