Allan S. MacDonald

A Worldwide, Phase Iii, Randomized, Controlled, Safety And Efficacy Study Of A Sirolimus/cyclosporine Regimen For Prevention Of Acute Rejection In Recipients Of Primary Mismatched Renal Allografts

Background. Despite the various immunosuppressive regimens presently in use, acute rejection in the early postoperative period continues to occur in 20 to 40% of renal transplant patients. In a double-blind, multicentred study, we investigated the ability of two different doses of sirolimus (rapamycin, RAPAMUNE), a new class of immunosuppressant that blocks cell cycle progression, to prevent acute rejection in recipients of primary mismatched renal allografts when added to a regimen of cyclosporine (cyclosporin A, CsA) and corticosteroids. Methods. Between October 1996 and September 1997, 576 recipients of primary mismatched cadaveric or living donor renal allografts were randomly assigned in a 2:2:1 ratio (before the transplant operation) to receive an initial loading dose of either 6 or 15 mg of orally administered sirolimus, followed by a daily dose of either 2 or 5 mg/day, or to receive a matched placebo. All groups received cyclosporine (microemulsion formula, CsA) and corticosteroids. The primary endpoint was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 6 months after transplantation. Safety data were monitored by an independent drug safety monitoring board. Results. Based on an intention-to-treat analysis of 576 patients, there were no significant differences in patient demographic or baseline characteristics among treatment groups. The overall rate of the primary composite endpoint for the 6-month period after transplantation was 30.0% (68/227) in the 2 mg/day sirolimus group and 25.6% (56/219) in the 5 mg/day sirolimus group, significantly lower than the 47.7% (62/130) in the placebo group (P =0.002, P <0.001, respectively). During this period, the incidence of biopsy-confirmed acute rejection was 24.7% (56/227) in the 2 mg/day sirolimus group and 19.2% (42/219) in the 5 mg/day sirolimus group, compared with 41.5% (54/130) in the placebo group (P =0.003, P <0.001, respectively), representing a significant reduction in acute rejection of 40.5 and 53.7%, respectively. The need for antibody therapy to treat the first episode of biopsy-confirmed acute rejection was significantly reduced in the 5 mg/day sirolimus group (3.2%) compared to the placebo group (8.5%;P =0.044). The results 1 year after transplantation were similar for the efficacy parameters studied. Adverse events and infections occurred in all groups. Conclusions. The addition of either 2 mg/day sirolimus or 5 mg/day sirolimus to CsA/corticosteroid therapy significantly reduces the incidence of acute rejection episodes in primary mismatched renal allograft recipients, without an increase in immunosuppressant-related side effects, including infections and malignancy, at 6 months and at 1 year after transplantation.

Sirolimus-tacrolimus combination immunosuppression

A series of 32 recipients of liver, kidney, or pancreas transplants who were treated with sirolimus and low-dose tacrolimus experienced a low rate of rejection and excellent graft function without drug-related toxic effects.

Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus.

