European Journal of Radiology. 13 (1991) 126-133 0 1991 Elsevier Science Publishers B.V. All rights reserved. 0720-048X/91/$03.50
126
EURRAD
00188
Preliminary European intravenous clinical experience with a new, low osmolar, nonionic contrast medium: ioversol (OptirayR) M.M. Le Mignon, C. Azau, A. Arthaud
and B. Bonnemain
Research and Development DivisionLaboratoire Guerbet Aulnay sous Bob, France (Received 24 January
Key words: Contrast
1991; accepted
after revision 5 April 1991)
medium, clinical trial; Contrast
medium, comparative
study
Abstract The intravenous clinical trial program of ioversol (OptirayR), a low osmolar, nonionic, monomeric contrast agent characterized by high hydrophilicity, is evaluated on the basis of results from the first clinical trials conducted in Europe as part of the development of the 300 and 350 mgI/ml formulations: 7 double-blind, comparative trials and 5 single trials were performed in a total of 743 patients, ofwhom 472 received ioversol and 271 a monomeric nonionic reference product. The diagnostic effkacy of ioversol was equivalent or superior to that of the reference products and tolerance was comparable to that of nonionic agents in terms of pain and heat sensations. No significant difference in adverse reactions was found and all the contrast agents studied were well tolerated by the patients.
Introduction Ioversol (OptirayR, Mallinckrodt Inc., St Louis, U.S.A.; Laboratoire Guerbet, Villepinte, France) is a new nonionic triiodinated, low osmolar contrast medium (LOCM) for urographic and angiographic applications (Fig. 1). The osmolality and viscosity of ioversol 300 and 350 are comparable or slightly lower than those of the nonionic monomers in clinical use (Table 1). Ioversol is the most hydrophilic of these
i
6
iOH Fig. 1. Chemical structure of ioversol. Chemical name: N,N’bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamidol]-2,4,6triiodoisophthalamide. Molecular weight: 807.13.
Address for reprints: Marie-Madeleine Le Mignon, BSc. Research and Development Division Laboratoire Guerbet, B.P. 15, 93601 Aulnay sous Bois Cedex, France
compounds [l] (Table 2). This valuable advantage of contrast media which supposedly minimizes their interactions with the lipid layers of biological and particularly neuronal, membranes [2,3], so far has been reflected by the lower neurotoxicity of ioversol after intracisternal injection in animals [4]. Ioversol has already been evaluated in a number of preclinical studies [ 5-81, demonstrating its good tolerability. Human pharmacokinetics of ioversol [9] have shown that it presumably behaves in the same way as other nonionic urographic and angiographic contrast media [ 10,111. Findings from phase II and III clinical trials performed on ioversol concentrations of 160, 240 and 320 mgI/ml to evaluate the safety of the compound were published [ 121, indicating that ioversol was better tolerated than conventional contrast media in terms of side effects, pain and heat sensations, and hemodynamic and cardiac reactions. All the agents showed equivalent safety in terms of laboratory values and the overall tolerability of ioversol was statistically comparable to that of other nonionic reference monomers. The aim of this publication is to summarize findings from the first clinical trials performed on ioversol by the intravenous route as part of the European development of this agent, using the 300 and 350 mgI/ml formu-
127 TABLE 1 Osmolality Contrast
and viscosity of ioversol (OptirayR), compared Concentration
agent
Iopamidol ( IopamironR) Iopromide (UltravistK) Ioversol (OptirayR) Iohexol (OmnipaqueR) Ioversol (OptirayR) Iopamidol ( IopamironR) Iohexol (OmnipaqueR) Iopromide (UltravistR) a Tonometer
with low osmolality urographic
(mgI/ml)
370 370 350 350 300 300 300 300
Comparative hydrophilicity of ioversol, iohexol, iopamidol, iopromide and metrizamide as determined by the octanol/water partition coefficient (Log P) (Bonnemain B, Meyer D [I])
lovers01 Iohexol Iopamidol Iopromide Metrizamide
contrast
agents ~__
Osmolality (mosm/kg)
Viscosity at 37 “C (mPa/s or cp)
870” 790” 790 850” 630 630” 680” 600”
9.4 9.5 8.0 10.6 5.0 4.7 6.1 4.6
Wescor 5500 at 37 “C.
TABLE 2
Contrast agent
and angiographic
Octanol/water
partition
coefficient
(Log P) pH = 7.4, 37 “C -
2.98 2.71 2.42 2.05 1.41
lations. These studies were designed formances of ioversol in the proposed pare its efficacy to that of reference used in Europe and verify the overall compound.
increasing hydrophilicity I
to check the perindications, comnonionic LOCM tolerability of the
Materials and Methods Organization Twelve studies including 7 randomized, doubleblind, comparative studies on parallel groups and 5 single trials were conducted from May lo,1988 to March 14,1989 in France, Belgium, Switzerland and the F.R.G. in various private or university hospital centers (Table 3). Each protocol was reviewed and approved by the U.S. Food and Drug Administration and by the relevant Ethics Committees. Written informed consent was obtained from all the patients. Population studied Of 743 adult patients who entered the trials, 472 received ioversol(242 were given ioversol 300 and 230 ioversol 350) and 271 were administered a reference nonionic LOCM. Patients presenting one of the usual
contraindications to the injection of contrast material were excluded from the trials. To prevent any biased evaluation of ioversol, patients who had undergone a radiological procedure 24 h or less before entering the trial (or 48 h in the case of cholecysto- or cholangiography) were also excluded. Subjects with a positive history of allergy or with a previous history of adverse reactions to intravascular radiodiagnostic compounds were included in the trial after receiving appropriate premeditation, histamine H, and/or HZ-receptor blockers or AINS. Proper hydration of diabetic patients upon injection of the contrast agent and for 24 h after the procedure was carefully checked. Attribution of contrast media Each patient entered the trial in chronological order. Contrast agents used in the comparative trials were administered according to a previously established randomization chart. The patients received the agents at the doses and under the injection conditions specific of each indication and usually applied in the routine clinical practice. These conditions remained unchanged throughout the trials. Contrast agents used were ioversol at 300 and 350 mgI/ml (OptirayR 300 and 350), iopamidol at 300 and 370 mgI/ml (IopamironR 300 and 370), iohexol at 300 and 350 mgI/ml (OmnipaqueR 300 and 350) and iopromide at 370 mgI/ml (UltravistR 370). Evaluation criteria (a) Efficacy. Efficacy was evaluated in most cases on the basis of (1) the quality of images or films, i.e., opacitication scores appreciated blindly using a visual analog rating scale (VARS) and expressed in figures from 0 to 100, (2) the diagnostic quality of images or films, results being expressed as a percentage of diagnostic procedures, and (3) the degree of diagnostic certainty (also on a VARS ).
