Xavier Fonrose

Variability of Voriconazole Plasma Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Cytochrome P450 Polymorphisms and Comedications on Initial and Subsequent Trough Levels

ABSTRACT Voriconazole (VRC) plasma trough concentrations (Cmin) are highly variable, and this could affect treatment efficacy and safety in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). We aimed to describe the intra- and interindividual variation of VRC Cmin throughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRC Cmin (n = 308) of 33 AHSCT patients were retrospectively collected. Cytochrome P450 (CYP450) genotypes of CYP2C19, CYP3A4, and CYP3A5 patients were retrospectively determined before allografting, and a combined genetic score was calculated for each patient. The higher the genetic score, the faster the metabolism of the patient. The VRC Cmin inter- and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRC Cmin (r = 0.412, P < 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRC Cmin. Considering oral therapy, patients with a genetic score of <2 had higher initial VRC Cmin/D than patients with a genetic score of >2 (P = 0.009). Subsequent VRC Cmin remained influenced by the genetic score (P = 0.004) but were also affected by pump proton inhibitor comedication (P < 0.0001). The high variability of VRC Cmin in AHSCT patients is partially explained by the route of administration, treatment with pump proton inhibitors, and the combined genetic score. This study suggests the interest in combined genetic score determination to individualize a priori the VRC dose and underlines the need for longitudinal therapeutic drug monitoring to adapt subsequent doses to maintain the VRC Cmin within the therapeutic range.

Symptomatic Hypoglycemia Associated with Trimethoprim/Sulfamethoxazole and Repaglinide in a Diabetic Patient

Objective To report a case of clinically significant hypoglycemia attributed to the concomitant use of trimethoprim/sulfamethoxazole (TMP/SMX) and repaglinide by a diabetic patient. Case summary A 76-year-old diabetic patient with impaired renal function and no history of hypoglycemia was receiving treatment with repaglinide 1 mg 3 times daily. Five days after TMP/SMX therapy was started for a urinary tract infection, the man developed symptomatic hypoglycemia. Repaglinide and TMP/SMX were stopped and intravenous d-glucose was administered to normalize glucose levels. Repaglinide, but not TMP/SMX, was reintroduced 5 days later and no other hypoglycemic episode occurred. Objective causality assessments revealed that the interaction was probable (World Health Organization-Uppsala Monitoring Centre) or possible (Horn Drug Interaction Probability Scale). Discussion This interaction between TMP/SMX and repaglinide was predictable according to available pharmacokinetic data in healthy subjects. Trimethoprim induced CYP2C8 inhibition, thus increasing the plasma concentration of repaglinide. This interaction is mentioned in the repaglinide product information. To our knowledge, however, no case of symptomatic hypoglycemia associated with a combination of repaglinide and trimethoprim has been described before. This discrepancy may be explained by the subtherapeutic dosage used in the pharmacokinetic study. Moreover, our patient had impaired renal function, which may have led to trimethoprim accumulation and potentiated its interaction with repaglinide. A direct lowering of blood glucose levels due to sulfamethoxazole, also potentiated by renal failure, could also be involved in triggering hypoglycemia. Conclusions This interaction between TMP/SMX and repaglinide may have involved inhibition of CYP2C8 by trimethoprim. Clinicians should be aware that this association may lead to symptomatic hypoglycemia, particularly in patients with renal dysfunction.

Pharmacogenetics of Voriconazole: CYP2C19 but Also CYP3A4 Need to Be Genotyped

To the Editor:We read with great interest the article entitled “Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19” byMoriyama et al. recently published inClinical Pharmacology & Therapeutics. This article summarizes all data linking voriconazole trough concentrations and genetic variants of CYP2C19, but also proposes dosing recommendations for voriconazole treatment based on the CYP2C19 genotype. In addition to the CYP2C19 genotype, the authors raised the possible influence of genetic variations affecting other cytochromes implicated in the voriconazole metabolism, namely, CYP3A4, 3A5, and 2C9 (paragraph entitled “Other considerations,” section Therapeutic Recommendation). In this paragraph, the authors mentioned that “genetic variation in CYP3A4, CYP3A5, and CYP2C9 appears not to significantly affect the pharmacokinetics of voriconazole” and referred to two studies that, in fact, had exactly shown the opposite. Indeed, we demonstrated in a retrospective study that the CYP3A4*22 polymorphism (rs35599367) significantly influenced voriconazole trough concentrations adjusted on the dose in 29 allograft hematopoietic stem cell transplant patients (see Figure 1a and 1b reproduced from our previously published article in Antimicrobial Agents Chemotherapy 2015). In addition, a retrospective Chinese study conducted in 158 patients identified another single nucleotide polymorphism (SNP) located in an intronic area of the CYP3A4 (rs4646437) as associated with higher VRC levels. In each of these works, the CYP2C19 genotype was also determined and the impact of genetic variants of CYP3A4 on voriconazole trough concentration was independent of the latter. Very recently, the impact of rs4646437 SNP was also confirmed in a retrospective study conducted in 86 patients by another Chinese team. Although these data are preliminary and need to be confirmed in independent and larger cohorts of patients treated by voriconazole and genotyped for CYP2C19, CYP34A, 3A5, and 2C9, they strongly suggest that genetic variants of CYP3A4 may significantly impact VRC trough plasma concentrations.