BACKGROUND Sirolimus is a novel macrocyclic antibiotic that has an immunosuppressive mechanism of action distinct from that of cyclosporine and tacrolimus. OBJECTIVE The objective of this report is to provide an overview of the clinical development of sirolimus with emphasis on the mechanism of immunosuppressive activity, prevention of acute renal allograft rejection, clinical pharmacokinetics, concentration-effect relationships, and therapeutic drug monitoring (TDM). RESULTS Pharmacokinetic studies in adult renal transplant patients have shown that sirolimus may be characterized as a drug with rapid absorption (t(max) = 1 to 2 hours), low systemic availability (F = 14%), linear dose proportionality (2 to 24 mg), extensive partitioning into formed blood elements (B/P = 36), large apparent volume of distribution (1.7 L/kg), prolonged terminal half-life (62 hours), and large intersubject (CV = 52%) and intrasubject (CV = 26%) variability in oral-dose clearance. Results from phase 111 pivotal trials showed that sirolimus (2 or 5 mg/d) reduced acute renal graft rejection (generally, P < 0.01) without TDM. Although TDM may not be required for a regimen consisting of full-dose cyclosporine and corticosteroids with sirolimus 2 mg/d (4 hours after cyclosporine), it may be warranted in patients (1) with hepatic impairment, (2) who are young children, (3) who are receiving concurrent doses of strong CYP3A/p-glycoprotein inhibitors or inducers, (4) in whom cyclosporine dosing is markedly reduced or discontinued, and (5) who are at a high risk for rejection. A whole-blood sirolimus therapeutic window of 5 to 15 ng/mL (measured by microparticle enzyme immunoassay) is recommended for patients at standard risk of rejection. The large intrapatient variability observed in trough sirolimus concentrations indicates that dose adjustments should be optimally based on more than a single trough sample. Because of the time required to reach steady state, sirolimus dose adjustments would optimally be based on trough levels obtained >5 to 7 days after a dose change. CONCLUSIONS The effective use of sirolimus in an immunosuppressive regimen for the prevention of acute renal allograft rejection requires an understanding of the drugs clinical pharmacokinetics, concentration/adverse-effect relationship, concentration-efficacy relationship, and TDM.

The incidence and impact of early rejection episodes on graft outcome in recipients of first cadaver kidney transplants

The objective of this study was to define the incidence and significance of acute rejection occurring in the first year following transplantation. The influence of contemporary induction immunosuppression on rejection, as well as the effect of rejection on graft and patient loss, renal function, and maintenance immunosuppression during the first year in 110 recipients of first cadaver renal transplants were analyzed. All patients received CsA, Aza, and prednisone for 30 days with withdrawal of Aza at 30 days and then prednisone at 105 days; 57 patients were prospectively randomized to receive ALG (Merieux) until serum creatinine was less than 300 mumol/L. Short-term ALG administration did not influence the incidence, severity, nature, or outcome of rejection episodes. Fifty-five (50%) patients had at least 1 rejection in the first 90 days. All patients with delayed graft function and 7/8 (88%) sensitized patients (current PRA greater than 50%) had at least 1 rejection episode; 71% (n = 35) of all rejection episodes occurred in the first 30 days posttransplant. Patients rejection free at 90 days remained rejection free the entire first year. Graft loss was 18% for rejections in the first month, 13% for rejections occurring later (P = NS); 20% (n = 11) of patients had a second rejection and 1% (n = 2) had a third rejection. The risk of graft loss was 9% with a first rejection, 38% with a second rejection, and 50% with a third rejection. Of 12 (22%) rejections that were steroid resistant, 10 (83%) were reversed with OKT3. One-year graft survival for patients without rejection, with steroid-sensitive rejection, and with steroid-resistant rejection was 96%, 88% (P = ns), and 58% (P less than 0.001), respectively; 1 year SCr was 168 +/- 93, 196 +/- 77 (P = ns), and 268 +/- 96 microMol/L (P less than 0.05), respectively. Patients free of rejection and with stable renal function continued to do well on maintenance CsA monotherapy, and they were more likely to be on CsA monotherapy than those with rejection episodes (P less than 0.01).

Is routine ureteric stenting needed in kidney transplantation? A randomized trial.

