Long-term safety and efficacy of neoral in heart transplantation

Long-Term Safety and Efficacy of Neoral in Heart Transplantation N.A. Yonan, T. Aziz, A. El-Gamel, C.S. Campbell, A.N. Rahman, and A.K. Deiraniya

N

EORAL is the new microemulsion-based formulation of Cyclosporine A (CyA). It was developed to overcome the problems of poor and unpredictable absorption of CyA associated with Sandimmun.1 Clinical studies have confirmed the superior, more predictable, and more sustained absorption compared with Sandimmun in renal, cardiac, and liver transplantation.2– 4 Other studies have demonstrated the safety of converting patients from Sandimmun to Neoral in renal5 and heart transplant recipients.6 The optimum dose of CyA to achieve adequate immunosuppression without significant side effects is guided by the use of the trough CyA blood level.7 The interpatient variation in CyA with Sandimmun is high, so frequent blood concentration levels are required to maintain the balance between efficacy and toxicity.8 Neoral offers more predictable absorption with less variation within and between patients.9 This will theoretically provide better sustained immunosuppression compared with Sandimmun. Trough levels with Neoral tend to underestimate the exposure to CyA and studies have confirmed higher peak and area under the time concentration curve (AUC).5,9 This may be beneficial in reducing the incidence of acute rejection or graft vasculopathy.10 It may, however, also cause an increase in CyA side effects including nephrotoxicity and posttransplant lymphoproliferative disorder (PTLD). Medium term safety and efficacy of Neoral was reported in 70 out-patient heart transplant patients (Htx) with 9 months follow up.11 It concluded that the improved bioavailability of Neoral has resulted in a long lasting dosesparing effect. Neoral was well tolerated with no increase in renal toxicity. A higher trough level stability was found with a decrease in the number of required dose changes. There are no data regarding the use of Neoral in long-term Htx recipients, so this study was designed to assess the long term efficacy, safety, and tolerability of Neoral in Htx recipients. PATIENTS AND METHODS In this retrospective study, 235 thoracic transplant recipients were analysed; 65 were treated with Neoral de novo and 170 patients were converted from Sandimmun to Neoral. The mean follow up was 26 months (m). They were divided into 2 groups. The Conversion Group consisted of 170 recipients who were converted to Neoral according to a 1:1 conversion protocol. Mean age was 42.9 years; the group comprised 137 males and 33 females, 140 had orthotopic Htx and 30 had a lung transplants (Ltx). The

mean follow-up since conversion was 28 m (range, 22 to 35 m). The following observations were recorded, before conversion, 4 weeks and, 1 year after conversion: CyA dose, level and pharmacokinetics, serum creatinine, number of 3a rejection episodes, infection episodes, incidence of PTLD, CyA-related side effects, and diuretic requirement. The de novo Group (Table 1) represents 115 Htx recipients subdivided into (1) the Neoral de novo group, consisting of 65 consecutive recipients and (2) the Sandimmun group, consisting of 50 consecutive patients. Each recieved Sandimmun for the first year posttransplant. These patients were part of the conversion group. The mean follow-up (since Htx) for the Neoral group was 24.1 m (range, 6 to 38 m) and that for the Sandimmun group was 48 m (range, 39 to 60 m). We compared CyA dose, level, L/D ratio, and serum creatinine (at 1 week, 1 month, 3 months, and 1 year). We also compared the time between starting oral CyA therapy and achieving adequate level (. 175 ng/mL), the number of 3a rejection (first year), percent freedom from rejection, the number of infection episodes, PTLD, survivals, and the incidence of significant CyA-related side effects, including systolic and diastolic blood pressure. The two groups had a similar protocol for immunosuppression and follow-up.

RESULTS The Conversion Group CyA Dose and Level

There was a reduction in CyA dose (mg/d) from 287 6 9.9 preconversion to 255 6 9.04 at 4 weeks in group 1 (P 5 .0001) (Table 2). This represented an 11% dose reduction. A further reduction was observed at 1 year to 194 6 8.06 (P 5 .0001) which represented a total reduction of 33%. There was a rise in the CyA trough level (EMIT Essay in ng/mL) following conversion from the baseline of 156 6 3.9 to 176 6 6.07 at 4 weeks (P 5 .001). CyA trough levels were lower at 1 year 129 6 4.5 (P 5 2.0001). Serum Creatinine

There was a reduction in serum creatinine (mmol/L) in group 1 from 168.4 6 3.4 to 157 6 3.3 at 4 weeks (P 5 .0001). The serum creatinine remained lower at 1 year; 161 6 3.9 (P 5 .001). From the Department Cardiothoracic Surgery and Cardiopulmonary Transplantation, Wythenshawe Hospital (N.A.Y., T.A., A.E.-G., C.S.C., A.N.R., A.K.D.) Manchester, United Kingdom. Address reprint requests to Nizar A Yonan FRCS, Associate Surgical Specialist, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK.