128 TABLE 3 Summary of population
data and doses studied in the different clinical trials
Procedure
Intravenous
Investigator
urography
Test solutions
A. Pinet (F)
Whole-body
CT
Mean height
Mean dose
(kg)
(cm)
ml
mgI/kg
gI
49.6 58.1 47.8 46.6 46.2 50.7 51.7
70.5 70.1 69.6 65.8 66.3 65.9 67.8
168.3 167.2 167.5 167.3 167.4 168.1 168.1
80 86 84 65 60 71 79
353 383 358 353 347 382 443
24 26 25 23 22 25” 29
Ioversol Iohexol Ioversol Iopamidol
300 300 350 370
41 39 40 40
56.8 57.7 53.3 54.7
12.6 72.6 68.5 70.4
170.0 171.2 167.1 168.0
111 182 154 168
144 760 800” 906
53 55 54” 62
Y. Palmers (B) J. Theron (F)
Ioversol Ioversol
300 350
40 40
43.0 52.5
67.4 67.0
168.9 166.8
67 66
300 347
20 23
N. Vasile (F)
lovers01 Iohexol Ioversol
300 300 350
41 42 40
55.7 55.4 56.8
70.9 65.9 66.6
170.4 168.1 166.7
99.5 96.7 100.0
437 459 546
30 29 35
Ioversol Ioversol Iopamidol
300 350 370
40 30 30
57.8 64.8 56.9”
68.6 69.3 72.1
162.7 164.4 165.5
153 200 197
684 1067 1062
46 70 73
F.J. Roth (FRG) (F)
J. Boverie (F) Venography
Mean weight
40 40 40 40 40 40 40
J. Drouillard
Head CT
age (years)
300 300 300 350 370 350 370
B. Ody (CH)
angiography
Mean age
Ioversol Iopamidol Ioversol Ioversol Iopamidol Ioversol Iopromide
M. Elke (CH) A Pinet (F)
IV digital subtraction
No. of cases
JB. Carey (F) P. Rouleau (F)
a Significant difference (P < 0.05). b Significant difference (P < 0.01).
In Roth’s study, the quality of the films was rated as excellent, good, acceptable, poor, and no evaluation of the degree of diagnostic certainty was made. The efficacy of the contrast solutions was evaluated by the same investigator throughout the trial. In intravenous urography, the evaluation was consistently made on the basis of the first injection, i.e., 60 ml for clinical trials on ioversol300 and 50 ml on ioversol350.
Statistical analysis
Results were analyzed individually for each study. Quantitative data were averaged and compared between two groups using Student’s t-test or Wilcoxon’s test. Data expressed as proportion or percentage were compared between two groups using Fisher’s exact test. Results
(b) Tolerance
Population
All objective and subjective adverse reactions observed by the investigator and reported by the patient spontaneously or after questioning were recorded in the case reports forms. Patients were observed for one hour after the injection of contrast medium. Tolerance data were interpreted based (1) on the number of patients presenting one or several adverse reactions attributed to the drug, apart from heat and pain sensations, (2) the number of patients who required treatment and (3) the mean scores for pain and heat sensations experienced by the total population.
Demographic data (Table 3) were consistently comparable between the two study groups, apart from mean age in the phlebographic study. Furthermore, the number of male and female patients, subjects with a history of allergy or of previous untoward reaction to iodinated contrast media, or diabetic subjects was always comparable among the study groups. Intravenous urography
Results are summarized in Table 4. The degree of diagnostic certainty found with ioversol 300 was statis-
129 TABLE 4 Intravenous
urography
Test solutions
data Diagnostic
Safety
efficacy
Mean opacification (0 to 100)
scorea
Y0 diagnostic procedures
Mean degree of certainty (0 to 100)
Mean intensity of pain: (0 to 100)
Mean intensity of heat: (0 to 100)
100
84
0.0
12.8
Ioversol 300 (n = 40) Iopamidol 300 (n = 40)
49, 76, 76, 65, 62 45, 71, 71, 59, 57
95
81
0.P
13.8
Ioversol 350 (n = 40) Iopamidol 370 (n = 40)
53, II, 16, 67, 67
100
91
0.0
24.6
54, 75, 77, 70, IO
100
91
0.0
24.8
Ioversol 350 (n = 40) Iopromide 370 (n = 40)
63, 72, 74, 67, 75
100
80
0.5’
I.0
64, 68, 11, 65, 13
100
77
0.0
7.3
Ioversol 300 (n = 40)
95, 94, 97, 95, 100
100
96
0.0
13.6
* a b ’
*
Significant difference: P < 0.05. Opacitication scores at each level are indicated in the following order: parenchyma, Only one patient reported a pain sensation graded 20 on the VARS. Only one patient reported a pain sensation graded 22 on the VARS.
tically higher than with iopamidoi 300 (p < 0.05). This could be related to slightly better opacification scores with ioversol300 though the difference in this parameter between ioversol300 and iopamidol300 was not statistically significant. The efficacy of ioversol 350 was found to be equivalent to that of iopamidol 370 and iopromide 370 despite comparable injection volumes (Table 3). Pain and heat sensations were minor in most cases. Intravenous digital subtraction angiography
Results are summarized in Table 5. For comparable injection volumes, image quality proved significantly better with ioversol 300 than with iohexol 300 (P < 0.05). This difference cannot be explained by patient motion since the incidence of motion was comparable in both groups (10%). Despite a significantly lower amount of iodine injected, ioversol350 showed a comparable efficacy to iopamidol 370. Mean heat and pain sensations were null or low. CT Scanning
Results for cranial CT summarized in Table 6 show that ioversol 300 and 350 injected in 1.0 ml/kg doses
calyces, renal pelvis, ureter, bladder.