Background. Whether routine ureteric stenting in low-urological-risk patients reduces the risk of urological complications in kidney transplantation is not established. Methods. Eligible patients were recipients of single-organ renal transplants with normal lower urinary tracts. Patients were randomized intraoperatively to receive either routine stenting or stenting only in the event of technical difficulties with the anastomosis. All patients underwent Lich-Gregoire ureteroneocystostomy. Results. Between June 1994 and December 1997, 331 kidney transplants were performed at a single center, 305 patients were eligible, and 280 patients were enrolled and randomized. Donor and recipient age, sex, donor source, whether first or subsequent grafts, ureteric length, native renal disease, and immunosuppression were similar in each group. In the no-routine-stenting group 6 of 137 patients (4.4%) received stents after randomization for intraoperative events that in the surgeon’s opinion required use of a stent. In an intention-to-treat analysis there was no difference between groups in the primary outcome cluster of obstruction or leak [routine stenting 5 of 143 (3.5%) vs. no routine stenting 9 of 137 (6.6%);P =0.23], or in either of these complications analyzed separately. All urological complications were successfully managed without major morbidity. Living donor organs and shorter ureteric length (after trimming) were univariate risk factors for leaks, although increasing donor age was associated with obstruction. Conclusions. Routine ureteric stenting is unnecessary in kidney transplantation in patients at low risk for urological complications. Careful surgical technique with selective stenting of problematic anastomoses yields similar results.

Conversion to rapamycin immunosuppression in renal transplant recipients : Report of an initial experience

Background. The aim of thisstudy is to evaluate the effects of RAPA conversion in patients undergoing cyclosporine (CsA) or tacrolimus (Tac) toxicity. Methods. Twenty renal transplant recipients were switched to fixed dose rapamycin (RAPA) (5 mg/day) 0 to 204 months posttransplant. Drug monitoring was not initially used to adjust doses. The indications for switch were chronic CsA or Tac nephrotoxicity (12), acute CsA or Tac toxicity (3), severe facial dysmorphism (2), posttransplant lymphoproliferative disorder (PTLD) in remission (2), and hepatotoxicity in 1. Follow-up is 7 to 24 months. Results. In the 12 patients switched because of chronic nephrotoxicity there was a significant decrease in serum creatinine [233±34 to 210±56 &mgr;mol/liter (P <0.05) at 6 months]. Facial dysmorphism improved in two patients. No relapse of PTLD was observed. Five patients developed pneumonia (two Pneumocystis carinii pneumonia, one infectious mononucleosis with polyclonal PTLD lung infiltrate) and two had bronchiolitis obliterans. There were no deaths. RAPA was discontinued in four patients, because of pneumonia in two, PTLD in one, and oral aphtous ulcers in one. RAPA levels were high (>15 ng/ml) in 7 of 13 (54%) patients. Conclusions. RAPA conversion provides adequate immunosuppression to enable CsA withdrawal. However, when converting patients to RAPA drug levels should be monitored to avoid over-immunosuppression and adequate antiviral and Pneumocystis carinii pneumonia prophylaxis should be given.

A Clinical Pharmacokinetic Study of Tacrolimus and Sirolimus Combination Immunosuppression Comparing Simultaneous to Separated Administration

The pharmacokinetic (PK) interaction between tacrolimus (TAC) and sirolimus (SRL), similarly structured immunosuppressive compounds that share binding proteins, is unknown. The combination of SRL with cyclosporin (CsA) has been studied, and a 4-hour interval between dosing of the two drugs is recommended even though it is inconvenient for patients and may affect compliance. Twenty-five liver and kidney–pancreas transplant recipients treated with a combination of SRL and low-dose TAC completed full PK studies while being treated with 4-hour interval dosing (ID) and then with simultaneous dosing. Whole blood was sampled for immunoassay measurement of TAC and SRL levels. Blood concentration/dose ratios of SRL and TAC varied between patients by a factor of 8 and 5, respectively, but correlation between trough concentration levels (C0) and drug exposure area under the concentration–time curve (AUC) was excellent (TAC: r2 = 0.82; SRL: r2 = 0.83). Neither PK profiles of SRL nor those of TAC were altered by simultaneous administration. Dose-corrected AUC and C0 of TAC correlated with SRL (r2 = 0.8 and 0.8, respectively). Bone marrow suppression and nephrotoxicity were not enhanced nor were any new toxicities observed when TAC and SRL were used in combination. These data confirm that simultaneous dosing of TAC and SRL after transplantation is safe and that trough level monitoring is adequate to control therapy.

