Oral Communications

Hepatic Disposition Of [11C] Erlotinib at Methods:  Lung transplant patients receiving TAC and either PCZ-
Micro- and Therapeutic Doses Assessed tab or both galenic forms between June 2015 and March 2016 were
with Pet Imaging included. PCZ and TAC exposure were respectively assessed by the
M. Bauer1; A. Matsuda1; B. Wulkersdorfer1; C. Philippe1; measurement of plasma or blood Cmin.
L. Nics1; E.M. Klebermass1; J. Stanek2; W. Wadsak1,2; M. Hacker1; Results:  Eighteen patients (median age [Q1;Q3]= 48.5[34.7;57.4]
M. Zeitlinger1; and O. Langer1,3 years; 50% women) were included, among whom 8 received PCZ-
1
Medical University of Vienna, Vienna, Austria; 2Centre for tab only while others received both PCZ galenic forms. In patients
Biomarker Research in Medicine-CBmed GmbH, Graz, Austria; (n= 10) who received both PCZ galenic forms, PCZ Cmin were
and 3AIT Austrian Institute of Technology GmbH, Seibersdorf, higher for PCZ-tab compared to PCZ-susp (susp: 0.88±0.18 mg/L,
Austria n= 48 vs. tab: 1.9±0.44mg/L, n= 62; p< 0.0001). PCZ therapy initia-
Background:  The tyrosine kinase inhibitor erlotinib displays large tion led to a significant increase in TAC Cmin adjusted on dose (D)
inter-individual variability in plasma PK. Erlotinib undergoes hepa- (0.002±0.001L-1 before initiation vs. 0.008±0.007L-1 after initiation,
tobiliary clearance and is a substrate and/or inhibitor of different p= 0.02). TAC Cmin/D was significantly higher during PCZ-tab treat-
hepatic ABC and SLC transporters (P-gp, BCRP, OATPs). In this ment compared to PCZ-susp (0.004±0.004L-1 vs. 0.009±0.006L-1,
PET study we assessed hepatic disposition of 11C-erlotinib both at p< 0.0001). A weak correlation was observed between PCZ Cmin/D
micro- and therapeutic doses to investigate the involvement of carrier- and TAC Cmin/D for both PCZ galenic forms (PCZ-tab: r= 0.37,
mediated processes in the hepatic clearance of erlotinib. p= 0.0001 and PCZ-susp: r= 0.33, p= 0.02).
Methods:  Six healthy volunteers (mean age: 27 ± 6 years) under- Conclusions:  Increased PCZ-Cmin obtained during PCZ-tab treat-
went two consecutive abdominal [11C]erlotinib PET scans and arterial ment was associated with an increased TAC exposure, which could
blood sampling. The first scan was performed after administration of be explained by the higher bioavailability of PCZ with the PCZ-tab
a microdose of 11C-erlotinib (< 20 µg). In the second scan a microdose formulation and a subsequent enhanced enzymatic inhibition of TAC
of 11C-erlotinib was administered at 3 hours after oral treatment metabolism.
with a therapeutic erlotinib dose (300 mg). Radiolabelled metabolites
of 11C-erlotinib in plasma were assessed with a solid-phase extrac- Public Knowledge, Beliefs, and Behavior
tion protocol. PET and blood data were analysed with compartment Regarding the Use of Antibiotics in Serbia
modelling. O. Horvat; T. Halgato; A. Tomas; M. Paut-Kusturica; Z. Tomić ;
Results:  During the PET scans only a low amount (< 5%) of radiola- and A. Sabo
belled metabolites of [11C]erlotinib was detected in plasma both for University of Novi Sad, Medical Faculty, Novi Sad, Serbia
the micro- and therapeutic dose scans. As compared with the micro- Background:  A substantial evidence has shown that the general com-
dose scan, AUC values of concentration-time curves of 11C-erlotinib munity plays a role in the increase and spread of antibiotic resistance.
in plasma were significantly increased in the therapeutic dose scan Thus, the objective of this study was to determine the public knowl-
by 99 ± 27%, whereas AUC values in the liver and liver-to-plasma edge, beliefs, and behavior regarding the use of antibiotics in Serbia.
AUC ratios were decreased by 55 ± 5% and 77 ± 5%, respectively. Methods:  The survey was conducted on a random sample of 325
For the therapeutic dose a significant decrease (-39 ± 18%) in the adult subjects who consulted general practitioners (GP) at health
influx rate constant of 11C-erlotinib from blood into hepatocytes was centers. A self-administered questionnaire included questions on
found, whereas the efflux rate constant from hepatocytes into gall demographic characteristics, knowledge about antibiotics, beliefs
bladder and bile duct remained unchanged. and behaviours toward antibiotic use. The study was approved by
Conclusions:  Our data show that liver uptake of a microdose of the Ethical Committees of the Medical Faculty in Novi Sad and the
[11C]erlotinib occurred via a carrier-mediated process, which became Health Center Bačka Topola.Participants have signed an informed
inhibited at therapeutic erlotinib doses. Active uptake transport of consent.
erlotinib into the liver may account for variability in plasma PK Results:  A total of 253 adults participated. The average age was
and potentially play a role in transporter-mediated drug interactions. 50.56 ± 17.05 years, and 64.82% of the respondents were women.