always allowed to make a diagnosis with a satisfactory degree of certainty in both studies. Results for whole body CT scanning summarized in Table 7 demonstrate comparable efficacy of the agents under study. Mean heat sensations were consistently low and no pain was reported. Venography
Venographic data summarized in Table 8 show comparable efficacy of ioversol 350 and iopamidol 370, despite the slightly higher iodine concentration of the latter agent and equivalent injection volumes. Heat sensations were comparable with both contrast agents. There were slightly less pain sensations with ioversol350 than with iopamidol370, but the difference was not significant. Adverse reactions Of 472 patients
given ioversol, 11 y0 presented adverse reactions attributable to the contrast agent. When considering only the comparative trials, 11% of the population had adverse reactions with ioversol and 10% with the other nonionic reference products. No statistically significant difference was found between
130 TABLE 5 IV digital subtraction
angiography
data
a
Diagnositc
Test solutions
Ioversol 300 (n = 41) Iohexol 300 (n = 39)
efficacy
Safety
Image quality good or excellent (% cases)
% diagnostic procedures
Mean score for pain: (0, 1, 2 or 3)
Mean score for heat: (0, 1, 2 or 3)
16 51 *
98 100
0.0 0.0
1.3 1.4
* Significant difference: P < 0.05. b
Diagnostic
Test solutions
Ioversol 350 (n = 40) Iopamidol 370 (n = 40)
efficacy
Safety
Mean opacilication score (0 to 100)
% diagnostic procedures
Mean degree of certainty (0 to 100)
Mean intensity of pain: (0 to 100)
Mean intensity of heat: (0 to 100)
14 16
95 95
19 80
0.0 0.0
0.0 7.2
TABLE 6 Cranial computed
tomography
data Diagnostic
Test solutions
Safety
efficacy
Mean opacification score (0 to 100)
y0 diagnostic procedures
Mean degree of certainty (0 to 100)
Mean intensity of pain: (0 to 100)
Mean intensity of heat: (0 to 100)
Ioversol 300 (n = 40)
86
100
95
0.0
17.7
Iopamidol
59
100
91
0.0
15.2
350 (n = 40)
TABLE I Whole-body
computed
tomography
data
Diagnostic
Test solutions
efficacy
Safety
Mean opacification score (0 to 100)
% diagnostic procedures
Mean degree of certainty (0 to 100)
Mean intensity of pain: (0 to 100)
Mean intensity of heat: (0 to 100)
Ioversol 300 (n = 41) Iohexol 300 (n = 42)
II 82
100 100
91 99
0.0 0.0
0.5 0.0
Ioversol 350 (n = 40)
95
95
0.0
2.0
a Diagnosis
was impossible
98”
for one patient for reasons unrelated
the contrast media. The dverall incidence of adverse reactions in those comparative studies, according to the nature of the effects, was as follows:
to the agent.
- cardiovascular: 0.4% - nervous (paresthesia, muscle spasm): 3.7%
dizziness,
cranial
pressure,
131 TABLE 8 Venography
data
Test solutions
Diagnositic
Safety
efficacy
Mean opacitication (0 to 100)
score”
% diagnostic procedures
Mean degree of certainty (0 to 100)
Mean intensity of pain: (0 to 100)
Mean intensity of heat: (0 to 100) 40.9 43.6
Ioversol 350 (n = 30) Iopamidol 370 (n = 30)
92 (92, 90, 90) 91 (93, 90, 87)
100 100
95 95
5.0b 11.2’
Ioversol 300 (n = 40)
78 (83, 82, 77, 60)
100
94
0.0
a Opacitication and caval for ’ Two patients ’ Five patients
1.7
scores at each level are indicated in the following order: tibial, femoral, iliac and caval for the ioversol 350 study, and iliac the ioversol 300 study. reported a pain sensation. reported a pain sensation.
digestive (nausea, vomiting): 1.7% allergic-like (erythema, urticaria, pruritus): 2.7% respiratory (cough, chest oppression): 0.4% miscellaneous (bad taste, general pain, urge to void, dry mouth): 2.4% The overall incidence of reactions requiring treatment was 1.3 %. This incidence was comparable for the two groups. Discussion These 12 clinical trials represent the first European experience in the use of ioversol 300 and 350 by the intravenous route. The principal aim of this review was to try to situate ioversol in the range of the most recent contrast agents of the same chemical class via the comparison of their respective efficacy and tolerability. As regards adverse reactions, except heat and pain, only comparative data on a very large number of subjects obtained through consolidation of many studies can now allow to conclude as to whether the new contrast agents are comparable or not. The data relating to the adverse reactions reported here should therefore be considered only as indicative. Discomfort criteria, such as pain and heat, which are the most commonly experienced sensations, which depend on the radiological indication and for which comparisons of the incidence and intensity can be made on small series, have been considered separately and for each indication. Efficacy
Whatever the radiological applications in which it was studied, ioversol was found to be a suitable contrast agent as it permitted to make a diagnosis in all the examinations except in 4 cases, thus yielding a 99% success rate. Ioversol 350 proved equivalent to the re-
ference product at 370 mgI/ml despite comparable injection volumes in urography and venography and statistically lower iodine doses of ioversol 350 in intravenous digital subtraction angiography. Ioversol 300 was shown to be slightly superior to iohexol or iopamidol 300 in intravenous urography (mean degree of certainty) and in intravenous digital subtraction angiography (image quality). At this point pharmacokinetic data available cannot provide a satisfactory and accurate explanation for this difference which must be further confirmed on other series. In contrast, one or several physicochemical characteristics of the product could come into play: higher hydrophilicity, slightly lower viscosity at 350 mgI/ml compared with other nonionic monomers at 350 or 370 mgI/ml and slightly lower osmolality than that of iohexol. In intravenous urography, due to the low osmotic potential of ioversol, it is possible like with other LOCM to obtain high urinary iodine concentrations as a result of low osmotic diuresis [ 13,141. This leads to high contrast enhancement in the excretory cavities. Due to its low viscosity, ioversol can be injected rapidly thus allowing to obtain good peak plasma concentrations. Further, it can be assumed that high hydrophilicity yields high ‘freely filtrable’ plasma concentrations as a result of low protein binding, thus allowing easy passage through glomerular filter. Therefore, both nephrograms and pyelograms should be satisfactory. In intravenous digital subtraction angiography, if we assume that the better image quality provided by ioversol 300 compared with the same dose of iohexol 300 is related to higher peak plasma iodine concentrations with ioversol300, an explanation could be smaller changes in cardiac output with ioversol than with iohexol, as suggested by Burbank [ 15,161. The theoretical factor to account for the difference in efficacy could
