Download Physico-chemical compatibility of Palonosetron HCl, Fosaprepitant

Physico-chemical compatibility of Palonosetron HCl, Fosaprepitant dimeglumine and
Dexamethasone-21-dihydrogene-phospahte IV admixtures over at least 24 hours
Hans-Peter Lipp, Wieland Gfrörer, Nicole Herbst
Department of Hospital Pharmacy, Eberhard Karl‘s University, 72076 Tübingen, Germany
Introduction
According to currently available MASCC, ESMO and ASCO guidelines (Table 1), a combination consisting of a 5HT3
receptor antagonist, a neurokinin receptor antagonist and the glucocorticoid dexamethasone has been classified
to be state of the art in patients receiving highly as well as moderately emetogenic chemotherapy (CTX) with
underlying risk factors [1]. Compared to other available 5HT3 receptor antagonists, Palonosetron HCl represents
the most potent agent with the longest elimination half-life and additional pharmacological effects. Recently,
Fosaprepitant 150 mg (as dimeglumine) once (day 1) has been introduced to alleviate supportive cancer care,
because it may substitute conventional oral regimens with Aprepitant day 1 to 3 in the near future based on
comparable efficacy and tolerability [2, 3]. In everyday clinical practice, an ad-hoc admixture of antiemetic drugs
in the same IV infusion solution (e.g. NaCl 0.9 % 50 mL) is often highly preferred to accelerate the management
of ambulatory procedures. However, physicochemical stability data are needed before to avoid unexpected drug
loss or even precipitation (Table 2) [4].
Materials and Methods
0.25 mg Palonosetron HCl, 150 mg Fosaprepitant (as dimeglumine) and 12 mg Dexamethasone-21-dihydrogenephosphate were admixed in NaCl 0.9 % 50 mL. Drug levels of the parent compounds over time were analyzed by
HPLC immediately after admixture (t0h), 2 hours (t2h), 4 hours (t4h), 6 hours (t6h) and 24 hours (t24h) later. The
solution was stored at room temperature. Mean values were determined by three measurements per time point.
Based on the elution time of Fosaprepitant, which is distinctly longer than the elution time of Palonosetron HCl
and Dexamethasone-21-dihydrogene-phosphate, the neurokinin antagonist was detected in a separate course
(Graph 1 and 2). A RP8-column (150x 4 mm; 5 µm) by Restek was used to measure the components. For the
MASCC and ESMO guidelines
emetogenic potency
Pharmacological and physico-chemical data
antiemetic regimen 30 minutes before
CTX (day 1)
CTX (examples)
Cisplatin
highly emetogenic
(>90 %)
5HT3-antagonist IV
Dacarbazine
+ Fosaprepitant / Aprepitant
Cyclophosphamide (≥1500 mg/m2)
+ Dexamethasone 12 mg IV
Anthracycline / Cyclophosphamide
5HT3-antagonist IV
+ Fosaprepitant / Aprepitant
moderately emetogenic
(30-90 %)
Low
(<30 %)
detection of Fosaprepitant an admixture of acetonitrile (ACN) and phosphoric acid 0.1 % (9:11) served as mobile
phase. The temperature of the column was adjusted to 20°C. 20 µL of the solution were injected. The flow rate
was 1 mL/min. UV-detection was performed at 215 nm. To detect Palonosetron HCl and Dexamethason-21dihydrogen-phosphate 40 µL solution were injected. The mobile phase consisting of ACN and phosphoric acid
0.1% (1:3) was pumped with a flow rate of 1 mL/min. The temperature of the column was 20 °C. The UVdetection was performed at 250 nm.
