Disponible en ligne sur
ScienceDirect www.sciencedirect.com Médecine et maladies infectieuses 44 (2014) 174–179
Original article
Factors influencing posaconazole plasmatic concentrations in patients presenting with acute myeloid leukemia夽 Facteurs influen¸cant les concentrations plasmatiques de posaconazole chez les patients atteints de leucémie aiguë myéloïde P.-Y. Desplanques a , R. Burlacu b , V. Poinsignon c , H. Boussion b , I. Borget d , B. Wyplosz e , S. de Botton b , E. Billaud c , E. Chachaty f , B. Gachot g , F. Netzer a , J.-B. Micol b,∗ a
Service de pharmacie clinique, Institut Gustave-Roussy, 94805 Villejuif cedex, France b Service d’hématologie, Institut Gustave Roussy, 94805 Villejuif cedex, France c Service de pharmacologie et toxicologie, Hôpital Européen George-Pompidou, 75015 Paris, France d Service de biostatistique et d’épidémiologie, Institut Gustave-Roussy, université Paris-Sud, 94805 Villejuif cedex, France e Service de maladies infectieuses, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France f Service de microbiologie, Institut Gustave-Roussy, 94805 Villejuif cedex, France g Département de soins aigus, Institut Gustave-Roussy, 94805 Villejuif cedex, France Received 27 August 2013; received in revised form 8 January 2014; accepted 12 February 2014 Available online 19 March 2014
Abstract Purpose. – The effectiveness of posaconazole (PSZ) prophylaxis on invasive fungal infections, in patients presenting with acute myeloid leukemia (AML), seems to be correlated to its blood plasma concentration. Our goal was to identify the risk factors for underdosing. Patients and methods. – We retrospectively reviewed the records of patients treated for AML treated with PSZ, during a 2-year period. Assays < 500 ng/mL were considered as under dosed. Results. – Fifty-nine assays (43 patients) were performed during induction (n = 22) or consolidation (n = 37) chemotherapy. PSZ treatment was initiated within a median of 3 days before neutropenia with a first assay performed at 8 days (3–28). The median PSZ blood plasma concentration was 375 ng/mL (< 200–1900). Forty-one (69%) treatment were maintained until the end of neutropenia. One patient presented with candidemia, 9 with possible invasive aspergillosis, without any significant association with underdosing. The univariate analysis showed that co-administration of proton pump inhibitors (PPIs) (P = 0.01) and cause of hospitalization (induction chemotherapy vs consolidation, P = 0.008) were associated with underdosing, contrary to feeding difficulties (P = 0.07) and digestive disorders (P = 0.5). The multivariate analysis confirmed the impact of PPI use (P = 0.01) and the cause of hospitalization (P = 0.003). Conclusion. – This study highlights the major impact of PPI administration on PSZ blood plasma levels and stresses the risk of non-effective prophylaxis during induction treatment of AML. © 2014 Elsevier Masson SAS. All rights reserved. Keywords: Posaconazole; Drug interactions; Acute myeloid leukemia; Invasive aspergillosis
Résumé Introduction. – L’efficacité du posaconazole (PSZ) en prophylaxie des infections fongiques invasives chez les patients atteints de leucémies aiguës myéloïdes (LAM) semble être corrélée aux concentrations plasmatiques du médicament. Notre objectif a été d’identifier les facteurs de risques de sous-dosage. Patients et méthodes. – Nous avons étudié rétrospectivement les dossiers des patients traités pour une LAM sur une période de 2 ans et ayant rec¸u du PSZ à dose préventive. Les dosages < 500 ng/mL ont été considérés comme sous dosés. Résultats. – Cinquante-neuf dosages ont été effectués chez 43 patients au cours de cures de chimiothérapie d’induction (n = 22) ou de consolidation (n = 37). Le traitement par PSZ était instauré avec une médiane de 3 jours avant l’aplasie avec un premier dosage effectué à 8 jours (3–28). Les 夽 ∗
This study was presented orally at the congress of the French Society of Medical Mycology in Dijon, on May 17, 2013. Corresponding author. E-mail address: [email protected] (J.-B. Micol).
0399-077X/$ – see front matter © 2014 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.medmal.2014.02.005
P.-Y. Desplanques et al. / Médecine et maladies infectieuses 44 (2014) 174–179
175
patients avaient une concentration plasmatique médiane de PSZ de 375 ng/mL (< 200–1900). À 41 reprises (69 %) le traitement a été poursuivi jusqu’à la sortie d’aplasie. Un patient a présenté une candidémie, 9, une aspergillose invasive possible sans association significative avec le sousdosage. En analyse univariée, la co-administration d’inhibiteurs de la pompe à proton (IPP) (p = 0,01) et le motif d’hospitalisation (chimiothérapie d’induction vs consolidation, p = 0,008) étaient associés à un sous-dosage en PSZ, contrairement aux difficultés alimentaires (p = 0,07) et aux troubles digestifs (p = 0,5). L’analyse multivariée confirmait l’impact de l’utilisation d’IPP (p = 0,01) et du motif d’hospitalisation (p = 0,003). Conclusion. – Ce travail démontre l’impact des IPP sur les concentrations plasmatiques de PSZ et appelle à la vigilance quant au risque d’inefficacité de la prophylaxie en induction de LAM. © 2014 Elsevier Masson SAS. Tous droits réservés. Mots clés : Posaconazole ; Interaction médicamenteuse ; Leucémie aiguë myéloïde ; Aspergillose invasive
1. Introduction Invasive fungal infections (IFI) are one of the main causes of morbidity-mortality for patients presenting with acute myeloid leukemia (AML) [1,2]. Their incidence may reach 12% during induction chemotherapy treatments, more than 2 thirds of which are invasive pulmonary aspergillosis (IPA) [3]. These infections concern most often patients with long-term aplasia; reason for which 60% of IPA occurs in patients undergoing induction chemotherapy compared to 3% only in patients undergoing consolidation therapy [4]. Furthermore IFI remain, despite recent therapeutic progress with new antifungal [5–7], the first cause of infectious death for hematology unit patients in aplasia [1]. Besides this “early” mortality related to the infection, proven IFI are associated to a decreased survival related to the hemopathy because of the therapeutic adaptations imposed by their management [8]. Antifungal prophylaxis has become part of the therapeutic strategy because of these important risks [9–11]. Implementing posaconazole (PSZ) prophylaxis allowed decreasing the global incidence of fungal infections (Table 1) and the associated mortality [12] for this type of patients, leading to the marketing authorization for this agent. Nevertheless, PSZ, like most azoles [13], presents a great inter and intra-individual variability of blood plasma concentrations requiring therapeutic monitoring [14]. This variability may Table 1 Main studies on posaconazole prophylaxis in patients presenting with acute myeloid leukemia. Principales études de prophylaxie par posaconazole chez des patients atteints de leucémies aiguës myéloïdes. Reference
Number of patients given prophylactic treatment
Cornely et al. [12] 304 72 Dolton et al. [18] Michallet et al. [32] 55 76a Egerer et al. [33] Vehreschild et al. [34] 77 260 Pagano et al. [35] 74a Vaes et al. [25] Girmenia et al. [36] 195a Ananda-Rajah et al. [28] 153 Total 1266 NA: not applicable. a Chemotherapy courses.