Suivi thérapeutique pharmacologique des 6-thioguanine nucléotides dans les maladies inflammatoires cryptogéniques de l’intestin : intérêt et limites

Azathioprine, 6-mercaptopurine, and 6-thioguanine are immunosuppressive drugs indicated in the prevention of graft rejection, and treatment of auto-immune disease or inflammatory bowel disease. Their anti-nucleotidic properties are also used for the treatment of acute leukaemia. Their metabolism involves thiopurine methyl transferase, which activity varies according to genetic polymorphisms. In inflammatory bowel disease patients, there is no recommended therapeutic range of intra-erythrocyte 6-thioguanine nucleotide concentration, the active metabolite. Therapeutic drug monitoring of 6-thioguanine nucleotide concentrations is however proposed in the following clinical situations: to check the observance, to try to explain therapeutic failure, to manage patients with limited thiopurine methyl transferase activity or patients treated with associated drugs that can modify thiopurine methyl transferase activity. The literature review shows that high concentrations of 6-thioguanine nucleotides and methylated metabolites are associated with an increased risk of bone marrow toxicity. In addition, high concentrations of methylated metabolite might increase the risk of hepatic toxicity. These major side-effects can be prevented by the use of pre-treatment screening for thiopurine methyl transferase activity or genotype in inflammatory bowel disease patients in order to propose an adapted dosing.Azathioprine, 6-mercaptopurine, and 6-thioguanine are immunosuppressive drugs indicated in the prevention of graft rejection, and treatment of auto-immune disease or inflammatory bowel disease. Their anti-nucleotidic properties are also used for the treatment of acute leukaemia. Their metabolism involves thiopurine methyl transferase, which activity varies according to genetic polymorphisms. In inflammatory bowel disease patients, there is no recommended therapeutic range of intra-erythrocyte 6-thioguanine nucleotide concentration, the active metabolite. Therapeutic drug monitoring of 6-thioguanine nucleotide concentrations is however proposed in the following clinical situations: to check the observance, to try to explain therapeutic failure, to manage patients with limited thiopurine methyl transferase activity or patients treated with associated drugs that can modify thiopurine methyl transferase activity. The literature review shows that high concentrations of 6-thioguanine nucleotides and methylated metabolites are associated with an increased risk of bone marrow toxicity. In addition, high concentrations of methylated metabolite might increase the risk of hepatic toxicity. These major side-effects can be prevented by the use of pre-treatment screening for thiopurine methyl transferase activity or genotype in inflammatory bowel disease patients in order to propose an adapted dosing.

Pharmacogenetics may influence the impact of inflammation on voriconazole trough concentrations

How pharmacogenetics modulates the inhibitory effects of inflammation on voriconazole trough concentration (Cmin) remains unknown. In 29 recipients of allogeneic hematopoietic stem cell transplantation retrospectively studied, both a genetic score (which aggregated CYP2C19 and CYP3A genotypes) and inflammation significantly influenced voriconazole Cmin (n = 260). A trend toward (p = 0.03) a greater impact of inflammation in patients with the highest genetic score (corresponding to ultra-rapid metabolizers) was observed. Further researches are needed to confirm these data.

A genetic score combining CYP450 2C19 and 3A4 genotypes to predict voriconazole plasma exposure