0041-1345/98/$19.00 PII S0041-1345(98)00477-1

© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

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Table 1. Comparison Between the Neoral de novo and Sandimmun Groups Regarding Demographic data, HLA, Rejection, Infection, PTLD, Follow-up, Survivals, and Side Effects

N Age (y) Gender (M/F) HLA match Mean follow-up (range) 3a rejection/Y No of biopsies/Y Freedom from R (%) Infection episodes/Pt PTLD Side effects (%) SBP mm Hg DBP mm Hg Survival (%)

Neoral

Sandimmun

P

65 46.8 6 9.7 5/1 1.7 24.1 m (6 –38)

50 47.5 6 10.1 6/1 1.8 48 m (39 – 60)

— NS NS NS —

1.3 6 0.22 12.7 6 0.49 34.0 1.3 6 0.08 3 18 131.6 6 2.82 85.4 6 1.66 50/65 (75.5)

2.4 6 0.34 14.1 6 0.5 19.5 1.1 6 0.07 1 16 137.0 6 3.1 87.8 6 2.01 36/50 (70)

.0018 .01 .01 NS NS NS NS NS NS

Abbreivations: M, males; F, females; HLA, human leucocyte antigen; m, month; Y, year; R, rejetion; SBP, systolic BP; DBP, diastolic BP; NS, not significant.

Diuretic Dose

The mean diuretic dose in group 1 (frusemide or equivalent) was lower 1 year after conversion (P 5 .01). Acute 3a Rejection

The incidence of acute 3a rejection (ARE) per 100 patient days was lower in group 1 compared to preconversion (0.27 6 0.05 to 0.1 6 0.05; P 5 .0001). Despite the reduction in incidence of ARE, 3 patients presented with symptomatic 3a rejection 3 to 9 months after conversion and with a trough CyA level of , 50 ng/mL. They were successfully rescued with intravenous steroids and an increase in the Neoral dose. At conversion, these patients had a 40% dose reduction. Side Effects

A 22% rise in the incidence of CyA related side effects was reported in group 1, which settled with time and/or a reduction in Neoral dose. Only two patients had to be switched back to Sandimmun. The main side effects were upper gastrointestinal tract disturbances (15%), headache

12%, hyperuricemia (11%), tremor (8%), hypertension (5%), clinical gout (5%), and hyperkalaemia (5%). The incidence of infection episodes was significantly lower after conversion (0.87 6 0.11 to 0.31 6 0.1; P 5 .005). Two patients developed localised PTLD 6 to 12 m following conversion which settled with dose reduction.

The De Novo Group

There was no significant difference between the 2 subgroups within the de novo group (Tables 1 and 3) regarding age, gender, HLA match, serum creatinine, the number of infection episodes, PTLD, and survival. Although the CyA dose, trough level, and L/D ratio were similar between the two groups, the time between starting oral therapy and achieving adequate level was shorter with Neoral (P 5 .01). A reduction in the incidence of ARE in the first year was seen in the Neoral group (P 5 .01). Freedom from ARE for the first year was higher with Neoral (34% versus 19.5%; P 5 .001). The incidence of CyA-related side effects was similar between the two groups. Three patients from the

Table 2. Cyclosporine Data, Rejection, Infection, Renal Function, and Diuretic Data Before Conversion, 4 Weeks, and 1 Year After Conversion

CyA dose (mg/d) Cmin (ng/mL) Cmax (ng/mL) Tmax (h) AUC (ng/h/mL) Cr (mmol/L) Infection episodes Rejection/100 pt days Diuretic dose

Sandimmun

Neoral

P

N (1 y)