Incidence of IFI (%) 2 4 3.6 1.3 3.9 3.8 2.7 11.8 0 4
Median PSZ blood plasma concentration 490 ng/mL 466 ng/mL NA NA 555 ng/mL NA 430 ng/mL NA NA 490 ng/mL
be related to gastric absorption disorders, the agent currently being available only as a drinkable suspension, and to, less frequently, the hepatic metabolism of the drug [15–17]. There is currently no final consensus as to the minimal effective prophylactic blood plasma concentration but some study results give a threshold ranging between 500 ng/mL and 700 ng/mL [18]. We had for aim to assess the various factors associated to under dosing of PSZ in the management of patients presenting with AML treated by intensive chemotherapy. 2. Patients and methods 2.1. Patients We retrospectively studied the medical records of patients treated intensively for AML in laminar flow rooms from our hematology ward from October 2010 to December 2012. One hundred and eighty courses of intensive chemotherapy were administrated; PSZ was administrated at prophylactic doses (200 mg × 3/d) in 137 (76%) cases. PSZ blood plasma concentration was measured at least once in 67 of these courses (44% of PSZ prophylaxis). Eight results were not considered because of the patient’s therapeutic non-observance, with a final number of 59 blood plasma concentration measures. 2.2. Modes of posaconazole administration PSZ was administrated at 200 mg/5 mL per intake (for a dose of 600 mg/d) of drinkable suspension, using a graduated syringe for the per os administration prepared by nurses so as to prevent the imprecision of the measure spoon provided and check observance. PSZ was given during morning, noon, and evening meals so as to improve absorption. 2.3. Blood plasma concentration assays The blood plasma concentration was measured by liquid chromatography coupled with mass spectrometry in the pharmacology and toxicology departments of the GeorgePompidou European Hospital, with a threshold of detection set at 200 ng/mL (blood plasma concentration below this threshold are considered as unreliable by the laboratory). We focused our study on the results of the first PSZ blood plasma concentration measured in each course of chemotherapy (whether at diagnosis for induction chemotherapy or during consolidation
176
P.-Y. Desplanques et al. / Médecine et maladies infectieuses 44 (2014) 174–179
chemotherapy) so as to avoid intra-individual variations, dose adaptation, modifications of the patient’s clinical status, and of associated treatments. The target concentration was set at 500 ng/mL; patients with a lower blood plasma concentration were considered as under dosed. 2.4. Studied variables The biological data was the one collected on the day blood plasma concentration was measured. The creatinine clearance was calculated with the Cockcroft and Gault equation [19]. The clinical data, including potential drug interactions, was collected during the 5 days before blood plasma concentration was measured. All the documented digestive disorders (mucositis grade 2 or more according to the WHO score, nausea/emesis, diarrhea) were grouped for the statistical analysis. The nutritional evaluation made weekly by our dieticians allowed identifying patients with decreased ingesta (inferior to two third of daily nutritional requirements) or considered as “normal”.
Table 2 Initial characteristics of patients and posaconazole assays. Caractéristiques initiales des patients et des dosages de posaconazole. Parameters
Values
Age (years) Weight (kg) Gender: F/M (n/%) Treatment: I/C (n/%) Duration of aplasia (d) Delay chemo/prophylaxis (d) Delay prophylaxis/aplasia (d) Delay prophylaxis/assay (d) Delay assay/results (d) Results of assaya (ng/ml)
53 (24–76) 68 (46–112) 23 (53%)/20 (47%) 22 (37%)/37 (63%) 18 (7–47) 3 (-5 ± 15) 3 (-14 ± 15) 8 (3–28) 3 (1–11) 375 (≤200–1900)
kg: kilograms; F: female; M: male; n: number; %: percentage; I: induction; C: consolidation; d: days. a Median delay for results.
aplasia compared to 5 days before aplasia for consolidation chemotherapy (P = 0.001). 3.2. Posaconazole blood plasma concentration assays
2.5. Diagnostic criteria Aspergillosis was assessed and classified according to the 2008 criteria of the European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) [20]. A systematic bi-weekly surveillance of aspergillus antigens was made in all patients.
The first blood plasma concentration was measured 8 days (3–28) after initiation of PSZ treatment and the results were sent to the clinician in a median of 3 days (1–11) (Table 2). The median of PSZ blood plasma concentration was 375 ng/mL (< 200–1,900), 19 measures (32%) had reached the target threshold of 500 ng/mL, 13 (22%) that of 700 ng/mL.
2.6. Statistical analysis
3.3. Factors influencing blood plasma concentration
The quantitative variables were presented as average ± SD; the qualitative variables were presented as percentages. The quantitative variables were compared with the Mann-Whitney test in the absence of normal distribution. The qualitative variables were compared with Fisher’s exact test. The factors associated to a risk of PSZ under-dosing were studied with univariate and multivariate analyses, using a logistic regression model. The analyses were made with the SAS software, version 9.2.
Twenty of the 22 (91%) patients in induction chemotherapy were under dosed and the median of their blood plasma concentration was 25% lower than that of patients in consolidation chemotherapy (350 ng/mL vs 465 ng/ml, P = 0.08). Thirty-two of the 41 patients (78%) receiving proton pump inhibitors (PPI) were under-dosed compared to 8/18 (44%) for the others. The patients receiving PPI had a 44% lower median blood plasma concentration (355 ng/mL vs 640 ng/mL, P = 0.02). The decreased ingesta was associated to a 50% decrease of PSZ blood plasma concentration de (220 ng/mL vs 430 ng/mL, P = 0.001), (Fig. 1). The type of chemotherapy requiring hospitalization (induction vs. consolidation, P = 0.008) and the co-administration of the PPI (P = 0.01) were associated with under-dosing in the univariate analysis (Table 3). The decrease of ingesta, digestive disorders (mucositis and/or nausea, and/or emesis, and/or diarrhea), the creatinine clearance, the prothrombin ratio, the level of ␥GT, the proteinemia, as well as the co-administration of benzamides and the use of anthracycline in the 5 days did not significantly change the risk of PSZ under-dosing. The multivariate analysis (Table 4) allowed demonstrating that use of PPI and the period of induction chemotherapy were independent risk factors for PSZ under-dosing (respectively P = 0.01 and P = 0.003) contrary to decreased ingesta (P = 0.33).
3. Results 3.1. Population Fifty-nine PSZ blood plasma concentration measures were analyzed in 43 patients (median age 53 years [24–76]), 23 female and 20 male patients, presenting with AML and managed in 59 courses of chemotherapy (median duration of aplasia of 18 days [7–47]) (Table 2). Twenty-two patients were hospitalized for induction chemotherapy (median duration of aplasia of 26 days [12–47]), and 37 for consolidation chemotherapy (median duration of aplasia of 16 days [7–30]) (P < 0.001). PSZ treatment was initiated within a median of 3 days (-14 ± 15) before aplasia; patients at diagnosis (induction chemotherapy) received the treatment a median of 1 day before
P.-Y. Desplanques et al. / Médecine et maladies infectieuses 44 (2014) 174–179
177
Fig. 1. Distribution of posaconazole blood plasma concentrations in patients treated or not with PPIs, following induction or consolidation chemotherapy, and in patients with decreased ingesta or not. The blood plasma concentration considered to be effective (500 ng/mL) is drawn as a solid line. PSZ: posaconazole; PPIs: proton pump inhibitors. Distribution des concentrations plasmatiques de posaconazole chez les patients traités ou non par IPP, en cure d’induction ou de consolidation et chez les patients ayant des ingesta réduits ou non. La concentration plasmatique considérée comme efficace (500 ng/mL) est figurée par un trait continu. PSZ : posaconazole ; PPIs : proton pump inhibitors.
