Ciclosporin Trough-Level before Switch (ng/ml). | dose Increased g dose unchanged. Q doss diereased. M=month; 'dose reduction In percent for all patients.
Nephrol Dial Transplant (1996) 11: 165-172
Nephrology Dialysis Transplantation
Original Article
Substitution of conventional cyclosporin with a new microemulsion formulation in renal transplant patients: results after 1 year H.-H. Neumayer 1 , L. Farber 3 , P. Haller2, R. Kohnen 4 , A. Maibucher 3 , A. Schuster3, J. Vollmar 2, K. Budde1, J. Waiser1 and F. C. Luft5 1
Department of Medicine-Nephrology, University Hospital Charite, Humboldt University of Berlin; 2 Department of Medicine and Nephrology, 4th Medical Clinic, Friedrich Alexander University, Erlangen-Nurnberg; 3 The Sandoz Corporation, Nurnberg; 4 The Imerem Company, Nflrnberg; 5 Franz Volhard Clinic, Rudolf Virchow University Hospital, Humboldt University, Berlin, Germany
Abstract Background. A new galenic form of cyclosporin A has been developed, based on microemulsion technology. The bioavailability of the compound is relatively independent of food intake and bile flow. It was the purpose of this prospective clinical trial to study the safety of the microemulsion form of cyclosporin A. Methods. Three hundred and two renal transplant patients, stratified according to transplant age, were switched from the conventional to the new microemulsion formulation of cyclosporin A. A 1:1 conversion ratio was used. Measurements included CsA levels, S-creatinine, liver enzymes, uric acid, and blood pressure. Measurements were performed at baseline and on days 4, 8, 15, 29 and months 3, 6 and 12 after conversion. Dose adjustments were performed to achieve trough levels of 80-120 ng/ml.
biopsy-proven rejection and seven episodes of cyclosporin-attributed nephrotoxicity. Conclusions. The 1:1 conversion from conventional cyclosporin A to the microemulsion formulation is efficacious and safe, but an initial dose reduction of 10% is advised in patients with trough levels in the high-normal range. Key words: cyclosporin as microemulsion; nephrotoxicity; rejection episodes; renal transplantation
Introduction
Cyclosporin is not an easy drug to use. The drug's pharmacokinetic profile is difficult to predict because its water insolubility results in variable gastrointestinal Results. Within the 12-month observation period the absorption [1-5]. A new microemulsion formulation cyclosporin dose was reduced by 14.7% (from has been developed, the bioavailability of which is 204 + 60 mg/day at baseline to 174 ±51 mg/day after independent of food intake and bile flow [6-8]. The conversion, P 120 ng/ml the average dose reduction reached 26.2% of the previous total dose and dose reductions were achieved in 77.8% of patients (Figure lb). Thus the additional dose reduction related to the predefined therapeutic window of 80-120 ng/ml accounted for approximately 6% only.
167
Microemulsion cyclosporin Table 1. Summarized results after one year Day/Month
Units
Dl
CyA dose
mg/day
204.4
140