P*

287 6 9.9 156 6 3.9 636 6 37 4.5 3996 6 225 168.4 6 3.4 1.2 0.27 6 0.05 58 6 4.1

255 6 9.04 176 6 6.07 956 6 48 1.5 4974 6 324 157 6 3.3 — — —

.0001 .001 .0001 .0001 .0001 .0001 — — —

194 6 8.06 129 6 4.5 706 6 39 1.5 4079 6 242 161 6 3.9 0.42 0.1 6 0.05 48.6 6 4.7

.0001 2.0001 .01 .0001 NS .001 .0001 .0001 .01

Abbreviations: CyA, cyclosporine A; Cmin, CyA trough level; Cmax, maximum concentration of CyA after oral dose; Tmax, time from oral dose to Cmax; AUC, area under the time– concentration curve; Cr, serum creatinine; Pt, patient. *Compare this column to Sandimmun column.

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Table 3. Comparison Between Neoral and Sandimmun De Novo Groups Regarding CyA Dose, Trough Level, D/L Ratio, and Serum Creatinine at 1 week, 4 weeks, 3 months, and 12 months

One week D/L D L Cr 4 weeks D/L D L Cr 3 months D/L D L Cr 12 months D/L D L Cr

Neoral Group

Sandimmun group

P

0.4 382.5 6 20.0 150.1 6 11.06 146.2 6 13.3 0.76 334.2 6 14.02 275.3 6 12.5 140.1 6 9.8 0.76 331.0 6 15.3 252.3 6 11.6 147.6 6 13.2 0.55 299.6 6 16 167.3 6 15.9 155.6 6 5.9

0.39 393.3 6 23.5 154.8 6 12.5 127.02 6 9.4 0.74 350.6 6 17.4 259.6 6 15.7 132.7 6 7.45 0.68 358.9 6 15.3 247.9 6 17.2 146.9 6 6.03 0.57 326.4 6 19.2 189.4 6 14.5 166.9 6 6.0

NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS

Abbreviations: D/L, dose level; D, dose; L, level; Cr, serum creatinine;N S, not significant; Fu, follow-up period.

Neoral group developed early (3 to 12 m) localised PTLD; they responded to a reduction in Neoral dose. DISCUSSION

In this study, we attempted to address the long-term efficacy, safety, and tolerability of Neoral in clinical Htx. The first part of the study demonstrated the clear pharmacokinetic advantages of Neoral over Sandimmun following 1:1 conversion protocol. Apart from the rise in the trough CyA level that allowed a 11% dose reduction at 4 weeks and a mean reduction of 33% at 1 year, there was an increase in the Cmax, AUC, and shorter Tmax.12 A higher exposure with Neoral was observed in spite of a similar or even lower dose and trough levels. Other studies have reported an increase in the rate and extent of CyA absorption with Neoral4 which is reflected by a shorter Tmax, a mean increase in Cmax of 67%, and a mean increase in CyA exposure to of 34%. These findings continued until 1 year following conversion. The sustained higher exposure to CyA with Neoral makes it a completely different drug to handle compared with Sandimmun. CyA is a powerful immunosuppressive agent with a narrow therapeutic window and a variety of dose-related side/toxic effects. Higher sustained levels may theoretically be advantageous in reducing the incidence and severity of acute rejection and chronic graft vasculopathy. Our data from both the conversion and the de novo studies have demonstrated a significant reduction in the incidence of 3a rejection with Neoral, and a 34% freedom from rejection. Similar findings were observed by other studies in heart11,13 and kidney transplantation.14 Despite lower 3a rejection postconversion, three long term follow-up patients (4, 7, and 9 years posttransplant) presented with acute cellular rejection with hemodynamic compromise. They required hospitalization and intravenous steroid rescue therapy.