The mean antibiotic knowledge score was 8.77±2.27. Respondents
Posaconazole Tablets Versus with with higher education, employed, with a family member work-
Posaconazole Oral Suspension in ing in the heath care sector were significantly more knowledgeable
Lung Transplant Patients: Which of antibiotics (p< 0.001). Overall, 47.83% of respondents believed
Consequences on Immunosuppressive that antibiotics could be used to treat common cold. 86.56% believed
Therapy? that frequent and inappropriate antibiotic use was dangerous Among
E. Gautier-Veyret1,2,3; S. Chanoine1,3; H. Pluchart1; J. Tonini3; X. the respondents, 31.62% stated that they used antibiotics without
Fonrose3; J. Claustre1,3; P. Bedouch1,3; and F. Stanke-Labesque1,2,3 previous physicians’ consultation (self-medication). Although 85%
1
Univ. Grenoble Alpes, HP2, F-38041 Grenoble, France; of respondents claimed that antibiotic treatment should be taken as
2
INSERM U1042, 38041 Grenoble, France; and 3Centre long as their GP prescribed (knowledge), only 61% followed this
Hospitalier Universitaire des Alpes, 38043, Grenoble, France advice during the last infection (behaviour).
Background:  Posaconazole (PCZ) is an antifungal agent widely used Conclusions: Respondents had a relatively adequate knowledge
for prophylaxis of invasive fungal infections in lung transplanta- about antibiotics (scoring 8.77 out of maximum 13). However, in
tion. The new formulation of PZC delayed-release tablets (PCZ- further rationalization of the use of antibiotics, effective public edu-
tab) improves PZC bioavailability and plasma trough concentrations cation initiative should provide practical and appropriative means
(Cmin) compared to oral suspension formulation (PCZ-susp). Since to change their behavior.
PZC is a well-known enzymatic inhibitor, we hypothesized that Acknowledgments:  This work was supported by the Ministry of
higher PZC exposure attributable to this new formulation could Science and Technological Development, Serbia (project No. 41012)
induce a greater drug-drug interaction with immunosuppressive and by the Provincial Secretariat for Higher Education and Scientific
therapies, especially with tacrolimus (TAC). Research of Vojvodina (project No.: 142-451-3680/2016-02).

August 2017 e3
 Clinical Therapeutics

The Pharmacodynamic Effects of Results:  Thirty-eight patients completed two to five treatment cycles
Rituximab at Very Low Doses (secondary RP, n= 12). Aggregated data demonstrates that the probabil-
C. Schoergenhofer1; C. Firbas1; U. Derhaschnig1; R.M. Mader1; ity that the efficacy of sildenafil 40 mg is superior to that of the placebo
R. Sunder-Plaßmann1; P. Jilma-Stohlawetz1; K. Desai2; P. Misra2; on the frequency of RP is 93%, and 90.6% for the RCS; and 91.5%
U. Jäger1; and B. Jilma1 and 62.6%, respectively, for sildenafil 80 mg. Sildenafil was associated
1
Medical University of Vienna, Austria; and 2Apotex Inc, Toronto, with significantly more adverse events than placebo. We observed a
Canada dose-dependent effect of sildenafil on skin blood flow during cooling.
Background:  No dose-finding trials are available for rituximab that Conclusions:  On demand sildenafil has a greater probability of effi-
could guide dosing in non-malignant diseases. We hypothesized that cacy than placebo in patients with RP. Individual data show highly
currently used doses (≥ 375mg/m2) exceed several hundred-fold the heterogeneous response, highlighting the need for personalized treat-
half-maximal effective dose, which is most sensitive for detecting ment for these patients.
putative differences between biosimilars and important for dose- ClinicalTrials.gov Identifier: NCT02050360
finding.
Methods:  In an exploratory, dose-finding, trial healthy volunteers
received single infusions of 0.1 (n= 4), 0.3 (n= 4) and 1 mg/m2 Reference
(n= 8) rituximab. Subsequently, in a randomized, double-blind trial, 1. Roustit M, Blaise S, Allanore Y, Carpentier PH, Caglayan E, Cracowski
healthy volunteers received single infusions of 0.1 (n= 24) or 0.3 mg/ J-L. Phosphodiesterase-5 inhibitors for the treatment of secondary
m2 (n= 12) of two rituximab products. CD19/20+ cell counts were Raynaud’s phenomenon: systematic review and meta-analysis of
measured, pharmacokinetics and, immunogenicity were assessed. randomised trials. Ann. Rheum. Dis. 2013;72:1696–1699.
