Formation Rate–Limited Pharmacokinetics of Biologically Active Epoxy Transformers of Prodrug Treosulfan

Romański, Michał; Kasprzyk, Anna; Karbownik, Agnieszka; Szałek, Edyta; Główka, Franciszek

doi:10.1016/j.xphs.2016.03.001

Cited by 13 publications

(22 citation statements)

References 31 publications

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“…1 ]. In a clinical setting, Cl f may be determined indirectly as Cl tot –Cl R or Cl tot × (1– f R ), based on the treosulfan concentration in plasma and its amounts in urine [ 10 , 17 , 26 – 29 , 31 ]. Following basic pharmacokinetic concepts, it might be predicted that the Cl f of treosulfan depends on the rate constant of the S,S-EBDM formation from the prodrug ( k f ) and the volume of fluids in which this process occurs.…”

Section: Pharmacokinetics Of the Prodrug Treosulfanmentioning

confidence: 99%

“…A surrogate method for Cl f estimation is to use a product of the V ss of treosulfan and the k f corresponding to the average pH of body fluids and 37 °C. For that purpose, the k f value can be calculated from the equation that was established for the nonenzymatic conversion of treosulfan to S,S-EBDM in buffer solutions at 37 °C [ 10 , 11 , 17 ]. Application of this approach, with the average pH of 7.35, enables to predict the Cl f with good accuracy (error rate < 20%) in 10 of 12 pharmacokinetic datasets reported previously for children above 1 year of age, as well as adults (electronic supplementary Table S1).…”

Section: Pharmacokinetics Of the Prodrug Treosulfanmentioning

confidence: 99%

“…As blood pH in children does not differ from adults, one may take a reasonable assumption that the average pH of the body fluids, and consequently the average k f , have the same values in both groups. Accordingly, the higher V ss of treosulfan observed in children is supposedly responsible for the higher drug Cl f , which in turn contributes to the higher Cl tot (the sum of Cl f and Cl R ) [ 10 , 16 , 17 , 21 – 29 ]. The reason children > 1 year of age (average treosulfan Cl tot 3–6 mL/min/kg) experience a similar AUC as adults (approximate Cl tot 2.0–2.5 mL/min/kg) following the same drug dosing per m 2 of body surface area (BSA) is that the BW increases unproportionally faster with age than the BSA.…”

Section: Pharmacokinetics Of the Prodrug Treosulfanmentioning

confidence: 99%

“…In the later study enrolling 16 pediatric patients, the t ½ of S,S-EBDM was found to not differ statistically from the parent drug [ 16 ]. The pharmacokinetics of S,S-EBDM and S,S-DEB remained unresolved until the preformed epoxides were administered to animals (rabbits) [ 17 ]. A very fast elimination of the compounds was then observed ( t ½ 0.069 and 0.046 h, respectively), which was associated with the extremely high Cl tot (167 and 233 mL/min/kg, respectively).…”

Section: Pharmacokinetics Of Biologically Active Epoxy Derivatives Ofmentioning

confidence: 99%

“…Thus, it was proved that after administration of treosulfan, the elimination of its epoxides is limited by their formation from the parent compound (formation rate-limited kinetics). Consequently, the t ½ of S,S-EBDM and S,S-DEB is the same as that of treosulfan, despite the levels of epoxides in the body being very low compared with the prodrug due to their high Cl tot [ 17 ]. Additional confirmation for this phenomenon was provided by an observation that the organ elimination of S,S-EBDM in rats proceeded at a similar rate as that of treosulfan (lungs, muscle, and bone marrow), except the brain, from which the epoxide was eliminated faster [ 19 ].…”

Section: Pharmacokinetics Of Biologically Active Epoxy Derivatives Ofmentioning

confidence: 99%

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Treosulfan Pharmacokinetics and its Variability in Pediatric and Adult Patients Undergoing Conditioning Prior to Hematopoietic Stem Cell Transplantation: Current State of the Art, In-Depth Analysis, and Perspectives

Romański

Wachowiak²,

Główka

2018

Clin Pharmacokinet

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Treosulfan is a prodrug that undergoes a highly pH- and temperature-dependent nonenzymatic conversion to the monoepoxide {(2S,3S)-1,2-epoxy-3,4-butanediol 4-methanesulfonate [S,S-EBDM]} and diepoxide {(2S,3S)-1,2:3,4-diepoxybutane [S,S-DEB]}. Currently, treosulfan is tested in clinical trials as an alternative to busulfan in conditioning prior to hematopoietic stem cell transplantation (HSCT). Of note, the optimal dosing of the prodrug is still unresolved, especially in infants. In this paper, the pharmacokinetics of treosulfan, together with its biologically active epoxides, is comprehensively reviewed for the first time, with the focus on conditioning prior to HSCT. Most of the insightful data presented in this review comes from studies that have been conducted in the last 3 years. The article widely discusses the volume of distribution and total clearance of treosulfan. In particular, the interindividual variability of these key parameters in infants, children above 1 year of age, and adults is analyzed, including possible covariates. A clinically important aspect of the formation rate-limited elimination of S,S-EBDM and S,S-DEB is described, including the correlation between the exposure of the prodrug and S,S-EBDM in children. The significance of the elimination half-life of treosulfan and its epoxides for successful conditioning prior to HSCT is also raised. Furthermore, the organ disposition of treosulfan and S,S-EBDM in rats is discussed in the context of the clinical toxicity and myeloablative activity of treosulfan versus busulfan. Moreover, perspectives for future therapeutic drug monitoring of treosulfan are presented. The review is intended to be helpful to pharmacists and doctors in the comprehension of the clinical pharmacokinetics of treosulfan.Electronic supplementary materialThe online version of this article (10.1007/s40262-018-0647-4) contains supplementary material, which is available to authorized users.