Rapamycin in combination with cyclosporine or tacrolimus in liver, pancreas, and kidney transplantation.

A 10-year experience with the immunosuppressive drug rapamycin that begins in the laboratory then extends through multicentre trials in combination with cyclosporine in kidney transplant recipients, exploration of its use as a single agent and in combination with tacrolimus, and its potential in nonrenal organs is described. Rapamycin is a potent inhibitor of endothelial injury in rat aortic allografts. When added to full-dose cyclosporine it achieves low rejection rates, but it augments the nephrotoxicity and hyperlipidemia of cyclosporine. On the other hand, it allows discontinuation of calcineurin inhibitors in stable kidney and liver patients suffering from nephrotoxicity late posttransplant. At least in Caucasian patients, discontinuation of cyclosporine is possible as early as 3 months post-kidney transplant. In combination with low-dose tacrolimus, exceptionally low rates of rejection were seen in recipients of kidney, pancreas, and liver recipients with preservation of excellent renal function. These pilot studies have been confirmed in several single-centre and, more recently, multicentre trials in kidney and pancreas transplantation. The side-effect profile of hyperlipidemia, lymphocoeles, delayed wound healing, and possible liver effects are coming into focus, and ways of minimizing these problems being introduced. The lessons learned include the need for early adequate blood levels, the lack of correlation between dose and drug exposure, and the potency that allows marked dose reductions in calcineurin inhibitors and steroids.

The role of psychological functioning in morbid obesity and its treatment with gastroplasty.

Background: The authors evaluated the psychological characteristics of the morbidly obese.The condition-specific and quality-of-life characteristics of a large sample of vertical banded gastroplasty (VBG) patients were evaluated.The role that these psychological characteristics play in moderating the success of gastroplasty surgery,as well as the impact of surgery on quality of life, was examined. Methods: This is a cross-sectional evaluative study of a clinical sample, with longitudinal followup and with non-surgical comparison groups. 89 morbidly obese individuals were assessed before VBG (but after having been accepted for surgery) and again 1.27 years after surgery.This group represents 98% of the patients who receivedVBG (ie. a 2% dropout rate). We used established psychological measures (quality of life, adjustment to obesity,functional impairment, and eating attitudes), including a scale developed by our group specifically for morbid obesity, to identify distinct psychological profiles of the morbidly obese before surgery. Results: The three profile groups differed significantly in psychological characteristics, ranging from high functioning (little emotional distress, functional impairment or dysfunctional eating) to poor functioning (high emotional distress, functional impairment and dysfunctional eating). The subgroups did not differ on pre-surgical weight, and did not differ from morbidly obese groups not seeking surgery. For the surgery group, regardless of pre-surgery psychological profile, VBG produced significant weight loss, maintained at 1 year after surgery. As well, surgery resulted in significant improvements in quality of life and psychological adjustment, especially in the profile group initially presenting with psychological disturbance. Conclusion: There was no evidence to suggest that those with pre-surgical psychological difficulties did more poorly with VBG. These data call into question screening out individuals with psychological problems from gastroplasty surgery. Furthermore, psychological difficulties, if they exist, appear more related to the nature of morbid obesity than to the character of the individual. Psychological difficulties pre-surgery were normalized following surgery.

TREATMENT OF STRESS-INDUCED UPPER GASTROINTESTINAL HÆMORRHAGE WITH METIAMIDE

The H-2-blocking antihistamine metiamide was used to treat 14 episodes of bleeding from the stomach or duodenum in eleven patients. In 11 instances bleeding was due to erosive gastritis or duodenitis and bleeding promptly ceased after one or two doses of 300 mg at 6 h intervals and did not recur as long as the drug was continued. In the 2 instances in which bleeding continued, chronic ulcers had eroded into major blood-vessels. There were no complications from the drug even in five patients with severe bone-marrow suppression after renal transplantation. Metiamide seems to be a safe and highly effective agent in the control of bleeding due to erosive gastritis.