3.4. Outcome PSZ treatment was stopped 10 times to manage an IFI (Candida tropicalis candidemia) or a possible IPA (n = 9). The difference in IFI incidence between patients under-dosed or not
was not significant, with respectively an incidence of 8/40 (20%) in under-dosed patients vs 2/19 (10%), (P = 0.5). 2 treatments were stopped because of a risk of drug interaction with a tyrosine kinase inhibitor, 1 for hepatic intolerance, and 1 because of digestive disorders. 4 other treatments were modified empirically. The treatment was continued in 41 cases (69%) until the resolution of aplasia, without any interruption.
Table 3 univariate analysis results. Résultats de l’analyse univariée.
4. Discussion
Parameters
Concentration < 500 ng/mL (n = 40)
Concentration > 500 ng/mL (n = 19)
P
Weight (kg) Chemotherapy (induction/consolidation) (n) Decreased ingesta (yes/no) (n) Digestive disordersa : yes/no (n) Mucositis Nausea/emesis Diarrhea Associated treatments (n) PPI (with/without) Benzamides (with/without) Anthracyclines (with/without) Proteinemia (≥60 g/L/ < 60 g/L) (n) Creatinine clearance (ml/mn) Prothrombin ratio (%) Delay PSZ/assay (days)
66 (46–108) 20/20
68 (53–112) 2/17
0.9 0.008
16/24
3/16
0.07
16/24
6/13
0.5
2/38 7/33 10/30
2/17 3/16 3/16
32/8 18/22
9/10 11/8
0.01 0.35
6/34
2/17
1
26/14
8/11
0.1
117 (71–202)
111 (55–230)
0.6
89% (70–100) 8 (3–24)
87% (58–100) 7 (5–28)
0.6 0.44
We identified factors associated to the under-dosing of PSZ used as prophylaxis for patients presenting with AML, treated by intensive chemotherapy. The relatively low median of blood plasma concentration in our patients (375 ng/mL) compared to other studies (Table 1) remained associated with a weak incidence of fungal infections. We eliminated the lack of observance, which is the first risk for under-dosing in per os treatment [21]. Furthermore we avoided the possibility of dose variations by having the nurses deliver an accurate PSZ dose to the patient with a graduated syringe instead of having the patient use the measure spoon provided by the laboratory. Nevertheless, the drug absorption being Table 4 Multivariate analysis results. Résultats de l’analyse multivariée. Multivariate analysis
kg: kilograms; n: number; PPI: proton pump inhibitors; PSZ: posaconazole. a Some patients presented with several different digestive disorders in the same period.
Type of chemotherapy Consolidation/Induction Ingesta Normal/Decreased PPI No/yes
OR [CI 95%]
P
19.4 [2.6–144.0] 2.3 [0.4–11.8] 8.9 [1.6–49.2]
0.003
OR: odd ratio; CI: confidence interval; PPI: proton pump inhibitors
0.33 0.01
178
P.-Y. Desplanques et al. / Médecine et maladies infectieuses 44 (2014) 174–179
improved by ingestion of fatty food [22], we preferred to administer the agent during meals (morning/noon/evening), thus not respecting stricto sensu the 8 hour inter-dose delay, and this may have had an impact of blood plasma concentrations. Contrary to the results of other recent studies [18], we could not demonstrate any influence of blood plasma concentrations on the incidence of fungal infections, which was very low, with only 1 infection for 59 patients at risk (the possible IPA were usually not taken into account). The patient sample size may explain this; but the studied patients were also all hospitalized in rooms with laminar airflow, which along with antifungal prophylaxis helps to decrease the risk of IPA. Furthermore, none of these patients was resistant to induction chemotherapy, limiting de facto the duration of neutropenia. And whatever the blood plasma concentration, the global incidence of IFI in patients treated with PSZ, in most of all the published studies, was inferior to 5% (Table 1); some authors suggested that the blood plasma concentration of PSZ did not necessarily reflect its concentration in tissues [23]. The retrospective method of our study and the fact that we focused on the first PSZ assay probably led to under estimating the impact of digestive disorders, especially of mucositis, or of food-intake, which other studies took into account [15,17,18,22,24–27]. The co-prescription of a PPI seemed to be strongly correlated to the risk of under-dosing. This interaction had already been reported [28], PSZ absorption being promoted by an acid pH [28]. Many patients (69% in our study) were given PPI, probably in an excessive manner. The 44% decrease of PSZ blood plasma concentrations in patients treated with a PPI, most often as prophylaxis, led us to reflect on the use of this drug. The systematic prescription of a PPI at diagnosis (because of the supposedly increased risk of digestive hemorrhage related to thrombopenia) was not recommended. If necessary, antacids were prescribed in first intention, because these interact more weakly with PSZ, [29] and in a lesser way with H2 antihistamine agents (such as ranitidine) [18]. This allowed, without increasing the risk of acute bleeding (data not detailed), significantly increasing PSZ blood plasma concentrations (the median of all assays performed in our department increasing from 469 ng/mL in 2010 to 618 ng/mL in 2011 [before/after changing our PPI policy]). Interestingly, and, as far as we know, not reported in other studies, it seems that the cause of hospitalization was associated to a risk of under-dosing. This risk seemed to be higher during induction chemotherapy, corresponding to the initial management of a patient presenting with AML, than during consolidation chemotherapy, corresponding to the management of a patient in remission, hence without any apparent disease. This did not seem to be directly related to chemotherapy the metabolic pathway of which differs from that of PSZ [24]. We did not demonstrate any association between the use of anthracyclines and under-dosing. The multiplication of non significant factors in our study, but present in patients undergoing induction chemotherapy, such as anorexia induced by chemotherapy, mucositis, digestive disorders, emotional state, hypoalbuminemia (only proteinemia was assessed) may have had an impact on the drug intake and absorption, as well as for the use of
CYP3A4 substrate agents (setrons, benzamides, corticosteroids for example) and interacted with PSZ. On the physiopathological level, some modifications of the distribution volume caused by the hemopathy and hyper-hydration often initiated, the inflammatory or infectious state, and denutrition, may have had an impact. This is an interesting consideration since patients presenting with AML are more at risk of IFI during induction than consolidation chemotherapy [28]. PSZ prophylaxis per os must be initiated along with, on one hand taking into account associated treatments, both for initiation of prophylaxis the effectiveness of which was previously proven [12] and to ensure the effectiveness of other treatments, and on the other hand a strict monitoring of patients in induction chemotherapy because of the significant risk of decreased exposure to the prophylactic agent for the patient. The various parameters we identified were only risk factors for under-dosing, compared to acknowledged pharmacokinetic models [15,17,24,26,30]; they cannot alone explain all the inter-individual variability. Monitoring PSZ concentration remains necessary to assess the quality of prophylaxis. New drug formulations in the future, such as gastro-resistant tablets (99% of patients presenting with AML had a drug concentration > 500 ng/mL in the pivotal study [31]) or intravenous administration (http://clinicaltrials.gov/ct2/show/NCT01075984) should probably help to improve PSZ blood plasma concentrations. 5. Contributors Study design: P-Y. Desplanques, B. Wyplosz, B. Gachot, F. Netzer, J-B. Micol. Provided biological material and patient data: V. Poinsignon, E. Billaud, E. Chachaty, R. Burlacu, H. Boussion, J-B. Micol, S. de Botton. Data collection and processing: P-Y. Desplanques, V. Poinsignon, J-B. Micol. Analysis and interpretation of results: P-Y. Desplanques, I. Borget, J-B. Micol. Drafting and final approval of the manuscript: all authors. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Herbrecht R, Caillot D, Cordonnier C, Auvrignon A, Thiébaut A, Brethon B, et al. Indications and outcomes of antifungal therapy in French patients with haematological conditions or recipients of haematopoietic stem cell transplantation. J Antimicrob Chemother 2012;67(11):2731–8. [2] Cannas G, Pautas C, Raffoux E, Quesnel B, de Botton S, de Revel T, et al. Infectious complications in adult acute myeloid leukemia: analysis of the Acute Leukemia French Association-9802 prospective multicenter clinical trial. Leuk Lymphoma 2012;53(6):1068–76. [3] Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 2006;91(8):1068–75.