132
be the variations in cardiac output resulting from a different effect on cardiac function and/or from a slightly smaller increase in blood volume with ioversol due to its slightly lower osmolality. In the ioversol 350 versus iopamidol 370 trial, the smaller changes in cardiac output induced by ioversol could in this case too, make up for the smaller amount of iodine injected. This is only hypothetic since these parameters were not monitored during the trials discussed here. In CT studies, with ioversol like with the other LOCM, peak plasma iodine concentrations observed immediately after bolus injection of contrast material should be higher than those produced by HOCM. This should also be true for renal cortical enhancement [ 171 as a result of the lesser osmotic diuresis. The low viscosity of ioversol should allow to deliver contrast injections rapidly. This might be helpful when diagnosis is based on the visualization of vascular structures. When diagnosis is based on enhancement of interstitial spaces, the high hydrophilicity of media should favour for a good diffusibility. In venography, like for the other radiological indications, the quality of information provided by ioversol 350 proved identical to that obtained with the same volume of iopamidol 370. Tolerance
No significant difference was found between ioversol and the other nonionic low osmolality contrast media as to adverse reactions other than pain and heat, which in most cases were minor (no treatment required), and sometimes moderate. Incidences reported here for ioversol and the other nonionic agents, i.e., 11 y0 and 10 % respectively, are comparable to those published by Andrew [30] for iohexol after intravenous injection in 772 patients (8%). However, as underscored by this author, it is rather difficult to draw any comparison between the various publications since the methods used for collecting data on adverse reactions differ from one another (in this connection it should be pointed out that the incidence of subjective reactions classed as ‘nervous’ or ‘miscellaneous’, which alone account for more than half the effects reported as a consequence of a very detailed reporting method, is high). These findings provide additional information to that already published on ioversol in 1186 patients [ 121, which demonstrated (1) the lower incidence of adverse reactions, particularly those related to osmolality, with ioversol than with HOCM, and (2) equivalent overall tolerability compared with the other nonionic monomers. Heat and pain sensations were on the whole of minor or moderate intensity as expected for LOCM. When
large volumes were injected (i.e., intravenous digital subtraction angiography and venography) they seemed slightly, though not significantly lower with ioversol. These parameters might be worth monitoring in other studies. These characteristics of ioversol make it well suited for intravenous investigations in patients requiring the use of a low osmolality contrast medium, i.e., high-risk patients, especially those with cardiac failure, and all subjects who poorly tolerate an increase in blood volume. Patients with renal or hepatic failure, those who recently suffered a cerebrovascular accident or presenting damage of the blood-brain barrier are also often considered as high-risk patients. Patients with a positive history of allergy or of previous untoward reactions to radiological contrast media usually are also included in this category. However, the risk of allergic-like reactions does exist and is greater in patients with a history of allergy, regardless of the product used [ 19,201. Therefore, extra caution should be exercized in carrying out radiological procedures with contrast media in this type of patients. From these clinical findings, it appears that ioversol (OptirayR) is a well suited contrast medium for i.v. radiographic procedures.
References 1 Bonnemain B, Meyer D, Schaefer M, Dugast-Zrihen M, Legreneur S, Doucet D. New iodinated, low-osmolar contrast media: a revised concept of hydrophilicity. Invest Radio1 1990; 25 (suppl 1): S104-S106. 2 Speck U, Miitzel W, Weinmann HJ. Chemistry, physicochemistry and pharmacology of known and new contrast media for angiography, urography and CT enhancement. In: Taenzer V, Zeitler E, eds. Contrast media in urography, angiography and computerized tomography. Georg Thieme Verlag, 1983; 2-10. 3 Rapoport SI, Levitan H. Neurotoxicity of x-ray contrast media. Relation to lipid solubility and blood-brain barrier permeability. AJR 1974; 122: 186-193. 4 Ralston WH, Robbins MS, Coveney J, Blair M. Acute and subacute toxicity studies of ioversol in experimental animals. Invest Radio1 1989; 24(suppl 1): S2S9. 5 Ralston WH, Robbins MS, Coveney JR. Hemodynamic effects of ioversol in the dog and rat. Invest Radio1 1989; 24(suppl 1): SlOS15. 6 Ralston WH, Robbins MS, James P. Reproductive, developmental and genetic toxicology of ioversol. Invest Radio1 1989; 24(suppl 1): S16-S22. 7 Coveney JR, Robbins MS. Biodistribution and excretion of iz51 ioversol in conscious dogs. Invest Radio1 1989; 24 (suppl 1): S23-S27. 8 Piao ZE, Murdock DK, Hwang MH, Raymond RM, Scanion PJ. Hemodynamic effects of contrast media during coronary angiography: a comparison of three nonionic agents to hypaque-76. Cathet Cardiovasc Diagn 1988; 14: 53-58. 9 Wilkins RA, Whittington JR, Brigden GS, Lahiri A, Heber ME,
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Hughes LO. Safety and pharmacokinetics of ioversol in healthy volunteers. Invest Radio1 1989; 24: 781-788. McKinstry DN, Rommel AJ, Sugerman AA. Pharmacokinetic, metabolism and excretion of iopamidol in healthy subjects. Invest Radio1 1984; 19 (suppl 5): Sl71-S174. Olsson B, Aulie A, Sveen K, Andrew E. Human pharmacokinetics of iohexol: a new nonionic contrast medium. Invest Radio1 1983; 18: 177-182. Benamor M, Aten EM, McElvany KD, Lankin DG, James MA, Buy-Gandal T, Harashe LT, Weinandt WJ. Ioversol clinical safety summary. Invest Radio1 1989; 24 (suppl 1): S67-S72. Spataro RF. New and old contrast agents: pharmacology, tissue opacilication and excretory urography. Urol Radio1 1988; 10: 2-5. Lovett I, Benn I, Benness G, Doust B. Influence of contrast media osmolality on intravenous urographic quality. In: Frommhold W, Thurn P, eds.Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin, suppl, vol 128. Georg Thieme Verlag, 1989; 105-107.
