Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir, Efavirenz, or Rifampin

Dooley, Kelly E.; Luetkemeyer, Anne F; Park, Jeong‐Gun; Allen, R.; Cramer, Yoninah; Murray, Stephen R.; Sutherland, Deborah; Aweeka, Francesca; Koletar, Susan L.; Marzan, Florence; Bao, Jing; Savic, Rada; Haas, David W.

doi:10.1128/aac.03332-14

Cited by 44 publications

(29 citation statements)

References 27 publications

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“…Furthermore, delamanid is not affected by efavirenz, a CYP3A4 inducer . On the other hand, PA-824 exposures are substantially reduced by concomitant efavirenz, whereas lopinavir/ritonavir had minimal effect on PA-824 exposures (Dooley et al, 2014). These findings suggest that even though albumin metabolism may occur with PA-824, the contribution of albumin on PA-824 metabolism is lower than that for delamanid.…”

Section: Discussionmentioning

confidence: 80%

Pharmacokinetics and Metabolism of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo

et al. 2015

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Delamanid, a new anti-tuberculosis drug, is metabolized to M1, a unique metabolite formed by cleavage of the 6-nitro-2,3-dihydroimidazo[2,1-b] oxazole moiety, in plasma albumin in vitro. The metabolic activities in dogs and humans are higher than those in rodents. In this study, we characterized the pharmacokinetics and metabolism of delamanid in animals and humans. Eight metabolites (M1-M8) produced by cleavage of the imidazooxazole moiety of delamanid were identified in the plasma after repeated oral administration by liquid chromatography-mass spectrometry analysis. Delamanid was initially catalyzed to M1 and subsequently metabolized by three separate pathways, which suggested that M1 is a crucial starting point. The major pathway in humans was hydroxylation of the oxazole moiety of M1 to form M2 and then successive oxidation to the ketone form (M3) mainly by CYP3A4. M1 had the highest exposure among the eight metabolites after repeated oral dosing in humans, which indicated that M1 was the major metabolite. The overall metabolism of delamanid was qualitatively similar across nonclinical species and humans but was quantitatively different among the species. After repeated administration, the metabolites had much higher concentrations in dogs and humans than in rodents. The in vitro metabolic activity of albumin on delamanid probably caused the species differences observed. We determined that albumin metabolism is a key component of the pharmacokinetics and metabolism of delamanid. Nonhepatic formation of M1 and multiple separate pathways for metabolism of M1 suggest that clinically significant drug-drug interactions with delamanid and M1 are limited.

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Section: Discussionmentioning

confidence: 80%

Pharmacokinetics and Metabolism of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo

et al. 2015

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“…Clinical data for pretomanid that could support PK model development have been described in published phase 1 studies that evaluated (i) the safety, tolerability, and PK of pretomanid with escalating doses (13), (ii) the effects of pretomanid on renal function (14), (iii) the effect of food on pretomanid bioavailability, PK, and safety (15), and (iv) drug-drug interactions of pretomanid with efavirenz, ritonavir-boosted lopinavir, or rifampin (16) and pretomanid with midazolam (17). Additional PK data have been collected in phase 2 EBA studies with pulmonary TB patients for pretomanid as a single drug (6,7) and in various combinations with bedaquiline, pyrazinamide, and clofazimine (18).…”

mentioning

confidence: 99%

“…In the present study, a population PK model of pretomanid in TB patients was developed using mass-balance compartmental methods (19) and Bayesian hierarchical modeling (20). The completed analyses of pretomanid phase 1 data reported by Ginsberg et al (13,14), Winter et al (15), and Dooley et al (16) were used to construct the model equations and to inform prior probability distributions for the unmeasured model parameters. The prior distributions were updated, using Bayes' rule, to a posterior distribution conditioned on pretomanid plasma concentration-time measurements from adult patients with newly diagnosed pulmonary TB in two single-drug phase 2 studies, PA-824-CL-007 (CL-007) (6) and PA-824-CL-010 (CL-010) (7), conducted in Cape Town, South Africa.…”

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confidence: 99%

Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients

Lyons

2018

Antimicrob Agents Chemother

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Pretomanid is a nitroimidazole antibiotic in late-phase clinical testing as a component of several novel antituberculosis (anti-TB) regimens. A population pharmacokinetic model for pretomanid was constructed using a Bayesian analysis of data from two phase 2 studies, PA-824-CL-007 and PA-824-CL-010, conducted with adult (median age, 27 years) patients in Cape Town, South Africa, with newly diagnosed pulmonary TB. Combined, these studies included 63 males and 59 females administered once-daily oral pretomanid doses of 50, 100, 150, 200, 600, 1,000, or 1,200 mg for 14 days. The observed pretomanid plasma concentration-time profiles for all tested doses were described by a one-compartment model with first-order absorption and elimination and a sigmoidal bioavailability dependent on dose, time, and the predose fed state. Allometric scaling with body weight (normalized to 70 kg) was used for volume of distribution and clearance, with the scaling exponents equal to 1 and 3/4, respectively. The posterior population geometric means for the clearance and volume of distribution allometric constants were 4.8 ± 0.2 liters/h and 130 ± 5 liters, respectively, and the posterior population geometric mean for the half-maximum-effect dose for the reduction of bioavailability was 450 ± 50 mg. Interindividual variability, described by the percent coefficient of variation, was 32% ± 3% for clearance, 17% ± 4% for the volume of distribution, and 74% ± 9% for the half-maximum-effect dose. This model provides a dose-exposure relationship for pretomanid in adult TB patients with potential applications to dose selection in individuals and to further clinical testing of novel pretomanid-containing anti-TB regimens.

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“…This occurred despite the fact that delamanid is primarily metabolized in the plasma by albumin and to a lesser extent by CYP3A (4,25). The plasma concentration of a drug of the same class, pretomanid (PA-824), which was extensively metabolized via a combination of reductive and oxidative metabolic processes, including oxidation by CYP3A, was reduced by the coadministration of rifampin or efavirenz (32). Efavirenz is also an inducer of CYP3A, and the contribution of CYP3A to the overall metabolism of delamanid or pretomanid may increase when CYP3A is induced.…”

Section: Discussionmentioning

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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Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir, Efavirenz, or Rifampin

Cited by 44 publications

References 27 publications

Pharmacokinetics and Metabolism of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo

Pharmacokinetics and Metabolism of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo

Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients

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

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