We readwith great interest the recent publication entitled ‘Impact of CYP2C19 genetic polymorphisms on voriconazole dosing and exposure in adult patients with invasive fungal infections’ by Lamoureux et al [1] recently published in International Journal of Antimicrobial Agents. This article confirms that the CYP2C19 genotype has a significant influence on plasma exposure of voriconazole (VRC). The authors concluded that dose adjustment based on early CYP2C19 genotyping, together with therapeutic drugmonitoring (TDM), may improve clinical outcomes and may help determine the cause of the frequently observed subtherapeutic concentrations of VRC. However, and as mentioned by the authors, VCR undergoes several CYP-dependent metabolic pathways: the 2C19 pathway that has been extensively studied, but also the CYP3A4/5 pathway that has received less attention (see Fig. 1). A new CYP3A4 single nucleotide polymorphism (SNP) (CYP3A4*22;rs35599367) associated with low hepatic CYP3A4 expression and activity has been identified in the last few years as a promising CYP3A4 allele for personalizing pharmacotherapy [2]. This SNP, the frequency of which varies from 6% to 13% in populations with European ancestry, was already identified as a determinant of several drug metabolisms [3]. We recently clearly demonstrated in recipients of allogeneic haematopoietic stem cell transplantation the impact of this SNP on VRC concentrations, since the presence of one *22 allele was associated with increased initial VRC trough concentrations, an effect independent of the CYP2C19 genotype [4]. Unfortunately, this study was not mentioned in the paper by Lamoureux et al [1], albeit it was the first to provide strong evidence for the impact of CYP3A4*22 on VRC exposure. In addition, another SNP (rs4646437) located in an intronic area of CYP3A4 and associated with higher VRC levels was also described in a Chinese cohort [5]. In this work, the influence of CYP3A4*22 could not be investigated since the allelic frequency of this polymorphism is null in the East Asian population [5]. These findings support that in addition to CYP2C19, the CYP3A4 genotype probably also plays a major role in VRC metabolism. Thus, and as we recently proposed [4], an early dose adjustment of VRC based not only on CYP2C19 genotype but on a combined genetic score that includes the genotypes of both CYP2C19 and

Lethal cerebral hemorrhage after ticagrelor intoxication: a specific antidote is urgently needed

Abstract Background: Ticagrelor is a direct and reversible competitive antagonist of the P2Y12 receptor and inhibits platelet activation. Although adverse bleeding is common, fatal intoxication has never been documented. Case description: A 47-year-old man died from a severe cerebral hemorrhage secondary to a fall and cranial trauma 4 d after the massive intake of ticagrelor. Iterative platelet transfusions did not improve his condition. Toxicological analyses by liquid chromatography tandem mass spectrometry (LC-MS/MS) revealed high plasma concentrations of ticagrelor (3343 µg/L) and its active metabolite AR-C124910XX (656 µg/L) 10 h after intake. The approximate ingested dose was extrapolated to 1677 mg. Assessment of ADP-induced platelet aggregation and platelet Vasodilator Stimulated Phosphoprotein phosphorylation (VASP), 2 and 3 d after admission, respectively, showed the persistence of platelet inhibition. Discussion: To the best of our knowledge, no prior fatal cases have been reported and documented with both ticagrelor and AR-C124910XX concentrations. Our findings highlight the need for a specific antidote to manage such complications resulting from ticagrelor overdose.

Inflammation is the main risk factor of voriconazole overdose in hematological patients

Aim: Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. This case-control study performed in hematological patients who benefited from VRC therapeutic drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC overdose. Methods: Pharmacogenetic, biological, and demographic parameters at the time of VRC trough concentration (Cmin) were retrospectively collected from medical records. Cases (VRC overdose: defined by a VRC Cmin ≥ 4 mg/l; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using non-parametric or Chi-square tests followed by multivariable analysis. Results: VRC overdoses were significantly associated with high CRP and bilirubin levels, intra-venous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a genetic score1) were not significantly different between patients who experienced a VRC overdose and those who did not. In multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/l) was the sole independent risk factor of VRC overdose (p < 0.01). Patients with CRP levels > 96 mg/l had a 27-fold (IC 95%: [6-106]) higher risk of VRC overdose than patients with CRP levels ≤ 96 mg/l. Conclusion: This study demonstrates that inflammatory status, assessed by CRP levels, is the main risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic determinants do not appear to be involved.

Inflammation is a potential risk factor of voriconazole overdose in hematological patients

Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. This case–control study performed in hematological patients who benefited from VRC therapeutic drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC overdose. Pharmacogenetic, biological, and demographic parameters at the time of VRC trough concentration (Cmin) were retrospectively collected from medical records. Cases (VRC overdose: defined by a VRC Cmin ≥ 4 mg/L; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using nonparametric or chi‐square tests followed by multivariable analysis. VRC overdoses were significantly associated with high CRP and bilirubin levels, intravenous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a combined genetic score) were not significantly different between patients who experienced a VRC overdose and those who did not. In multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/L) was the sole independent risk factor of VRC overdose (P < 0.01). Patients with CRP levels > 96 mg/L) had a 27‐fold (IC 95%: [6–106]) higher risk of VRC overdose than patients with CRP levels ≤ 96 mg/L. This study demonstrates that inflammatory status, assessed by CRP levels, is the main risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic determinants do not appear to be involved.