P.-Y. Desplanques et al. / Médecine et maladies infectieuses 44 (2014) 174–179 [4] Pagano L, Caira M, Candoni A, Offidani M, Martino B, Specchia G, et al. Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM2008 registry study. Haematologica 2010;95(4):644–50. [5] Lortholary O, Gangneux JP, Sitbon K, Lebeau B, de Monbrison F, Le Strat Y, et al. Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005-2007). Clin Microbiol Infect 2011;17(12):1882–9. [6] Leventakos K, Lewis RE, Kontoyiannis DP. Fungal infections in leukemia patients: how do we prevent and treat them? Clin Infect Dis 2010;50(3):405–15. [7] Lewis RE. Current concepts in antifungal pharmacology. Mayo Clin Proc 2011;86(8):805–17. [8] Even C, Bastuji-Garin S, Hicheri Y, Pautas C, Botterel F, Maury S, et al. Impact of invasive fungal disease on the chemotherapy schedule and eventfree survival in acute leukemia patients who survived fungal disease: a case-control study. Haematologica 2011;96(2):337–41. [9] Rogers TR, Slavin MA, Donnelly JP. Antifungal prophylaxis during treatment for haematological malignancies: are we there yet? Br J Haematol 2011;153(6):681–97. [10] Robenshtok E, Gafter-Gvili A, Goldberg E, Weinberger M, Yeshurun M, Leibovici L, et al. Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol 2007;25(34):5471–89. [11] Maertens J, Marchetti O, Herbrecht R, Cornely OA, Fluckiger U, Frere P, et al. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3-2009 update. Bone Marrow Transplant 2011;46(5):709–18. [12] Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356(4):348–59. [13] Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 2009;53(1):24–34. [14] Dolton MJ, Ray JE, Marriott D, McLachlan AJ. Posaconazole exposureresponse relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents Chemother 2012;56(6):2806–13. [15] Cornely OA, Helfgott D, Langston A, Heinz W, Vehreschild JJ, Vehreschild MJ, et al. Pharmacokinetics of different dosing strategies of oral posaconazole in patients with compromised gastrointestinal function and who are at high risk for invasive fungal infection. Antimicrob Agents Chemother 2012;56(5):2652–8. [16] Li Y, Theuretzbacher U, Clancy CJ, Nguyen MH, Derendorf H. Pharmacokinetic/pharmacodynamic profile of posaconazole. Clin Pharmacokinet 2010;49(6):379–96. [17] AbuTarif MA, Krishna G, Statkevich P. Population pharmacokinetics of posaconazole in neutropenic patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Curr Med Res Opin 2010;26(2):397–405. [18] Dolton MJ, Ray JE, Chen SC, Ng K, Pont L, McLachlan AJ. Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother 2012;56(11):5503–10. [19] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31–41. [20] De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46(12):1813–21.
179
[21] Cambier C, Lafaurie M, Ribaud P, Raffoux E, Andreoli A, Sauvageon H, et al [cambier.pdf. 2013] Abstract ESCMMID; 2013. [22] Sansone-Parsons A, Krishna G, Calzetta A, Wexler D, Kantesaria B, Rosenberg MA, et al. Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers. Antimicrob Agents Chemother 2006;50(5):1881–3. [23] Campoli P, Al Abdallah Q, Robitaille R, Solis NV, Fielhaber JA, Kristof AS, et al. Concentration of antifungal agents within host cell membranes: a new paradigm governing the efficacy of prophylaxis. Antimicrob Agents Chemother 2011;55(12):5732–9. [24] Vehreschild JJ, Müller C, Farowski F, Vehreschild MJ, Cornely OA, Fuhr U, et al. Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome. Eur J Clin Pharmacol 2012;68(6):987–95. [25] Vaes M, Hites M, Cotton F, Bourguignon AM, Csergo M, Rasson C, et al. Therapeutic drug monitoring of posaconazole in patients with acute myeloid leukemia or myelodysplastic syndrome. Antimicrob Agents Chemother 2012;56(12):6298–303. [26] Krishna G, Moton A, Ma L, Medlock MM, McLeod J. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother 2009;53(3):958–66. [27] Eiden C, Meniane JC, Peyriere H, Eymard-Duvernay S, Le Falher G, Ceballos P, et al. Therapeutic drug monitoring of posaconazole in hematology adults under posaconazole prophylaxis: influence of food intake. Eur J Clin Microbiol Infect Dis 2012;31(2):161–7. [28] Ananda-Rajah MR, Grigg A, Downey MT, Bajel A, Spelman T, Cheng A, et al. Comparative clinical effectiveness of prophylactic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period. Haematologica 2012;97(3): 459–63. [29] Courtney R, Radwanski E, Lim J, Laughlin M. Pharmacokinetics of posaconazole coadministered with antacid in fasting or nonfasting healthy men. Antimicrob Agents Chemother 2004;48(3):804–8. [30] Lipp HP. Posaconazole: clinical pharmacokinetics and drug interactions. Mycoses 2011;54(Suppl 1):32–8. [31] Cornely OA, Duarte RF, Haider S, Chandrasakar P, Helfgott D, Lopez J, et al. Abstract ECCMID; 2013. [32] Michallet M, Sobh M, Morisset S, Kraghel S, Nicolini FE, Thomas X, et al. Risk factors for invasive aspergillosis in acute myeloid leukemia patients prophylactically treated with posaconazole. Med Mycol 2011;49(7):681–7. [33] Egerer G, Geist MJ. Posaconazole prophylaxis in patients with acute myelogenous leukaemia–results from an observational study. Mycoses 2011;54(Suppl 1):7–11. [34] Vehreschild JJ, Ruping MJ, Wisplinghoff H, Farowski F, Steinbach A, Sims R, et al. Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia (AML): a 6-year experience of the Cologne AML cohort. J Antimicrob Chemother 2010;65(7):1466–71. [35] Pagano L, Caira M, Candoni A, Aversa F, Castagnola C, Caramatti C, et al. Evaluation of the practice of antifungal prophylaxis use in patients with newly diagnosed acute myeloid leukemia: results from the SEIFEM 2010-B registry. Clin Infect Dis 2012;55(11):1515–21. [36] Girmenia C, Frustaci AM, Gentile G, Minotti C, Cartoni C, Capria S, et al. Posaconazole prophylaxis during front-line chemotherapy of acute myeloid leukemia: a single-center, real-life experience. Haematologica 2012;97(4):560–7.
