Pharmacologic basis for high-dose oral acyclovir prophylaxis of cytomegalovirus disease in renal allograft recipients

Abstract

The incidence of cytomegalovirus disease, the most important infectious complication of renal transplantation, was reduced in renal allograft recipients by a regimen of prophylactic high-dose oral acyclovir. To analyze the pharmacologic aspects of our prophylactic approach, we evaluated safety, pharmacodynamics, and in vitro susceptibility data. One hundred four recipients of cadaveric renal allografts received either oral acyclovir (n = 53) in doses of up to 3,200 mg/day or a placebo (n = 51) for 12 weeks posttransplant. Leukocyte count and serum creatinine were selected as markers of laboratory safety and were evaluated pretransplant, at study midpoint (creatinine only), and at study completion. Concentrations of acyclovir in plasma were determined to verify the ability of the dosing strategy to achieve predicted values. Viral Cytomegalovirus is the single most important cause of infectious disease after renal transplantation (10, 14). Because cytomegalovirus disease occurs almost exclusively during the first 3 months after renal transplantation (16) and treatment has been difficult (1), we developed a prophylactic approach using the antiviral drug acyclovir. We demonstrated that high-dose oral acyclovir, given according to a scheme that adjusted for estimated creatinine clearance, reduced the incidence and severity of cytomegalovirus disease in recipients of cadaveric renal allografts (2). In addition to efficacy, comprehensive analyses of safety, pharmacodynamics, and in vitro susceptibilities of cytomegalovirus strains collected from the subjects were needed to evaluate the risk/benefit ratio of this prophylactic approach more thoroughly. These issues are addressed in the present report.( clovir was provided as 800-mg tablets; placebo tablets were identical in appearance and taste. All patients received a single tablet just prior to transplantation and again 24 h later. The subsequent dosing schedules for the remainder of the 12-week dosing period were based upon creatinine clearance (CLCR) estimated by the method of Jelliffe and Jelliffe for unstable serum creatinine (11). Patients with an estimated CLCR of <10 ml/min/1.73 m2 (<0.167 ml/s) received 800 mg daily; those with an estimated CLCR of between 10 and 25 ml/min/1.73 m2 (0.167 and 0.417 ml/s) received 800 mg three times daily; and those with an estimated CLCR of >25 ml/min/1.73 m2 (>0.417 ml/s) received 800 mg four times daily. Patients undergoing hemodialysis received 800 mg twice daily. All patients were cared for according to standard protocols at The University of Minnesota Hospital and Clinic and received our standard immunosuppressive regimen, which included quadruple therapy with antilymphoblast globulin, cyclosporine, prednisone, and azathioprine (9). Study participants received daily clinical and laboratory evaluations during the first week posttransplant and twice weekly thereafter until discharge. Thereafter, patients were seen in the outpatient clinic at 3 months and 1 year posttransplant.Clinical laboratory evaluation of drug safety. S...

CMV Prophylaxis in High-Risk Renal Transplant Patients (D+/R-) by Ac&gamma;clovir with or without Hyperimmune (CMV) Immunoglobulins: A Prospective Study

“…The plasmatic half-live is short, i.e. around 3 h; elimination occurs via glomerular filtration and tubular active secre tion, thus the dosage has to be adapted according to creat inine clearance [6,19], For the prophylaxis of CMV infec tion after renal transplantation in D+/R-patients, high doses of acyclovir (3,200 mg/day) have been shown to decrease the incidence of CMV diseases from 100 (with out prophylaxis) to 20% [12], In another (uncontrolled) study the incidence of CMV disease was decreased to 8% [ 13], Other studies did not show that high doses of acyclo vir were beneficial, but there were either no controls [ 15] or the controls were historical [14,16], To our knowledge only two studies on the combined use of acyclovir with Igs for the treatment ofD +/R -CMV patients have been pub lished. The first one [17] used low doses of acyclovir (600 mg/day) for 3 months in combination with hyperim mune CMV globulins every 3 weeks for 6 months in renal transplant patients.…”

Antimicrobial strategies in the care of organ transplant recipients

“…A variety of prophylactic programs that use high-dose acyclovir administered orally (2,4,17,63), both CMV hyperimmune (33,49,50) and standard immunoglobulin (51,52), and the combination of these two approaches (36,53), as well as ganciclovir (3,32), have been studied for the prevention of the different patterns of CMV transmission in patients undergoing the various types of organ transplantation (Table 1). Although the data base is quite incomplete because of (i) High-dose acyclovir administered orally, as well as hyperimmune globulin (and perhaps standard immunoglobulin), administered singly or in combination over a period of 4 months has considerable efficacy in decreasing the incidence of primary CMV disease in renal transplant patients being immunosuppressed with cyclosporine, prednisone, and azathioprine.…”

“…(ii) Prevention of CMV disease in seropositive allograft recipients (at risk for either reactivation or superinfection disease) appears to be possible with any of these regimens, particularly when antilymphocyte antibody therapies are not used (2,4,17,32,33,36,(49)(50)(51)(52)(53).…”

“…In the case of acyclovir, prophylactic efficacy occurs when peak levels in blood are approximately 25 ,umol/liter, in the face of an average 50% inhibitory concentration of approximately 45 pLmol/liter (2,4,17), suggesting that inhibition of the virus is most easily accomplished as it emerges from latency and when only small amounts of replicating virus are present. In the case of intravenous immunoglobulin therapy, the nature of the protecting antibody, its epitopic specificity, and the titers necessary to protect the individual are currently unknown.…”

An earlier role for viral pharmacodynamics

“…Usually, the interpretation that a drug will not be effective becomes a self-fulfilling prophecy because drug development is stopped and the potency of the compound never becomes tested in vivo. However, at least one (aciclovir) was developed for another reason and shown to inhibit a virus (CMV) in vivo at lower levels than had been anticipated [2], so suggesting that exclusive reliance upon PK and preclinical findings is inappropriate.…”