15 Burbank FH. Determinants of contrast enhancement for intravenous digital subtraction angiography. Invest Radio1 1983; 18: 308-3 16. 16 Bonnemain B, Hart1 C, Cardinal A, Donadieu AM, SchoumanClayes E, Frija G. Tolerability of hypertonic and isotonic contrast media injected intravenously: a comparative study in the dog. Invest Radio1 1988; 23: 478-481. 17 Spataro RF, Fischer HW, Kormano M. Clinical comparison of hexabrix, iopamidol and urogratin-60 in whole body computed tomography. Invest Radio1 1984; 19(suppl): S372-S375. 18 Andrew E, Dahlstrom K, Sveen K, Humden G. Holager T, Mowinckel P, Renaa T, Laulund S. Intravascular studies with iohexol (OmnipaqueR) Eur J Radio1 1985; 5: 68-76. 19 Palmer FJ. The RACR survey of intravenous contrast media reactions. Final report. Australas Radio1 1988; 32: 426-428. 20 Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P., Matsuura K. Adverse reactions to ionic and nonionic contrast media: a report from the Japanese Committee on the safety of contrast media. Radiology 1990; 175 : 621-628.
126
EURRAD
00188
Preliminary European intravenous clinical experience with a new, low osmolar, nonionic contrast medium: ioversol (OptirayR) M.M. Le Mignon, C. Azau, A. Arthaud
and B. Bonnemain
Research and Development DivisionLaboratoire Guerbet Aulnay sous Bob, France (Received 24 January
Key words: Contrast
1991; accepted
after revision 5 April 1991)
medium, clinical trial; Contrast
medium, comparative
study
Abstract The intravenous clinical trial program of ioversol (OptirayR), a low osmolar, nonionic, monomeric contrast agent characterized by high hydrophilicity, is evaluated on the basis of results from the first clinical trials conducted in Europe as part of the development of the 300 and 350 mgI/ml formulations: 7 double-blind, comparative trials and 5 single trials were performed in a total of 743 patients, ofwhom 472 received ioversol and 271 a monomeric nonionic reference product. The diagnostic effkacy of ioversol was equivalent or superior to that of the reference products and tolerance was comparable to that of nonionic agents in terms of pain and heat sensations. No significant difference in adverse reactions was found and all the contrast agents studied were well tolerated by the patients.
Introduction Ioversol (OptirayR, Mallinckrodt Inc., St Louis, U.S.A.; Laboratoire Guerbet, Villepinte, France) is a new nonionic triiodinated, low osmolar contrast medium (LOCM) for urographic and angiographic applications (Fig. 1). The osmolality and viscosity of ioversol 300 and 350 are comparable or slightly lower than those of the nonionic monomers in clinical use (Table 1). Ioversol is the most hydrophilic of these
i
6
iOH Fig. 1. Chemical structure of ioversol. Chemical name: N,N’bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamidol]-2,4,6triiodoisophthalamide. Molecular weight: 807.13.
Address for reprints: Marie-Madeleine Le Mignon, BSc. Research and Development Division Laboratoire Guerbet, B.P. 15, 93601 Aulnay sous Bois Cedex, France
compounds [l] (Table 2). This valuable advantage of contrast media which supposedly minimizes their interactions with the lipid layers of biological and particularly neuronal, membranes [2,3], so far has been reflected by the lower neurotoxicity of ioversol after intracisternal injection in animals [4]. Ioversol has already been evaluated in a number of preclinical studies [ 5-81, demonstrating its good tolerability. Human pharmacokinetics of ioversol [9] have shown that it presumably behaves in the same way as other nonionic urographic and angiographic contrast media [ 10,111. Findings from phase II and III clinical trials performed on ioversol concentrations of 160, 240 and 320 mgI/ml to evaluate the safety of the compound were published [ 121, indicating that ioversol was better tolerated than conventional contrast media in terms of side effects, pain and heat sensations, and hemodynamic and cardiac reactions. All the agents showed equivalent safety in terms of laboratory values and the overall tolerability of ioversol was statistically comparable to that of other nonionic reference monomers. The aim of this publication is to summarize findings from the first clinical trials performed on ioversol by the intravenous route as part of the European development of this agent, using the 300 and 350 mgI/ml formu-
127 TABLE 1 Osmolality Contrast
and viscosity of ioversol (OptirayR), compared Concentration
agent
Iopamidol ( IopamironR) Iopromide (UltravistK) Ioversol (OptirayR) Iohexol (OmnipaqueR) Ioversol (OptirayR) Iopamidol ( IopamironR) Iohexol (OmnipaqueR) Iopromide (UltravistR) a Tonometer
with low osmolality urographic
(mgI/ml)
370 370 350 350 300 300 300 300
Comparative hydrophilicity of ioversol, iohexol, iopamidol, iopromide and metrizamide as determined by the octanol/water partition coefficient (Log P) (Bonnemain B, Meyer D [I])
lovers01 Iohexol Iopamidol Iopromide Metrizamide
contrast
agents ~__
Osmolality (mosm/kg)
Viscosity at 37 “C (mPa/s or cp)
870” 790” 790 850” 630 630” 680” 600”
9.4 9.5 8.0 10.6 5.0 4.7 6.1 4.6
Wescor 5500 at 37 “C.