These patients had 40% dose reduction with adequate levels at conversion. On admission they presented with a very low trough CyA level. We therefore recommend that patients with a significant dose reduction following conversion need 4 to 6 weekly follow up, until 1 year, even if initial trough CyA levels are adequate. The increased exposure to CyA with Neoral has been reported in other long term follow-up studies.5,8,9 Due to the narrow therapeutic window, there is a theoretical risk of an increase in incidence and severity of side effects. The data from the de novo groups showed no difference in the incidence of CyA-related side effects between Neoral and Sandimmun therapy; similarly there was no difference in the incidence of hypertension up to 1 year follow-up. Other studies show similar findings in kidney transplant recipients.5 Data from the conversion group, however, demonstrated a significant increase (22%) in CyA-related side effects following conversion which settled with time and/or dose reduction. This, we believe, is due to the conversion ratio of 1:1 mg which caused a rise in CyA exposure. These side effects decreased with dose reduction. CyA nephropathy is a major concern in long-term HTx follow-up recipients; virtually all HTx recipients develop a varying degree of nephrotoxicity.15 The renal function data in the de novo groups showed, as in other reports,11 no difference to the Sandimmun group, whereas the conversion data has shown a reduction in mean serum creatinine 4 weeks following conversion (with 11% dose reduction). A reduction in the mean level of urinary retinol binding protein was observed 4 weeks following Neoral conversion (after dose reduction) indicating reduced tubular toxicity with Neoral (unpublished data). This may also explain the reduced dose requirement for diuretics in the conversion groups. Infection data from de novo groups showed no increase in the incidence of infection episodes with Neoral therapy. In the conversion group, the incidence was lower in the Neoral group; a similar finding was reported by Pethig et al.11 This is not surprising as most infection episodes take place early following transplantation and most conversion took place more than 6 m posttransplantation. In this study, there was no statistical difference in the incidence of PTLD in either the conversion and the de novo groups; nevertheless, two patients from the conversion group developed a local form (throat, gum) of PTLD 6 and 7 years following transplantation. Within the Neoral de novo group, three patients developed an early, rapidly growing localized PTLD (stomach, breast, liver). These patients had a positive histologic diagnosis of B-cell lymphoma, histologically indistinguishable from the malignant form. Meticulous staging with CT scan failed to show systemic involvement. All five patients responded to a reduction of Neoral dose. They are alive and free from the disease 6 to 36 months following diagnosis. In the de novo groups, there was no difference in the CyA dose, trough level, and L/D ratio in the Neoral compared with Sandimmun group. This was an unusual finding be-

SAFETY AND EFFICACY OF NEORAL

cause our conversion data showed clearly that 1:1 conversion is associated with higher trough, peak, and AUC levels. Some reports suggested that despite higher CyA exposure with Neoral, the trough level is not necessarily higher. This is probably due to the shorter Tmax associated with Neoral therapy resulting in a longer elimination time for the active drug. Thus the earlier, higher, and more consistent peak with Neoral may lead to a lower trough level at the end of the dose interval.16 The majority of studies5,8,12 including ours show that despite similar trough CyA levels, the Cmax and AUC are higher by 60% and 30% respectively compared with Sandimmun and the only accurate assessment of the exposure to CyA is by performing a peak level 1.5 hours after the oral dose. In conclusion, this study confirmed that Neoral is a safe immunosuppressive agent; it is associated with reduced ARE and acceptable side effects. The trough CyA blood level may underestimate the Cmax and AUC. It may be beneficial to measure the peak blood concentration when dose changes are required or with adverse events in order to assess the magnitude of exposure to the drug. REFERENCES 1. Noble S, Markham A: Drugs 50:924, 1995 2. Friman S, Backman L: Clin Pharmacokinet 30:181, 1996

1909 3. Freeman D, Grant D, Levy G, et al: Ther Drug Monit 17:213, 1995 4. Wahlberg J, Wilczek HE, Fauchald P, et al: Transplantation 60:648, 1995 5. Kovarik JM, Mueller EA, van Bree JB, et al: Transplantation 58:658, 1994 6. Pethig K, Ruhparwar A, Korn A, et al: Transplant Proc 28:2287, 1996 7. Kahan BD, Shaw LM, Holt D, et al: Clin Chem 36:1510, 1990 8. Holt DW, Mueller EA, Kovarik JM, et al: Transplant Proc 27:1434, 1995 9. Dalrymple-Hay M, Meara M, Reynolds L, et al: Transplant Proc 28:2285, 1996 10. Miller L, Kobashigawa J, Valantine H, et al: J Heart Lung Transplant 14:S227, 1995 11. Pethig K, Geiger M, Korn A, et al: Transplant Proc 28:2282, 1996 12. White M, Pelletier GB, Tan A, et al: J Heart Lung Transplant 16:787, 1997 13. Niese D: Transplant Proc 27:1849, 1995 14. Senel FM, Yildirim S, Karakayali H, et al: Transplant Int 10:357, 1997 15. Greenberg A, Thompson ME, Griffith BJ, et al: Transplantation 50:589, 1990 16. Holt DW, Mueller EA, Kovarik JM, et al: Transplant Proc 26:2935, 1994