ScienceDirect www.sciencedirect.com Médecine et maladies infectieuses 44 (2014) 174–179
Original article
Factors influencing posaconazole plasmatic concentrations in patients presenting with acute myeloid leukemia夽 Facteurs influen¸cant les concentrations plasmatiques de posaconazole chez les patients atteints de leucémie aiguë myéloïde P.-Y. Desplanques a , R. Burlacu b , V. Poinsignon c , H. Boussion b , I. Borget d , B. Wyplosz e , S. de Botton b , E. Billaud c , E. Chachaty f , B. Gachot g , F. Netzer a , J.-B. Micol b,∗ a
Service de pharmacie clinique, Institut Gustave-Roussy, 94805 Villejuif cedex, France b Service d’hématologie, Institut Gustave Roussy, 94805 Villejuif cedex, France c Service de pharmacologie et toxicologie, Hôpital Européen George-Pompidou, 75015 Paris, France d Service de biostatistique et d’épidémiologie, Institut Gustave-Roussy, université Paris-Sud, 94805 Villejuif cedex, France e Service de maladies infectieuses, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France f Service de microbiologie, Institut Gustave-Roussy, 94805 Villejuif cedex, France g Département de soins aigus, Institut Gustave-Roussy, 94805 Villejuif cedex, France Received 27 August 2013; received in revised form 8 January 2014; accepted 12 February 2014 Available online 19 March 2014
Abstract Purpose. – The effectiveness of posaconazole (PSZ) prophylaxis on invasive fungal infections, in patients presenting with acute myeloid leukemia (AML), seems to be correlated to its blood plasma concentration. Our goal was to identify the risk factors for underdosing. Patients and methods. – We retrospectively reviewed the records of patients treated for AML treated with PSZ, during a 2-year period. Assays < 500 ng/mL were considered as under dosed. Results. – Fifty-nine assays (43 patients) were performed during induction (n = 22) or consolidation (n = 37) chemotherapy. PSZ treatment was initiated within a median of 3 days before neutropenia with a first assay performed at 8 days (3–28). The median PSZ blood plasma concentration was 375 ng/mL (< 200–1900). Forty-one (69%) treatment were maintained until the end of neutropenia. One patient presented with candidemia, 9 with possible invasive aspergillosis, without any significant association with underdosing. The univariate analysis showed that co-administration of proton pump inhibitors (PPIs) (P = 0.01) and cause of hospitalization (induction chemotherapy vs consolidation, P = 0.008) were associated with underdosing, contrary to feeding difficulties (P = 0.07) and digestive disorders (P = 0.5). The multivariate analysis confirmed the impact of PPI use (P = 0.01) and the cause of hospitalization (P = 0.003). Conclusion. – This study highlights the major impact of PPI administration on PSZ blood plasma levels and stresses the risk of non-effective prophylaxis during induction treatment of AML. © 2014 Elsevier Masson SAS. All rights reserved. Keywords: Posaconazole; Drug interactions; Acute myeloid leukemia; Invasive aspergillosis
Résumé Introduction. – L’efficacité du posaconazole (PSZ) en prophylaxie des infections fongiques invasives chez les patients atteints de leucémies aiguës myéloïdes (LAM) semble être corrélée aux concentrations plasmatiques du médicament. Notre objectif a été d’identifier les facteurs de risques de sous-dosage. Patients et méthodes. – Nous avons étudié rétrospectivement les dossiers des patients traités pour une LAM sur une période de 2 ans et ayant rec¸u du PSZ à dose préventive. Les dosages < 500 ng/mL ont été considérés comme sous dosés. Résultats. – Cinquante-neuf dosages ont été effectués chez 43 patients au cours de cures de chimiothérapie d’induction (n = 22) ou de consolidation (n = 37). Le traitement par PSZ était instauré avec une médiane de 3 jours avant l’aplasie avec un premier dosage effectué à 8 jours (3–28). Les 夽 ∗
This study was presented orally at the congress of the French Society of Medical Mycology in Dijon, on May 17, 2013. Corresponding author. E-mail address: [email protected] (J.-B. Micol).
0399-077X/$ – see front matter © 2014 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.medmal.2014.02.005
P.-Y. Desplanques et al. / Médecine et maladies infectieuses 44 (2014) 174–179
175
patients avaient une concentration plasmatique médiane de PSZ de 375 ng/mL (< 200–1900). À 41 reprises (69 %) le traitement a été poursuivi jusqu’à la sortie d’aplasie. Un patient a présenté une candidémie, 9, une aspergillose invasive possible sans association significative avec le sousdosage. En analyse univariée, la co-administration d’inhibiteurs de la pompe à proton (IPP) (p = 0,01) et le motif d’hospitalisation (chimiothérapie d’induction vs consolidation, p = 0,008) étaient associés à un sous-dosage en PSZ, contrairement aux difficultés alimentaires (p = 0,07) et aux troubles digestifs (p = 0,5). L’analyse multivariée confirmait l’impact de l’utilisation d’IPP (p = 0,01) et du motif d’hospitalisation (p = 0,003). Conclusion. – Ce travail démontre l’impact des IPP sur les concentrations plasmatiques de PSZ et appelle à la vigilance quant au risque d’inefficacité de la prophylaxie en induction de LAM. © 2014 Elsevier Masson SAS. Tous droits réservés. Mots clés : Posaconazole ; Interaction médicamenteuse ; Leucémie aiguë myéloïde ; Aspergillose invasive
1. Introduction Invasive fungal infections (IFI) are one of the main causes of morbidity-mortality for patients presenting with acute myeloid leukemia (AML) [1,2]. Their incidence may reach 12% during induction chemotherapy treatments, more than 2 thirds of which are invasive pulmonary aspergillosis (IPA) [3]. These infections concern most often patients with long-term aplasia; reason for which 60% of IPA occurs in patients undergoing induction chemotherapy compared to 3% only in patients undergoing consolidation therapy [4]. Furthermore IFI remain, despite recent therapeutic progress with new antifungal [5–7], the first cause of infectious death for hematology unit patients in aplasia [1]. Besides this “early” mortality related to the infection, proven IFI are associated to a decreased survival related to the hemopathy because of the therapeutic adaptations imposed by their management [8]. Antifungal prophylaxis has become part of the therapeutic strategy because of these important risks [9–11]. Implementing posaconazole (PSZ) prophylaxis allowed decreasing the global incidence of fungal infections (Table 1) and the associated mortality [12] for this type of patients, leading to the marketing authorization for this agent. Nevertheless, PSZ, like most azoles [13], presents a great inter and intra-individual variability of blood plasma concentrations requiring therapeutic monitoring [14]. This variability may Table 1 Main studies on posaconazole prophylaxis in patients presenting with acute myeloid leukemia. Principales études de prophylaxie par posaconazole chez des patients atteints de leucémies aiguës myéloïdes. Reference
Number of patients given prophylactic treatment
Cornely et al. [12] 304 72 Dolton et al. [18] Michallet et al. [32] 55 76a Egerer et al. [33] Vehreschild et al. [34] 77 260 Pagano et al. [35] 74a Vaes et al. [25] Girmenia et al. [36] 195a Ananda-Rajah et al. [28] 153 Total 1266 NA: not applicable. a Chemotherapy courses.