TABLE 2
Contrast agent
and angiographic
Octanol/water
partition
coefficient
(Log P) pH = 7.4, 37 “C -
2.98 2.71 2.42 2.05 1.41
lations. These studies were designed formances of ioversol in the proposed pare its efficacy to that of reference used in Europe and verify the overall compound.
increasing hydrophilicity I
to check the perindications, comnonionic LOCM tolerability of the
Materials and Methods Organization Twelve studies including 7 randomized, doubleblind, comparative studies on parallel groups and 5 single trials were conducted from May lo,1988 to March 14,1989 in France, Belgium, Switzerland and the F.R.G. in various private or university hospital centers (Table 3). Each protocol was reviewed and approved by the U.S. Food and Drug Administration and by the relevant Ethics Committees. Written informed consent was obtained from all the patients. Population studied Of 743 adult patients who entered the trials, 472 received ioversol(242 were given ioversol 300 and 230 ioversol 350) and 271 were administered a reference nonionic LOCM. Patients presenting one of the usual
contraindications to the injection of contrast material were excluded from the trials. To prevent any biased evaluation of ioversol, patients who had undergone a radiological procedure 24 h or less before entering the trial (or 48 h in the case of cholecysto- or cholangiography) were also excluded. Subjects with a positive history of allergy or with a previous history of adverse reactions to intravascular radiodiagnostic compounds were included in the trial after receiving appropriate premeditation, histamine H, and/or HZ-receptor blockers or AINS. Proper hydration of diabetic patients upon injection of the contrast agent and for 24 h after the procedure was carefully checked. Attribution of contrast media Each patient entered the trial in chronological order. Contrast agents used in the comparative trials were administered according to a previously established randomization chart. The patients received the agents at the doses and under the injection conditions specific of each indication and usually applied in the routine clinical practice. These conditions remained unchanged throughout the trials. Contrast agents used were ioversol at 300 and 350 mgI/ml (OptirayR 300 and 350), iopamidol at 300 and 370 mgI/ml (IopamironR 300 and 370), iohexol at 300 and 350 mgI/ml (OmnipaqueR 300 and 350) and iopromide at 370 mgI/ml (UltravistR 370). Evaluation criteria (a) Efficacy. Efficacy was evaluated in most cases on the basis of (1) the quality of images or films, i.e., opacitication scores appreciated blindly using a visual analog rating scale (VARS) and expressed in figures from 0 to 100, (2) the diagnostic quality of images or films, results being expressed as a percentage of diagnostic procedures, and (3) the degree of diagnostic certainty (also on a VARS ).
128 TABLE 3 Summary of population
data and doses studied in the different clinical trials
Procedure
Intravenous
Investigator
urography
Test solutions
A. Pinet (F)
Whole-body
CT
Mean height
Mean dose
(kg)
(cm)
ml
mgI/kg
gI
49.6 58.1 47.8 46.6 46.2 50.7 51.7
70.5 70.1 69.6 65.8 66.3 65.9 67.8
168.3 167.2 167.5 167.3 167.4 168.1 168.1
80 86 84 65 60 71 79
353 383 358 353 347 382 443
24 26 25 23 22 25” 29
Ioversol Iohexol Ioversol Iopamidol
300 300 350 370
41 39 40 40
56.8 57.7 53.3 54.7
12.6 72.6 68.5 70.4
170.0 171.2 167.1 168.0
111 182 154 168
144 760 800” 906
53 55 54” 62
Y. Palmers (B) J. Theron (F)
Ioversol Ioversol
300 350
40 40
43.0 52.5
67.4 67.0
168.9 166.8
67 66
300 347
20 23
N. Vasile (F)
lovers01 Iohexol Ioversol
300 300 350
41 42 40
55.7 55.4 56.8
70.9 65.9 66.6
170.4 168.1 166.7
99.5 96.7 100.0
437 459 546
30 29 35
Ioversol Ioversol Iopamidol
300 350 370
40 30 30
57.8 64.8 56.9”
68.6 69.3 72.1
162.7 164.4 165.5
153 200 197
684 1067 1062
46 70 73
F.J. Roth (FRG) (F)
J. Boverie (F) Venography
Mean weight
40 40 40 40 40 40 40
J. Drouillard
Head CT
age (years)
300 300 300 350 370 350 370
B. Ody (CH)
angiography
Mean age
Ioversol Iopamidol Ioversol Ioversol Iopamidol Ioversol Iopromide
M. Elke (CH) A Pinet (F)
IV digital subtraction
No. of cases
JB. Carey (F) P. Rouleau (F)
a Significant difference (P < 0.05). b Significant difference (P < 0.01).
In Roth’s study, the quality of the films was rated as excellent, good, acceptable, poor, and no evaluation of the degree of diagnostic certainty was made. The efficacy of the contrast solutions was evaluated by the same investigator throughout the trial. In intravenous urography, the evaluation was consistently made on the basis of the first injection, i.e., 60 ml for clinical trials on ioversol300 and 50 ml on ioversol350.
Statistical analysis
Results were analyzed individually for each study. Quantitative data were averaged and compared between two groups using Student’s t-test or Wilcoxon’s test. Data expressed as proportion or percentage were compared between two groups using Fisher’s exact test. Results
(b) Tolerance
Population
All objective and subjective adverse reactions observed by the investigator and reported by the patient spontaneously or after questioning were recorded in the case reports forms. Patients were observed for one hour after the injection of contrast medium. Tolerance data were interpreted based (1) on the number of patients presenting one or several adverse reactions attributed to the drug, apart from heat and pain sensations, (2) the number of patients who required treatment and (3) the mean scores for pain and heat sensations experienced by the total population.