Results:  Single infusions of 0.1, 0.3 and 1 mg/m2 rituximab tran-
siently depleted CD20+ cells by a mean 68% (95%CI: 24-100%), Do Electronic Prescribing Systems in
74% (95%CI: 59-84%) and 97% (95%CI: 95-99%), respectively. English Hospitals Support Antimicrobial
In the randomized trial infusion of 0.1mg/m2 or 0.3mg/m2 pro- Stewardship? an Analysis of ‘Start Smart–
posed biosimilar or reference rituximab decreased CD20+cells by Then Focus’ Functionality
45% (95%CI: 32-58%) - 55% (95%CI: 45-66%) and 81 (95%CI: I.K. Madar1; J.J. Coleman1; A. Slee2; and S.K. Pontefract1
1
73-87%) – 87% (95%CI: 74-100%), respectively. In the randomized University of Birmingham, Birmingham, United Kingdom; and
2
trial, 26 of 36 patients developed human anti-chimeric antibodies NHS England, London, United Kingdom
and 9 of 36 patients developed neutralizing anti-drug antibodies. Background:  Antimicrobial resistance is one of the greatest threats to
Pharmacokinetic analyses were limited by the assay sensitivity and global public health. The excessive and inappropriate use of antibiotics
the very low rituximab doses. However, there was a clear pharma- are significant contributors to the progression of resistance. This can be
cokinetic signal during the first 24 hours in the 1mg/m2 group. tackled through antimicrobial stewardship (AMS) initiatives. Electronic
Conclusions:  It is important to understand that < 1% of the author- prescribing (ePrescribing) systems have been shown to encourage appro-
ized rituximab doses depletes all circulating B lymphocytes in healthy priate antibiotic use. Despite a brief investigation into AMS capabilities
volunteers. This will help particularly countries struggling to meet by a self-assessment of digital maturity disseminated by NHS England in
the financial burden of therapy with biologics. 2015, the features of systems within English hospitals to support AMS
remains poorly understood. The main aim of this research was to further
On Demand Sildenafil as a Treatment of investigate how ePrescribing systems in English hospitals support AMS.
Raynaud’s Phenomenon: A Series of N-of-1 Methods:  An online self-reported questionnaire was developed to
Trials assess the capability of hospital ePrescribing systems to prompt
M. Roustit1,2,3; J. Giai4,5,6; O. Gaget3; M. Mouhib3; A. Lotito3; adherence to UK ‘Start Smart – Then Focus’ AMS. The question-
C. Khouri3; S. Blaise2,3; C. Seinturier3; F. Subtil4,5,6; B. Imbert3; naire was emailed to ePrescribing pharmacists from 34 acute English
P.H. Carpentier1,3; S. Vohra7; and J.L. Cracowski1,2,3 NHS Trusts, purposefully sampled based on their self-reported digi-
1
Univ. Grenoble-Alpes, F-38000 Grenoble, France; 2Inserm, HP2 tal maturity. The data were analysed according to the percentage
UMR 1042, F-38000 Grenoble, France; 3CHU Grenoble-Alpes, of Trusts demonstrating each element of ‘Start Smart–Then Focus’.
F-38000 Grenoble, France; 4Université de Lyon, F-69000, Lyon, Results:  Responses were received from 76.5% (n= 26/34) of hospi-
France; 5CNRS, UMR5558, F-69622, Villeurbanne, France; tals surveyed. No systems could demonstrate all elements of ‘Start
6
Hospices Civils de Lyon, F-69003, Lyon, France; and 7University Smart–Then Focus’. Systems had more capability to promote docu-
of Alberta, Edmonton, Alberta, Canada mentation of initial antibiotic therapy as part of ‘Start Smart’, with
Background:  Continuous treatment of Raynaud’s phenomenon (RP) the nature of allergy being the most common capability exhibited
with phosphodiesterase-5 inhibitors has shown moderate efficacy (1). (96.2%, n= 25/26). One system prompted prescribers to change to a
Moreover, patients with RP may not be willing to take a long-term narrower spectrum antibiotic as part of ‘Then Focus’, but no system
treatment; as RP attacks are usually triggered by exposure to cold, encouraged discontinuation of treatment if there was no evidence of
“as required” single doses before/during exposure may be a good a bacterial infection based on cultures and sensitivities.
alternative. The objective of the present study is to assess the efficacy Conclusions:  The ePrescribing systems investigated did not support
and safety of an on demand sildenafil treatment in RP. AMS fully according to ‘Start Smart –Then Focus’. However, systems
Methods:  A series of randomized, double-blind, N-of-1 trials was were more capable of promoting appropriate prescribing at initiation
conducted in patients with primary or secondary RP. Each trial con- compared to rationalising antibiotic therapy upon review.
sisted in repeated cycles of 1-week treatment periods with placebo,
sildenafil 40 mg or sildenafil 80 mg taken as required, with a maxi- Five-Year Antimicrobial Susceptibility
mum of two doses daily. Mixed models were used and parameters Trends Among Bacterial Isolates from
were estimated in a Bayesian framework to determine individual and King Faisal Hospital Tertiary Health-Care
aggregated probabilities of efficacy on the Raynaud’s Condition Score Facility in Kigali, Rwanda
(RCS) and the frequency of RP attacks. Skin blood flow in response M. Carroll1; A. Rangaiahagari2,3; E. Musabeyezu3; D.R.J. Singer4;
to cooling was assessed with laser speckle contrast imaging. and O. Ogbuagu5

e4 Volume 39 Number 8S