Incidence of IFI (%) 2 4 3.6 1.3 3.9 3.8 2.7 11.8 0 4
Median PSZ blood plasma concentration 490 ng/mL 466 ng/mL NA NA 555 ng/mL NA 430 ng/mL NA NA 490 ng/mL
be related to gastric absorption disorders, the agent currently being available only as a drinkable suspension, and to, less frequently, the hepatic metabolism of the drug [15–17]. There is currently no final consensus as to the minimal effective prophylactic blood plasma concentration but some study results give a threshold ranging between 500 ng/mL and 700 ng/mL [18]. We had for aim to assess the various factors associated to under dosing of PSZ in the management of patients presenting with AML treated by intensive chemotherapy. 2. Patients and methods 2.1. Patients We retrospectively studied the medical records of patients treated intensively for AML in laminar flow rooms from our hematology ward from October 2010 to December 2012. One hundred and eighty courses of intensive chemotherapy were administrated; PSZ was administrated at prophylactic doses (200 mg × 3/d) in 137 (76%) cases. PSZ blood plasma concentration was measured at least once in 67 of these courses (44% of PSZ prophylaxis). Eight results were not considered because of the patient’s therapeutic non-observance, with a final number of 59 blood plasma concentration measures. 2.2. Modes of posaconazole administration PSZ was administrated at 200 mg/5 mL per intake (for a dose of 600 mg/d) of drinkable suspension, using a graduated syringe for the per os administration prepared by nurses so as to prevent the imprecision of the measure spoon provided and check observance. PSZ was given during morning, noon, and evening meals so as to improve absorption. 2.3. Blood plasma concentration assays The blood plasma concentration was measured by liquid chromatography coupled with mass spectrometry in the pharmacology and toxicology departments of the GeorgePompidou European Hospital, with a threshold of detection set at 200 ng/mL (blood plasma concentration below this threshold are considered as unreliable by the laboratory). We focused our study on the results of the first PSZ blood plasma concentration measured in each course of chemotherapy (whether at diagnosis for induction chemotherapy or during consolidation
176
P.-Y. Desplanques et al. / Médecine et maladies infectieuses 44 (2014) 174–179
chemotherapy) so as to avoid intra-individual variations, dose adaptation, modifications of the patient’s clinical status, and of associated treatments. The target concentration was set at 500 ng/mL; patients with a lower blood plasma concentration were considered as under dosed. 2.4. Studied variables The biological data was the one collected on the day blood plasma concentration was measured. The creatinine clearance was calculated with the Cockcroft and Gault equation [19]. The clinical data, including potential drug interactions, was collected during the 5 days before blood plasma concentration was measured. All the documented digestive disorders (mucositis grade 2 or more according to the WHO score, nausea/emesis, diarrhea) were grouped for the statistical analysis. The nutritional evaluation made weekly by our dieticians allowed identifying patients with decreased ingesta (inferior to two third of daily nutritional requirements) or considered as “normal”.
Table 2 Initial characteristics of patients and posaconazole assays. Caractéristiques initiales des patients et des dosages de posaconazole. Parameters
Values
Age (years) Weight (kg) Gender: F/M (n/%) Treatment: I/C (n/%) Duration of aplasia (d) Delay chemo/prophylaxis (d) Delay prophylaxis/aplasia (d) Delay prophylaxis/assay (d) Delay assay/results (d) Results of assaya (ng/ml)
53 (24–76) 68 (46–112) 23 (53%)/20 (47%) 22 (37%)/37 (63%) 18 (7–47) 3 (-5 ± 15) 3 (-14 ± 15) 8 (3–28) 3 (1–11) 375 (≤200–1900)
kg: kilograms; F: female; M: male; n: number; %: percentage; I: induction; C: consolidation; d: days. a Median delay for results.
aplasia compared to 5 days before aplasia for consolidation chemotherapy (P = 0.001). 3.2. Posaconazole blood plasma concentration assays
2.5. Diagnostic criteria Aspergillosis was assessed and classified according to the 2008 criteria of the European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) [20]. A systematic bi-weekly surveillance of aspergillus antigens was made in all patients.
The first blood plasma concentration was measured 8 days (3–28) after initiation of PSZ treatment and the results were sent to the clinician in a median of 3 days (1–11) (Table 2). The median of PSZ blood plasma concentration was 375 ng/mL (< 200–1,900), 19 measures (32%) had reached the target threshold of 500 ng/mL, 13 (22%) that of 700 ng/mL.
2.6. Statistical analysis
3.3. Factors influencing blood plasma concentration
The quantitative variables were presented as average ± SD; the qualitative variables were presented as percentages. The quantitative variables were compared with the Mann-Whitney test in the absence of normal distribution. The qualitative variables were compared with Fisher’s exact test. The factors associated to a risk of PSZ under-dosing were studied with univariate and multivariate analyses, using a logistic regression model. The analyses were made with the SAS software, version 9.2.
Twenty of the 22 (91%) patients in induction chemotherapy were under dosed and the median of their blood plasma concentration was 25% lower than that of patients in consolidation chemotherapy (350 ng/mL vs 465 ng/ml, P = 0.08). Thirty-two of the 41 patients (78%) receiving proton pump inhibitors (PPI) were under-dosed compared to 8/18 (44%) for the others. The patients receiving PPI had a 44% lower median blood plasma concentration (355 ng/mL vs 640 ng/mL, P = 0.02). The decreased ingesta was associated to a 50% decrease of PSZ blood plasma concentration de (220 ng/mL vs 430 ng/mL, P = 0.001), (Fig. 1). The type of chemotherapy requiring hospitalization (induction vs. consolidation, P = 0.008) and the co-administration of the PPI (P = 0.01) were associated with under-dosing in the univariate analysis (Table 3). The decrease of ingesta, digestive disorders (mucositis and/or nausea, and/or emesis, and/or diarrhea), the creatinine clearance, the prothrombin ratio, the level of ␥GT, the proteinemia, as well as the co-administration of benzamides and the use of anthracycline in the 5 days did not significantly change the risk of PSZ under-dosing. The multivariate analysis (Table 4) allowed demonstrating that use of PPI and the period of induction chemotherapy were independent risk factors for PSZ under-dosing (respectively P = 0.01 and P = 0.003) contrary to decreased ingesta (P = 0.33).
3. Results 3.1. Population Fifty-nine PSZ blood plasma concentration measures were analyzed in 43 patients (median age 53 years [24–76]), 23 female and 20 male patients, presenting with AML and managed in 59 courses of chemotherapy (median duration of aplasia of 18 days [7–47]) (Table 2). Twenty-two patients were hospitalized for induction chemotherapy (median duration of aplasia of 26 days [12–47]), and 37 for consolidation chemotherapy (median duration of aplasia of 16 days [7–30]) (P < 0.001). PSZ treatment was initiated within a median of 3 days (-14 ± 15) before aplasia; patients at diagnosis (induction chemotherapy) received the treatment a median of 1 day before
P.-Y. Desplanques et al. / Médecine et maladies infectieuses 44 (2014) 174–179
177
Fig. 1. Distribution of posaconazole blood plasma concentrations in patients treated or not with PPIs, following induction or consolidation chemotherapy, and in patients with decreased ingesta or not. The blood plasma concentration considered to be effective (500 ng/mL) is drawn as a solid line. PSZ: posaconazole; PPIs: proton pump inhibitors. Distribution des concentrations plasmatiques de posaconazole chez les patients traités ou non par IPP, en cure d’induction ou de consolidation et chez les patients ayant des ingesta réduits ou non. La concentration plasmatique considérée comme efficace (500 ng/mL) est figurée par un trait continu. PSZ : posaconazole ; PPIs : proton pump inhibitors.