(59.8) (80-420) (32.3) (30-256) (0.71) (0.7-6.81) (21.5) (10.8-125.1) (21.8) (10.6-123.6) (2.3) (3.5-15.0) (8.5) (3-85) (109) (73.3-153.3) 18.8 (100-220)
86.4
9.6
85
(60-120) 12.3 (40-108) (1.46) d-8)
200
CyA trough level
ng/ml
Creatinine
mg/dl
GFR
ml/min
114.3 112.5 1.52 1.36 62.9 61.9 65 6 64.9 8.15 7.70 11.9
Cockcroft/Gault GFR
ml/min
Keller Uric Acid
mg/dl
ALAT
U/l
10 MBP
mmHg
105.5
SBP
mmHg
143.7
105
DBP HR
mmHg /min
69.7 68
Mood
1-9 1= excellent
2.41 20
D4
n = 299
D8
n = 299
D15
205.0 200 117.2* 113.0 1.54 1.38 62.0 61.8 64.6 65 4
(59.8) (80-420) (29.5) (40-262) (0.71) (0.76-6.39) (21.2) (11.5-127.3) (21.4)
205.2 200 119.82 116.0 1.54' 1 38 61.77 60.8 64.21 63.8
(59.5) (80-420) (30.2) (42-268) (0.7) (0.76-6.16) (20.6) (11.9-120.2) (20.8)
196.1 3 200 115.5 113.0 1.54
ND
ND
12.0 10 104 4 103.3 142 9 140 85.1 85 71.8 72 2 673 2.0
(8.0) (3-77) (10.4) (76.7-141.7) 19 1 (90-225) 9.7 (60-120) 12.4 (40-108) (1.53) (1-9)
119 10 103.6 103.3 141.1 140 84.9 85 71.8 72 2 663 2.0
(8.3) (3-82) (10.4) (73.3-140) 18.0 (90-200) 9.4 (60-120) 13.2 (42-120) (1.52) (1-8)
n
= 299
(59.3) (60-420) (26.6) (50-243) (0.73) 1.39 (0.74-6.15) 62.3 (21.5) 62.1 (11.9-124.3) 64.9 (21.7)
65.2 8.3O1 8.00 12.1 10 103.2
103.3 139 9 140 84.9 85 71.5 72 2.71 3 20
(2.3) (3.3-15.0) (8.2) (3-79) (10.8) (68.3-150) 18.1 (85-210)
D29
n = 299
187.43
(59.5) (60-420) (23.9) (46-194). (0.75) (0.7-6.44) (22.1) (11.2-123.8) (22.4)
180
::n 110.0 1.54 1.34 63 1 63.2 65.8 65.2 8.491 8.20 12.0 10
104.0 103.3 141.3 140
(2.4) (3 1-14.4) (8.8) (2-88) (9.8) (73.3-133.3) 16.7 (100-220)
9.6
85 3
92
(50-120) 12.4 (44-104) (1.49) (1-8)
85
(60-120) 13.0 (44-120) (1.58) (1-9)
71.4 68
2.643 2.0
Day/Month
Units
M3
n = 272
M6
. = 275
M12
71 = 280
CsA dose
mg/day
CsA trough level
ng/ml
Creatinine
mg/dl
GFR Cockcroft/ Gault GFR Keller Uric acid
ml/min
175.373 175 108.8 107.0 1.463 1.25 68.53 67.2
(53.85) (60-420) (30.9) (52-251) (0.85 (0.65-8 44) (25.1) (11.2-143.7)
171.93 160 110.1 105.0 1.483 1.24 67.53 68
(49.6) (60-420) (32.6) (31-287) (0.8) (0.67-6.58) (24.6) (10.1-154.7)
174.33 160 101.5 3 95.0 1.543 1.27 66.4 3 64.8
(51.1) (60-420) (32.3 (45-296) (0.97) (0.65-7.5) (25.75) (8.9-127.9)
mg/dl
ALAT
U/l
MBP
mmHg
SBP
mmHg
DBP
mmHg
HR
/min
Mood
1-9 1 = excellent
71.33 71.4 8.21 7.95 12.1 10 103.1 103.3 139.3 140 85.1 85 71.8 72 2.673 2.0
(25.3 (11-143.7) (2.26) (3.7-14.4) (8.0) (1-66) (10.1) (70-136.7) 17.6 (90-220) 9.7 (60-110) 10.7 (50-120) (1.38) (1-8)
70.23 71.4 8.20 8.0 12.7 10 102.62 103.3 137.63 140 85.1 85 70.2 68 2.683 2.0
(24.8) (10-154.7) (2.24) (2.9-15.1) (8.2) (2-56) (11.1) (70-146.7) 18.7 (90-220) 9.7 (60-125) 10.5 (48-116) (1.45) (1-7)
69.4 3 69.8 8.34 3 8.25 11.2 9 101.5 3 100.0 137.43 140 83.6 2 80 74.2 3 72 2.65 3 2.0
(26.1) (8.9-128.4) (2.25) (3.6-14.4) (7.0) (2-49) (10.4) (63.3-140) 17.1 (90-190) 9.7 (50-115) 12.4 (52-132) (1.45) (1-9)
ml/min
Dl, baseline: day of switch to Sandimmun Neoral. l / ) 5 years (n = 84, 28.1%); >3-5 years (« = patients transplanted between 1 month to 1 year before 65, 21.7%); 1-3 years (n = 103, 34.5%);