Demographic data (Table 3) were consistently comparable between the two study groups, apart from mean age in the phlebographic study. Furthermore, the number of male and female patients, subjects with a history of allergy or of previous untoward reaction to iodinated contrast media, or diabetic subjects was always comparable among the study groups. Intravenous urography
Results are summarized in Table 4. The degree of diagnostic certainty found with ioversol 300 was statis-
129 TABLE 4 Intravenous
urography
Test solutions
data Diagnostic
Safety
efficacy
Mean opacification (0 to 100)
scorea
Y0 diagnostic procedures
Mean degree of certainty (0 to 100)
Mean intensity of pain: (0 to 100)
Mean intensity of heat: (0 to 100)
100
84
0.0
12.8
Ioversol 300 (n = 40) Iopamidol 300 (n = 40)
49, 76, 76, 65, 62 45, 71, 71, 59, 57
95
81
0.P
13.8
Ioversol 350 (n = 40) Iopamidol 370 (n = 40)
53, II, 16, 67, 67
100
91
0.0
24.6
54, 75, 77, 70, IO
100
91
0.0
24.8
Ioversol 350 (n = 40) Iopromide 370 (n = 40)
63, 72, 74, 67, 75
100
80
0.5’
I.0
64, 68, 11, 65, 13
100
77
0.0
7.3
Ioversol 300 (n = 40)
95, 94, 97, 95, 100
100
96
0.0
13.6
* a b ’
*
Significant difference: P < 0.05. Opacitication scores at each level are indicated in the following order: parenchyma, Only one patient reported a pain sensation graded 20 on the VARS. Only one patient reported a pain sensation graded 22 on the VARS.
tically higher than with iopamidoi 300 (p < 0.05). This could be related to slightly better opacification scores with ioversol300 though the difference in this parameter between ioversol300 and iopamidol300 was not statistically significant. The efficacy of ioversol 350 was found to be equivalent to that of iopamidol 370 and iopromide 370 despite comparable injection volumes (Table 3). Pain and heat sensations were minor in most cases. Intravenous digital subtraction angiography
Results are summarized in Table 5. For comparable injection volumes, image quality proved significantly better with ioversol 300 than with iohexol 300 (P < 0.05). This difference cannot be explained by patient motion since the incidence of motion was comparable in both groups (10%). Despite a significantly lower amount of iodine injected, ioversol350 showed a comparable efficacy to iopamidol 370. Mean heat and pain sensations were null or low. CT Scanning
Results for cranial CT summarized in Table 6 show that ioversol 300 and 350 injected in 1.0 ml/kg doses
calyces, renal pelvis, ureter, bladder.
always allowed to make a diagnosis with a satisfactory degree of certainty in both studies. Results for whole body CT scanning summarized in Table 7 demonstrate comparable efficacy of the agents under study. Mean heat sensations were consistently low and no pain was reported. Venography
Venographic data summarized in Table 8 show comparable efficacy of ioversol 350 and iopamidol 370, despite the slightly higher iodine concentration of the latter agent and equivalent injection volumes. Heat sensations were comparable with both contrast agents. There were slightly less pain sensations with ioversol350 than with iopamidol370, but the difference was not significant. Adverse reactions Of 472 patients
given ioversol, 11 y0 presented adverse reactions attributable to the contrast agent. When considering only the comparative trials, 11% of the population had adverse reactions with ioversol and 10% with the other nonionic reference products. No statistically significant difference was found between
130 TABLE 5 IV digital subtraction
angiography
data
a
Diagnositc
Test solutions
Ioversol 300 (n = 41) Iohexol 300 (n = 39)
efficacy
Safety
Image quality good or excellent (% cases)
% diagnostic procedures
Mean score for pain: (0, 1, 2 or 3)
Mean score for heat: (0, 1, 2 or 3)
16 51 *
98 100
0.0 0.0
1.3 1.4
* Significant difference: P < 0.05. b
Diagnostic
Test solutions
Ioversol 350 (n = 40) Iopamidol 370 (n = 40)
efficacy
Safety
Mean opacilication score (0 to 100)
% diagnostic procedures
Mean degree of certainty (0 to 100)
Mean intensity of pain: (0 to 100)
Mean intensity of heat: (0 to 100)
14 16
95 95
19 80
0.0 0.0
0.0 7.2
TABLE 6 Cranial computed
tomography
data Diagnostic
Test solutions
Safety
efficacy
Mean opacification score (0 to 100)
y0 diagnostic procedures
Mean degree of certainty (0 to 100)
Mean intensity of pain: (0 to 100)
Mean intensity of heat: (0 to 100)
Ioversol 300 (n = 40)
86
100
95
0.0
17.7
Iopamidol
59
100
91
0.0
15.2
350 (n = 40)
TABLE I Whole-body
computed
tomography
data
Diagnostic
Test solutions
efficacy
Safety
Mean opacification score (0 to 100)
% diagnostic procedures
Mean degree of certainty (0 to 100)
Mean intensity of pain: (0 to 100)
Mean intensity of heat: (0 to 100)
Ioversol 300 (n = 41) Iohexol 300 (n = 42)
II 82
100 100
91 99
0.0 0.0
0.5 0.0
Ioversol 350 (n = 40)
95
95
0.0
2.0
a Diagnosis
was impossible
98”
for one patient for reasons unrelated
the contrast media. The dverall incidence of adverse reactions in those comparative studies, according to the nature of the effects, was as follows:
to the agent.