3.4. Outcome PSZ treatment was stopped 10 times to manage an IFI (Candida tropicalis candidemia) or a possible IPA (n = 9). The difference in IFI incidence between patients under-dosed or not
was not significant, with respectively an incidence of 8/40 (20%) in under-dosed patients vs 2/19 (10%), (P = 0.5). 2 treatments were stopped because of a risk of drug interaction with a tyrosine kinase inhibitor, 1 for hepatic intolerance, and 1 because of digestive disorders. 4 other treatments were modified empirically. The treatment was continued in 41 cases (69%) until the resolution of aplasia, without any interruption.
Table 3 univariate analysis results. Résultats de l’analyse univariée.
4. Discussion
Parameters
Concentration < 500 ng/mL (n = 40)
Concentration > 500 ng/mL (n = 19)
P
Weight (kg) Chemotherapy (induction/consolidation) (n) Decreased ingesta (yes/no) (n) Digestive disordersa : yes/no (n) Mucositis Nausea/emesis Diarrhea Associated treatments (n) PPI (with/without) Benzamides (with/without) Anthracyclines (with/without) Proteinemia (≥60 g/L/ < 60 g/L) (n) Creatinine clearance (ml/mn) Prothrombin ratio (%) Delay PSZ/assay (days)
66 (46–108) 20/20
68 (53–112) 2/17
0.9 0.008
16/24
3/16
0.07
16/24
6/13
0.5
2/38 7/33 10/30
2/17 3/16 3/16
32/8 18/22
9/10 11/8
0.01 0.35
6/34
2/17
1
26/14
8/11
0.1
117 (71–202)
111 (55–230)
0.6
89% (70–100) 8 (3–24)
87% (58–100) 7 (5–28)
0.6 0.44
We identified factors associated to the under-dosing of PSZ used as prophylaxis for patients presenting with AML, treated by intensive chemotherapy. The relatively low median of blood plasma concentration in our patients (375 ng/mL) compared to other studies (Table 1) remained associated with a weak incidence of fungal infections. We eliminated the lack of observance, which is the first risk for under-dosing in per os treatment [21]. Furthermore we avoided the possibility of dose variations by having the nurses deliver an accurate PSZ dose to the patient with a graduated syringe instead of having the patient use the measure spoon provided by the laboratory. Nevertheless, the drug absorption being Table 4 Multivariate analysis results. Résultats de l’analyse multivariée. Multivariate analysis
kg: kilograms; n: number; PPI: proton pump inhibitors; PSZ: posaconazole. a Some patients presented with several different digestive disorders in the same period.
Type of chemotherapy Consolidation/Induction Ingesta Normal/Decreased PPI No/yes
OR [CI 95%]
P
19.4 [2.6–144.0] 2.3 [0.4–11.8] 8.9 [1.6–49.2]
0.003
OR: odd ratio; CI: confidence interval; PPI: proton pump inhibitors
0.33 0.01
178
P.-Y. Desplanques et al. / Médecine et maladies infectieuses 44 (2014) 174–179
improved by ingestion of fatty food [22], we preferred to administer the agent during meals (morning/noon/evening), thus not respecting stricto sensu the 8 hour inter-dose delay, and this may have had an impact of blood plasma concentrations. Contrary to the results of other recent studies [18], we could not demonstrate any influence of blood plasma concentrations on the incidence of fungal infections, which was very low, with only 1 infection for 59 patients at risk (the possible IPA were usually not taken into account). The patient sample size may explain this; but the studied patients were also all hospitalized in rooms with laminar airflow, which along with antifungal prophylaxis helps to decrease the risk of IPA. Furthermore, none of these patients was resistant to induction chemotherapy, limiting de facto the duration of neutropenia. And whatever the blood plasma concentration, the global incidence of IFI in patients treated with PSZ, in most of all the published studies, was inferior to 5% (Table 1); some authors suggested that the blood plasma concentration of PSZ did not necessarily reflect its concentration in tissues [23]. The retrospective method of our study and the fact that we focused on the first PSZ assay probably led to under estimating the impact of digestive disorders, especially of mucositis, or of food-intake, which other studies took into account [15,17,18,22,24–27]. The co-prescription of a PPI seemed to be strongly correlated to the risk of under-dosing. This interaction had already been reported [28], PSZ absorption being promoted by an acid pH [28]. Many patients (69% in our study) were given PPI, probably in an excessive manner. The 44% decrease of PSZ blood plasma concentrations in patients treated with a PPI, most often as prophylaxis, led us to reflect on the use of this drug. The systematic prescription of a PPI at diagnosis (because of the supposedly increased risk of digestive hemorrhage related to thrombopenia) was not recommended. If necessary, antacids were prescribed in first intention, because these interact more weakly with PSZ, [29] and in a lesser way with H2 antihistamine agents (such as ranitidine) [18]. This allowed, without increasing the risk of acute bleeding (data not detailed), significantly increasing PSZ blood plasma concentrations (the median of all assays performed in our department increasing from 469 ng/mL in 2010 to 618 ng/mL in 2011 [before/after changing our PPI policy]). Interestingly, and, as far as we know, not reported in other studies, it seems that the cause of hospitalization was associated to a risk of under-dosing. This risk seemed to be higher during induction chemotherapy, corresponding to the initial management of a patient presenting with AML, than during consolidation chemotherapy, corresponding to the management of a patient in remission, hence without any apparent disease. This did not seem to be directly related to chemotherapy the metabolic pathway of which differs from that of PSZ [24]. We did not demonstrate any association between the use of anthracyclines and under-dosing. The multiplication of non significant factors in our study, but present in patients undergoing induction chemotherapy, such as anorexia induced by chemotherapy, mucositis, digestive disorders, emotional state, hypoalbuminemia (only proteinemia was assessed) may have had an impact on the drug intake and absorption, as well as for the use of
CYP3A4 substrate agents (setrons, benzamides, corticosteroids for example) and interacted with PSZ. On the physiopathological level, some modifications of the distribution volume caused by the hemopathy and hyper-hydration often initiated, the inflammatory or infectious state, and denutrition, may have had an impact. This is an interesting consideration since patients presenting with AML are more at risk of IFI during induction than consolidation chemotherapy [28]. PSZ prophylaxis per os must be initiated along with, on one hand taking into account associated treatments, both for initiation of prophylaxis the effectiveness of which was previously proven [12] and to ensure the effectiveness of other treatments, and on the other hand a strict monitoring of patients in induction chemotherapy because of the significant risk of decreased exposure to the prophylactic agent for the patient. The various parameters we identified were only risk factors for under-dosing, compared to acknowledged pharmacokinetic models [15,17,24,26,30]; they cannot alone explain all the inter-individual variability. Monitoring PSZ concentration remains necessary to assess the quality of prophylaxis. New drug formulations in the future, such as gastro-resistant tablets (99% of patients presenting with AML had a drug concentration > 500 ng/mL in the pivotal study [31]) or intravenous administration (http://clinicaltrials.gov/ct2/show/NCT01075984) should probably help to improve PSZ blood plasma concentrations. 5. Contributors Study design: P-Y. Desplanques, B. Wyplosz, B. Gachot, F. Netzer, J-B. Micol. Provided biological material and patient data: V. Poinsignon, E. Billaud, E. Chachaty, R. Burlacu, H. Boussion, J-B. Micol, S. de Botton. Data collection and processing: P-Y. Desplanques, V. Poinsignon, J-B. Micol. Analysis and interpretation of results: P-Y. Desplanques, I. Borget, J-B. Micol. Drafting and final approval of the manuscript: all authors. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Herbrecht R, Caillot D, Cordonnier C, Auvrignon A, Thiébaut A, Brethon B, et al. Indications and outcomes of antifungal therapy in French patients with haematological conditions or recipients of haematopoietic stem cell transplantation. J Antimicrob Chemother 2012;67(11):2731–8. [2] Cannas G, Pautas C, Raffoux E, Quesnel B, de Botton S, de Revel T, et al. Infectious complications in adult acute myeloid leukemia: analysis of the Acute Leukemia French Association-9802 prospective multicenter clinical trial. Leuk Lymphoma 2012;53(6):1068–76. [3] Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 2006;91(8):1068–75.