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Section: Pharmacokinetics Of the Prodrug Treosulfanmentioning

confidence: 99%

Section: Pharmacokinetics Of the Prodrug Treosulfanmentioning

confidence: 99%

Section: Pharmacokinetics Of the Prodrug Treosulfanmentioning

confidence: 99%

Section: Pharmacokinetics Of Biologically Active Epoxy Derivatives Ofmentioning

confidence: 99%

Section: Pharmacokinetics Of Biologically Active Epoxy Derivatives Ofmentioning

confidence: 99%

See 3 more Smart Citations

Treosulfan Pharmacokinetics and its Variability in Pediatric and Adult Patients Undergoing Conditioning Prior to Hematopoietic Stem Cell Transplantation: Current State of the Art, In-Depth Analysis, and Perspectives

Romański

Wachowiak²,

Główka

2018

Clin Pharmacokinet

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Treosulfan Exposure Predicts Thalassemia‐Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation

Pai,

Mohanan,

Panetta

et al. 2023

Clin Pharma and Therapeutics

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A toxicity‐reduced conditioning regimen with Treosulfan, Fludarabine, and Thiotepa in patients with high‐risk β‐ thalassemia major has significantly improved HCT outcomes. However, complications resulting from regimen‐related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose‐exposure‐response relationship of Treosulfan and its active metabolite S, S‐EBDM, in a uniform cohort of patients with β‐thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of Treosulfan is feasible. Plasma Treosulfan/S, S‐EBDM levels were measured in seventy‐seven patients using a validated LC‐MS/MS method, and the PK parameters were estimated using nlmixr2. The influence of Treosulfan & S, S‐EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1‐year Overall Survival (OS), and Thalassemia Free Survival (TFS) were assessed. We observed that Treosulfan exposure was lower in patients with graft rejection than those without (1655 vs. 2037 mg*h/L, p=0.07). Pharmacodynamic modeling analysis to identify therapeutic cut‐off revealed that Treosulfan exposure ≥1660 mg*hr/L was significantly associated with better 1‐year TFS (97% vs. 81%, p=0.02) and a trend to better 1‐year OS (90% vs. 69%, p=0.07). Further, multivariate analysis adjusting for known PreHCT risk factors also revealed Treosulfan exposure <1660mg*h/L (HR=3.23; 95% CI=1.12‐9.34; p=0.03) and GSTA1*B variant genotype (HR=3.75; 95% CI=1.04‐13.47; p=0.04) to be independent predictors for inferior 1‐year TFS. We conclude that lower Treosulfan exposure increases the risk of graft rejection and early transplant‐related mortality affecting TFS. As no RRTs were observed with increasing Treosulfan exposure, TDM‐based dose adjustment could be feasible and beneficial.

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Nonenzymatic hydrolysis of 1,2:3,4‐diepoxybutane: A kinetic study including pH, temperature, and ion effects

Romański,

Mikołajewski,

Główka

2023

Int J of Chemical Kinetics

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Abstract1,3‐Butadiene is a carcinogenic and mutagenic air pollutant metabolized to butane epoxides, among which 1,2:3,4‐diepoxybutane (DEB) exhibits the highest genotoxicity. DEB is also formed by 1,3‐butadiene oxidation in the air, producing a direct environmental and occupational exposure. In this paper, we studied the kinetics of the nonenzymatic hydrolysis of DEB at a wide range of pH and temperature, including the catalytic effect of ionic species. The compound degradation involved a general and specific acid‐base catalysis of the epoxide ring hydrolysis. DEB had the greatest stability at pH 5–9, when the rates of acid‐catalyzed and base‐catalyzed hydrolysis are negligible and the neutral hydrolysis predominates. The capability of the buffer anions to accelerate the DEB decay increased in the order H2PO4− < HCO3− < CH3COO− < HPO42− < and CO32−. The Arrhenius equation well described the influence of temperature on the acid‐catalyzed, base‐catalyzed, and neutral hydrolysis rate constants. According to the obtained hydrolysis model coupled with the found thermodynamic parameters, the half‐life of DEB in natural fresh waters spans from 2 days at 30°C to 31 days at 0°C, but in the laboratory waste adjusted to pH 1or 13, the half‐life shortens to 2–3 h at 20°C. Therefore, the results of the paper help to assess the risk of exposure to the genotoxic action of DEB.

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Formation Rate–Limited Pharmacokinetics of Biologically Active Epoxy Transformers of Prodrug Treosulfan

Cited by 13 publications

References 31 publications

Treosulfan Pharmacokinetics and its Variability in Pediatric and Adult Patients Undergoing Conditioning Prior to Hematopoietic Stem Cell Transplantation: Current State of the Art, In-Depth Analysis, and Perspectives

Treosulfan Pharmacokinetics and its Variability in Pediatric and Adult Patients Undergoing Conditioning Prior to Hematopoietic Stem Cell Transplantation: Current State of the Art, In-Depth Analysis, and Perspectives

Treosulfan Exposure Predicts Thalassemia‐Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation

Nonenzymatic hydrolysis of 1,2:3,4‐diepoxybutane: A kinetic study including pH, temperature, and ion effects

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