- cardiovascular: 0.4% - nervous (paresthesia, muscle spasm): 3.7%
dizziness,
cranial
pressure,
131 TABLE 8 Venography
data
Test solutions
Diagnositic
Safety
efficacy
Mean opacitication (0 to 100)
score”
% diagnostic procedures
Mean degree of certainty (0 to 100)
Mean intensity of pain: (0 to 100)
Mean intensity of heat: (0 to 100) 40.9 43.6
Ioversol 350 (n = 30) Iopamidol 370 (n = 30)
92 (92, 90, 90) 91 (93, 90, 87)
100 100
95 95
5.0b 11.2’
Ioversol 300 (n = 40)
78 (83, 82, 77, 60)
100
94
0.0
a Opacitication and caval for ’ Two patients ’ Five patients
1.7
scores at each level are indicated in the following order: tibial, femoral, iliac and caval for the ioversol 350 study, and iliac the ioversol 300 study. reported a pain sensation. reported a pain sensation.
digestive (nausea, vomiting): 1.7% allergic-like (erythema, urticaria, pruritus): 2.7% respiratory (cough, chest oppression): 0.4% miscellaneous (bad taste, general pain, urge to void, dry mouth): 2.4% The overall incidence of reactions requiring treatment was 1.3 %. This incidence was comparable for the two groups. Discussion These 12 clinical trials represent the first European experience in the use of ioversol 300 and 350 by the intravenous route. The principal aim of this review was to try to situate ioversol in the range of the most recent contrast agents of the same chemical class via the comparison of their respective efficacy and tolerability. As regards adverse reactions, except heat and pain, only comparative data on a very large number of subjects obtained through consolidation of many studies can now allow to conclude as to whether the new contrast agents are comparable or not. The data relating to the adverse reactions reported here should therefore be considered only as indicative. Discomfort criteria, such as pain and heat, which are the most commonly experienced sensations, which depend on the radiological indication and for which comparisons of the incidence and intensity can be made on small series, have been considered separately and for each indication. Efficacy
Whatever the radiological applications in which it was studied, ioversol was found to be a suitable contrast agent as it permitted to make a diagnosis in all the examinations except in 4 cases, thus yielding a 99% success rate. Ioversol 350 proved equivalent to the re-
ference product at 370 mgI/ml despite comparable injection volumes in urography and venography and statistically lower iodine doses of ioversol 350 in intravenous digital subtraction angiography. Ioversol 300 was shown to be slightly superior to iohexol or iopamidol 300 in intravenous urography (mean degree of certainty) and in intravenous digital subtraction angiography (image quality). At this point pharmacokinetic data available cannot provide a satisfactory and accurate explanation for this difference which must be further confirmed on other series. In contrast, one or several physicochemical characteristics of the product could come into play: higher hydrophilicity, slightly lower viscosity at 350 mgI/ml compared with other nonionic monomers at 350 or 370 mgI/ml and slightly lower osmolality than that of iohexol. In intravenous urography, due to the low osmotic potential of ioversol, it is possible like with other LOCM to obtain high urinary iodine concentrations as a result of low osmotic diuresis [ 13,141. This leads to high contrast enhancement in the excretory cavities. Due to its low viscosity, ioversol can be injected rapidly thus allowing to obtain good peak plasma concentrations. Further, it can be assumed that high hydrophilicity yields high ‘freely filtrable’ plasma concentrations as a result of low protein binding, thus allowing easy passage through glomerular filter. Therefore, both nephrograms and pyelograms should be satisfactory. In intravenous digital subtraction angiography, if we assume that the better image quality provided by ioversol 300 compared with the same dose of iohexol 300 is related to higher peak plasma iodine concentrations with ioversol300, an explanation could be smaller changes in cardiac output with ioversol than with iohexol, as suggested by Burbank [ 15,161. The theoretical factor to account for the difference in efficacy could
132
be the variations in cardiac output resulting from a different effect on cardiac function and/or from a slightly smaller increase in blood volume with ioversol due to its slightly lower osmolality. In the ioversol 350 versus iopamidol 370 trial, the smaller changes in cardiac output induced by ioversol could in this case too, make up for the smaller amount of iodine injected. This is only hypothetic since these parameters were not monitored during the trials discussed here. In CT studies, with ioversol like with the other LOCM, peak plasma iodine concentrations observed immediately after bolus injection of contrast material should be higher than those produced by HOCM. This should also be true for renal cortical enhancement [ 171 as a result of the lesser osmotic diuresis. The low viscosity of ioversol should allow to deliver contrast injections rapidly. This might be helpful when diagnosis is based on the visualization of vascular structures. When diagnosis is based on enhancement of interstitial spaces, the high hydrophilicity of media should favour for a good diffusibility. In venography, like for the other radiological indications, the quality of information provided by ioversol 350 proved identical to that obtained with the same volume of iopamidol 370. Tolerance
No significant difference was found between ioversol and the other nonionic low osmolality contrast media as to adverse reactions other than pain and heat, which in most cases were minor (no treatment required), and sometimes moderate. Incidences reported here for ioversol and the other nonionic agents, i.e., 11 y0 and 10 % respectively, are comparable to those published by Andrew [30] for iohexol after intravenous injection in 772 patients (8%). However, as underscored by this author, it is rather difficult to draw any comparison between the various publications since the methods used for collecting data on adverse reactions differ from one another (in this connection it should be pointed out that the incidence of subjective reactions classed as ‘nervous’ or ‘miscellaneous’, which alone account for more than half the effects reported as a consequence of a very detailed reporting method, is high). These findings provide additional information to that already published on ioversol in 1186 patients [ 121, which demonstrated (1) the lower incidence of adverse reactions, particularly those related to osmolality, with ioversol than with HOCM, and (2) equivalent overall tolerability compared with the other nonionic monomers. Heat and pain sensations were on the whole of minor or moderate intensity as expected for LOCM. When
large volumes were injected (i.e., intravenous digital subtraction angiography and venography) they seemed slightly, though not significantly lower with ioversol. These parameters might be worth monitoring in other studies. These characteristics of ioversol make it well suited for intravenous investigations in patients requiring the use of a low osmolality contrast medium, i.e., high-risk patients, especially those with cardiac failure, and all subjects who poorly tolerate an increase in blood volume. Patients with renal or hepatic failure, those who recently suffered a cerebrovascular accident or presenting damage of the blood-brain barrier are also often considered as high-risk patients. Patients with a positive history of allergy or of previous untoward reactions to radiological contrast media usually are also included in this category. However, the risk of allergic-like reactions does exist and is greater in patients with a history of allergy, regardless of the product used [ 19,201. Therefore, extra caution should be exercized in carrying out radiological procedures with contrast media in this type of patients. From these clinical findings, it appears that ioversol (OptirayR) is a well suited contrast medium for i.v. radiographic procedures.
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