P.-Y. Desplanques et al. / Médecine et maladies infectieuses 44 (2014) 174–179 [4] Pagano L, Caira M, Candoni A, Offidani M, Martino B, Specchia G, et al. Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM2008 registry study. Haematologica 2010;95(4):644–50. [5] Lortholary O, Gangneux JP, Sitbon K, Lebeau B, de Monbrison F, Le Strat Y, et al. Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005-2007). Clin Microbiol Infect 2011;17(12):1882–9. [6] Leventakos K, Lewis RE, Kontoyiannis DP. Fungal infections in leukemia patients: how do we prevent and treat them? Clin Infect Dis 2010;50(3):405–15. [7] Lewis RE. Current concepts in antifungal pharmacology. Mayo Clin Proc 2011;86(8):805–17. [8] Even C, Bastuji-Garin S, Hicheri Y, Pautas C, Botterel F, Maury S, et al. Impact of invasive fungal disease on the chemotherapy schedule and eventfree survival in acute leukemia patients who survived fungal disease: a case-control study. Haematologica 2011;96(2):337–41. [9] Rogers TR, Slavin MA, Donnelly JP. Antifungal prophylaxis during treatment for haematological malignancies: are we there yet? Br J Haematol 2011;153(6):681–97. [10] Robenshtok E, Gafter-Gvili A, Goldberg E, Weinberger M, Yeshurun M, Leibovici L, et al. Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol 2007;25(34):5471–89. [11] Maertens J, Marchetti O, Herbrecht R, Cornely OA, Fluckiger U, Frere P, et al. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3-2009 update. Bone Marrow Transplant 2011;46(5):709–18. [12] Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356(4):348–59. [13] Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 2009;53(1):24–34. [14] Dolton MJ, Ray JE, Marriott D, McLachlan AJ. Posaconazole exposureresponse relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents Chemother 2012;56(6):2806–13. [15] Cornely OA, Helfgott D, Langston A, Heinz W, Vehreschild JJ, Vehreschild MJ, et al. Pharmacokinetics of different dosing strategies of oral posaconazole in patients with compromised gastrointestinal function and who are at high risk for invasive fungal infection. Antimicrob Agents Chemother 2012;56(5):2652–8. [16] Li Y, Theuretzbacher U, Clancy CJ, Nguyen MH, Derendorf H. Pharmacokinetic/pharmacodynamic profile of posaconazole. Clin Pharmacokinet 2010;49(6):379–96. [17] AbuTarif MA, Krishna G, Statkevich P. Population pharmacokinetics of posaconazole in neutropenic patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Curr Med Res Opin 2010;26(2):397–405. [18] Dolton MJ, Ray JE, Chen SC, Ng K, Pont L, McLachlan AJ. Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother 2012;56(11):5503–10. [19] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31–41. [20] De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46(12):1813–21.
179
[21] Cambier C, Lafaurie M, Ribaud P, Raffoux E, Andreoli A, Sauvageon H, et al [cambier.pdf. 2013] Abstract ESCMMID; 2013. [22] Sansone-Parsons A, Krishna G, Calzetta A, Wexler D, Kantesaria B, Rosenberg MA, et al. Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers. Antimicrob Agents Chemother 2006;50(5):1881–3. [23] Campoli P, Al Abdallah Q, Robitaille R, Solis NV, Fielhaber JA, Kristof AS, et al. Concentration of antifungal agents within host cell membranes: a new paradigm governing the efficacy of prophylaxis. Antimicrob Agents Chemother 2011;55(12):5732–9. [24] Vehreschild JJ, Müller C, Farowski F, Vehreschild MJ, Cornely OA, Fuhr U, et al. Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome. Eur J Clin Pharmacol 2012;68(6):987–95. [25] Vaes M, Hites M, Cotton F, Bourguignon AM, Csergo M, Rasson C, et al. Therapeutic drug monitoring of posaconazole in patients with acute myeloid leukemia or myelodysplastic syndrome. Antimicrob Agents Chemother 2012;56(12):6298–303. [26] Krishna G, Moton A, Ma L, Medlock MM, McLeod J. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother 2009;53(3):958–66. [27] Eiden C, Meniane JC, Peyriere H, Eymard-Duvernay S, Le Falher G, Ceballos P, et al. Therapeutic drug monitoring of posaconazole in hematology adults under posaconazole prophylaxis: influence of food intake. Eur J Clin Microbiol Infect Dis 2012;31(2):161–7. [28] Ananda-Rajah MR, Grigg A, Downey MT, Bajel A, Spelman T, Cheng A, et al. Comparative clinical effectiveness of prophylactic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period. Haematologica 2012;97(3): 459–63. [29] Courtney R, Radwanski E, Lim J, Laughlin M. Pharmacokinetics of posaconazole coadministered with antacid in fasting or nonfasting healthy men. Antimicrob Agents Chemother 2004;48(3):804–8. [30] Lipp HP. Posaconazole: clinical pharmacokinetics and drug interactions. Mycoses 2011;54(Suppl 1):32–8. [31] Cornely OA, Duarte RF, Haider S, Chandrasakar P, Helfgott D, Lopez J, et al. Abstract ECCMID; 2013. [32] Michallet M, Sobh M, Morisset S, Kraghel S, Nicolini FE, Thomas X, et al. Risk factors for invasive aspergillosis in acute myeloid leukemia patients prophylactically treated with posaconazole. Med Mycol 2011;49(7):681–7. [33] Egerer G, Geist MJ. Posaconazole prophylaxis in patients with acute myelogenous leukaemia–results from an observational study. Mycoses 2011;54(Suppl 1):7–11. [34] Vehreschild JJ, Ruping MJ, Wisplinghoff H, Farowski F, Steinbach A, Sims R, et al. Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia (AML): a 6-year experience of the Cologne AML cohort. J Antimicrob Chemother 2010;65(7):1466–71. [35] Pagano L, Caira M, Candoni A, Aversa F, Castagnola C, Caramatti C, et al. Evaluation of the practice of antifungal prophylaxis use in patients with newly diagnosed acute myeloid leukemia: results from the SEIFEM 2010-B registry. Clin Infect Dis 2012;55(11):1515–21. [36] Girmenia C, Frustaci AM, Gentile G, Minotti C, Cartoni C, Capria S, et al. Posaconazole prophylaxis during front-line chemotherapy of acute myeloid leukemia: a single-center, real-life experience. Haematologica 2012;97(4):560–7.