+ Dexamethasone 8 mg IV
Non-AC
(e.g. Ifosfamide, Irinotecan,
Carboplatin, Bendamustine)
Palonosetron 0.25 mg IV
Taxane (monotherapy)
Dexamethasone 8 mg
+ Dexamethasone 8 mg
trade name
INN
(examples)
Aloxi®
Navoban®
Kevatril®
Zofran®
Anzemet®
5HT3-receptorbinding-affinity
Palonosetron-HCl
Tropisetron-HCl
Granisetron-HCl
Ondansetron-HCl
Dolasetron-mesylate
Ivemend® Fosaprepitant-Dimeglumine
Fortecortin® Dexamethasone-21-dihydrogene-phosphate
elimination
half life [h]
pH stability
(pKi)
10.06
8.79
8.91
8.19
7.70
37
ca. 7
9
4
7.5
4.5-5.5
4.6-5.2
4-6
3.3-4
3.2-3.8
-
9-13
3-5
ca. 6-9
ca. 7-10.5
Table 2 : comparative 5HT3-receptor binding affinity, elimination half life and pH stability (mod. from [2, 4])
+ NK1-antagonist on demand
Gemcitabine
(or 5HT3-antagonist IV )
Table 1: Current recommendations according to MASCC (mod. from [1])
HPLC graphs
Palonosetron HCl
Results – mean concentration of the compounds
time after
mixing
[h]
0
2
4
6
24
Palonosetron HCl
[µg/ml]
4.007
3.987
3.988
3.954
3.968
[%]
100.9
100.4
100.5
99.6
100 .0
Dexamethasone-21dihydrogene-phosphate
[%]
100.0
100.4
99.6
98.7
98.9
Fosaprepitant
(as dimeglumine)
[µg/ml]
[%]
2.418
101.5
2.427
101.9
2.389
100.3
2.421
101.7
2.448
102.8
Aprepitant
[%]
0.25
0.32
0.38
0.45
0.90
Dexamethasone-21-dihydrogene-phospahte
Table 3: physico-chemical compatibility and stability of Palonosetron-HCl (5 mL), Dexamethasone-21-dihydrogene-phosphate (3 mL) and Fosaprepitant (5 ml as
dimeglumine) added to NaCl 0.9 % 50 mL up to 24 hours Palonosetron HCl 250 µg (ALOXI®), Dexamethasone-21-dihydrogene-phosphate 12 mg (corresponding
disodium salt: FORTECORTIN® 8 mg and 4 mg), Fosaprepitant 150 mg (corresponding dimeglumine: IVEMEND® 150 mg); Aprepitant, slowly released from
Fosaprepitant by hydrolysis
Palonosetron HCl
a)
Dexamethasone-21Dihydrogene-phosphate
c)
Palonosetron HCl
increase /24 h: 105%
increase /24h : 142%
b)
Graph 1: a) straight calibration line of Palonosetron HCl; b) chromatogram of Palonosetron HCl and Dexamethasone-21-dihydrogen-phosphate (t0h); c) detailed
chromatogram of Palonosetron HCl and Dexamethasone-21-dihydrogen-phosphate (t24h)
Fosaprepitant (as dimeglumine)
Graph 3 : stability of Palonosetron HCl in the tested solution (mean values)
Fosaprepitant (as dimeglumine)
a)
Aprepitant
Fosaprepitant (as dimeglumine)
c)
Aprepitant
increase /24h: 293%
b)
Graph 2: a) straight calibration line of Fosaprepitant (as dimeglumine); b) chromatogram of Fosaprepitant (as dimeglumine) (t0h); c) detailed
chromatogram of Fosaprepitant (as dimeglumine) (t24h)
Graph 4: stability of Fosaprepitant (as dimeglumine) in the tested solution (mean values)
Conclusion
A three-in-one IV admixture of 0.25mg Palonosetron HCl, 150mg Fosaprepitant (as dimeglumine) and 12 mg Dexamethasone-21-dihydrogene-phosphate is physicochemically stable in NaCl 0.9 % 50mL for at least 24 hours at RT (Table 3; Graph 3 and 4). Currently, this ad-hoc mixture, which is administered 30 minutes before
CTX, is successfully implemented in our gynecological unit to alleviate everyday clinical antiemetic practice.
References
[1] Roya, F. / Herrstedt J. / Aapro, M. et al.: „Guideline update for MASCC and ESMO in the prevention of chemotherapy- and
radiotherapy-induced nausea and vomiting / results of Perugia consensus conference“, Ann Oncol 2010; 21 (Suppl. 5): 232-43.
[2] Feyer, P. / Jordan, K.: „Update and new trends in antiemetic therapy: the continuing need for novel therapies“, Ann Oncol 2011;
22: 30-8.
[3] Rojas. C. / Li ,Y. / Zhang, J. et al.: „The antiemetic 5HT3 receptor antagonist Palonosetron inhibits substance P-mediated
responses in vitro and in vivo“, J Pharmacol Exp Ther 2010; 335: 362-8.
[4] Trissel, L. A.: „Handbook on injectable drugs“, Bethesda Maryland; 16th edition 2010.